Compositions and methods for regulating ATP and adenosine signaling for treatment of inflammation and immune disorders

Abstract

The present disclosure relates to a controlled release drug delivery system for immune modulating applications. Specifically, the discloses subject matter involves utilizing compound-loaded microparticles, formulated into compositions to provide a sustained release of therapeutic agents. The present disclosure further includes the application of these composition for use in methods of treating immune-mediates responses such as inflammation.

Description

[0001]072396.1066 PATENT COMPOSITIONS AND METHODS FOR REGULATING ATP AND ADENOSINE SIGNALING FOR TREATMENT OF INFLAMMATION AND IMMUNE DISORDERS CROSS-REFERENCES TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 548,639, filed on February 1, 2024, the contents of which are incorporated herein by reference in their entirety. GRANT INFORMATION This invention was made with government support under AR074285 and AI074490 awarded by the National Institutes of Health. The government has certain rights in the invention. 1. FIELD OF INVENTION The present disclosure pertains to compositions and methods for improved delivery of adenosine triphosphate (ATP) signaling antagonists and adenosine (Ado) signaling agonists for inflammation and immune modulation. 2. BACKGROUND The ATP / adenosine signaling axis is implicated in a variety of inflammatory diseases / conditions. ATP can be released from dying or activated immune cells, after which it functions as a danger-associated molecular pattern (DAMP) to increase inflammation by promoting secretion of inflammatory cytokines and proliferation / differentiation of effector immune cells. Extracellular ATP (eATP) can be converted to Ado, a known anti-inflammatory signaling cue, by immunosuppressive regulatory T cells (Tregs). Contrary to ATP signaling, Ado signaling can promote secretion of anti-inflammatory cytokines and inhibit differentiation of effector immune cells. Current clinical immunosuppressants for inflammatory conditions are repetitively administered (e.g., daily) in high concentrations to suppress inflammation. Recent studies with Ado signaling agonists (e.g., Piclidenoson / IB-MECA, Regadenoson) and ATP signaling antagonists (e.g., JNJ-55308942), both in preclinical and clinical research, explore their effect following intravenous infusion or repetitive oral dosing (e.g., daily or twice daily for weeks). However, frequent dosing places patients at risk for non-immune related side effects and overimmunosuppression, leaving individuals more susceptible to infections. Thus, there is a ACTIVE 130935777.2 1 072396.1066 PATENT need for novel therapeutic approaches that can overcome these side effects. The present disclosure addresses such needs. 3. SUMMARY The present disclosure provides microparticles, compositions and methods for improved delivery of adenosine triphosphate (ATP) signaling antagonists and adenosine (Ado) signaling agonists for inflammation and immune modulation. In a first embodiment, the present disclosure provides a method of treating an inflammatory disease and / or reducing inflammation in a subject in need thereof, the method comprising administering to the subject an effective amount of a microparticle or a composition thereof, wherein the microparticle is a controlled release microparticle comprising an ATP signaling antagonist, an adenosine receptor agonist, or a combination thereof. In one aspect of the first embodiment, the adenosine signaling agonist is selected from piclidenoson (IB-MECA), regadenoson, adenosine, Cl-IB-MECA, dipyridamole, CGS-21680, or 5'-N-ethylcarboxamidoadenosine. In a further aspect, the adenosine signaling agonist is IB- MECA (piclidenoson) or a derivative thereof. In another aspect, the adenosine signaling agonist is regadenoson or a derivative thereof. In one aspect of the first embodiment, the ATP signaling antagonist is a P2X7 receptor antagonist. In a further aspect, the ATP signaling antagonist is selected from JNJ-55308942, A438079, brilliant blue G (BBG), AZ11645373, JNJ-47965567, CE-224,535, oxidized ATP, Pyridoxal Phosphate-6-Azophenyl-2',4'-Disulfonic Acid, or Suramin. In another aspect, the ATP signaling antagonist is JNJ-55308942 or a derivative thereof. In another aspect, the ATP signaling antagonist is A438079 or a derivative thereof. In one aspect of the first embodiment, the microparticle further comprises a therapeutic agent that modulates immune-related blood cells. In one aspect of the first embodiment, the microparticle is a sustained release microparticle. In a further aspect, the microparticle is a delayed release microparticle. In another aspect, the microparticle is a long-term release microparticle. In one aspect of the first embodiment, the microparticle has a diameter up to about 100 µm. In a further aspect, the microparticle has a diameter larger than about 1 µm. In one aspect of the first embodiment, the composition comprises a pharmaceutically acceptable carrier. In a further aspect, the composition further comprises a second microparticle comprising a therapeutic agent that modulates immune-related blood cells. In another aspect, the therapeutic agent that modulates immune-related blood cells is IL-2, TGF-β, CCL22, IL- ACTIVE 130935777.2 2 072396.1066 PATENT 33, rapamycin, or a combination thereof. In another aspect, the second microparticle is a sustained release microparticle, a delayed release microparticle, or a long-term release microparticle. In one aspect of the first embodiment, the composition further comprises a third microparticle comprising a therapeutic agent that modulates immune-related blood cells. In a further aspect, the therapeutic agent that modulates immune-related blood cells is IL-2, TGFβ, CCL22, IL-33, rapamycin, or a combination thereof. In another aspect, the third microparticle is a sustained release microparticle, a delayed release microparticle, or a long-term release microparticle. In one aspect of the first embodiment, the inflammatory disease is an inflammatory disease associated with an autoimmune disease, a central nervous system (CNS) inflammatory disease, a joint inflammation disease, an inflammatory digestive tract disease, inflammatory skin and other inflammatory diseases related to epithelial cells, inflammation associated with cancer, inflammation associated with irritation, or inflammation associated with injury. In a further aspect, the inflammatory disease is selected from inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Alzheimer's disease, Parkinson, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, Sjogren's syndrome, bronchitis, asthma, or inflammation associated with cancer. In one aspect of the first embodiment, the inflammatory disease is dermatitis. In a further aspect, the dermatitis is an allergic contact dermatitis. In one aspect of the first embodiment, the subject has received or is receiving a transplant. In a further aspect, the subject is at risk of transplant rejection. In another aspect, the transplant is a tissue transplant. In another aspect, the tissue transplant is a skin transplant or a vascularized composite transplant. In one aspect of the first embodiment, the microparticle or composition thereof is administered at an amount from about 0.01 µg to about 100 g per kg of body weight of the subject. In a further aspect, the microparticle or composition thereof is administered once or more daily, weekly, monthly, or yearly. In another aspect, the microparticle or composition thereof is orally, subcutaneously, transdermally, topically, pulmonary inhalation, or parenterally administered. In a second embodiment, the present disclosure provides a controlled release microparticle comprising an ATP signaling antagonist, an adenosine receptor agonist, or a combination thereof. In one aspect of the second embodiment, the adenosine signaling agonist is selected ACTIVE 130935777.2 3 072396.1066 PATENT from piclidenoson (IB-MECA), regadenoson, adenosine, Cl-IB-MECA, dipyridamole, CGS- 21680, or 5'-N-ethylcarboxamidoadenosine. In a further aspect, the adenosine signaling agonist is IB-MECA (piclidenoson) or a derivative thereof. In another aspect, the adenosine signaling agonist is regadenoson or a derivative thereof. In one aspect of the second embodiment, the ATP signaling antagonist is a P2X7 receptor antagonist. In a further aspect, the ATP signaling antagonist is selected from JNJ- 55308942, A438079, brilliant blue G (BBG), AZ11645373, JNJ-47965567, CE-224,535, oxidized ATP, Pyridoxal Phosphate-6-Azophenyl-2',4'-Disulfonic Acid, or Suramin. In another aspect, the ATP signaling antagonist is JNJ-55308942 or a derivative thereof. In another aspect, the ATP signaling antagonist is A438079 or a derivative thereof. In one aspect of the second embodiment, the microparticle further comprises a therapeutic agent that modulates immune-related blood cells. In one aspect of the second embodiment, the microparticle is a sustained release microparticle. In a further aspect, the microparticle is a delayed release microparticle. In another aspect, the microparticle is a long-term release microparticle. In one aspect of the second embodiment, the microparticle has a diameter up to about 100 µm. In a further aspect, the microparticle has a diameter larger than about 1 µm. In a third embodiment, the present disclosure provides a composition comprising a microparticle disclosed herein. In a one aspect of the third embodiment, the composition comprises a pharmaceutically acceptable carrier. In a further aspect, the composition further comprises a second microparticle comprising a therapeutic agent that modulates immune- related blood cells. In another aspect, the therapeutic agent that modulates immune-related blood cells is IL-2, TGF-β, CCL22, IL-33, rapamycin, or a combination thereof. In another aspect, the second microparticle is a sustained release microparticle, a delayed release microparticle, or a long-term release microparticle. In another aspect of the third embodiment, the composition further comprises a third microparticle comprising a therapeutic agent that modulates immune-related blood cells. In a further aspect, the therapeutic agent that modulates immune-related blood cells is IL-2, TGFβ, CCL22, IL-33, rapamycin, or a combination thereof. In another aspect, the third microparticle is a sustained release microparticle, a delayed release microparticle, or a long-term release microparticle. In a fourth embodiment, the present disclosure provides a microparticle and / or a composition for use in treating an inflammatory disease in a subject in need thereof. In a further aspect, the subject has received or is receiving a transplant. In certain embodiments, the subject that is at risk of transplant rejection. In another aspect, the transplant is a tissue transplant. In ACTIVE 130935777.2 4 072396.1066 PATENT another aspect, the tissue transplant is a skin transplant or a vascularized composite transplant. As disclosed herein, the first embodiment directed to a method of treating an inflammatory disease and / or reducing inflammation in a subject in need thereof can include aspects of the microparticle disclosed in the second embodiment and aspects of the composition disclosed in the third embodiment. Additionally, the fourth embodiment directed to a microparticle and / or a composition for use in treating an inflammatory disease in a subject in need thereof can include aspects of the microparticle disclosed in the second embodiment and aspects of the composition disclosed in the third embodiment. 4. BRIEF DESCRIPTION OF THE DRAWINGS For a more complete understanding of the present disclosure and its features and advantages, reference is now made to the following description, taken in conjunction with the accompanying drawings. Figures 1A and 1B show a schematic depicting inflammation through ATP Signaling. Figure 1A shows extracellular ATP (eATP) is released by activated or dying cells, resulting in its local accumulation. By signaling through purinergic signaling receptors, eATP functions as a pro-inflammatory danger associated molecular pattern, promoting secretion of inflammatory cytokines (e.g., IL-18, IL-1β) and differentiation of effector T cell subtypes (Th1, Th17). eATP is converted to adenosine (Ado) by CD39 and CD73, enzymes expressed on the surface of regulatory T cells. Ado is an anti-inflammatory cue, promoting secretion of anti-inflammatory cytokines (e.g., IL-10) and preventing effector T cell differentiation (Th17). Figure 1B shows the local delivery of eATP signaling antagonists (P2X7R antagonists) and / or adenosine receptor agonists (AR) can promote immunosuppression in models of inflammation. Figure 2 shows contact allergens trigger the release of extracellular ATP (eATP). The graph depicts eATP release from THP1 monocytes upon exposure to the contact allergen 2,4- Dinitrochlorobenzene (DNCB) over a 4-hour period. The evaluation of eATP concentrations was conducted using the Cell Titer Glo assay. Figures 3A-3C show P2X7R antagonists suppress inflammatory cytokine secretion. Figure 3A-3C show graph depicting IL-1β secretion in LPS+ATP+ J774A.1 macrophage cell cultures, under increasing dosages of (Figure 3A) JNJ-55308942, (Figure 3B) Brilliant Blue G, and (Figure 3C) A438079. Figures 4A and 4B show the impact of P2X7R antagonists on the secretion of an anti- inflammatory cytokine. Figure 4A shows the effects of JNJ-55308942 on the secretion of anti- ACTIVE 130935777.2 5 072396.1066 PATENT inflammatory cytokine IL-10, while Figure 4B shows the effects of A438079. Macrophage cell cultures (LPS+ATP+J774A.1) underwent a 24-hour incubation with the respective P2X7R antagonists. Subsequently, the levels of IL-10 secretion were quantified from the collected supernatants using ELISA. Figures 5A and 5B show the effect of ATP / Ado signaling modulation on T cells. Figure 5A shows a graph depicting the effect of JNJ-55308942 on isolated CD4+ T cells. The experiment involved isolating CD4+ T cells, stimulating them with anti-CD3 / CD28, and culturing the cells with IL-2 and in combination with either JNJ-55308942, IB-MECA or Regadenoson for 72 hours. Flow cytometry was employed to evaluate the resultant T cell populations. Data demonstrated JNJ-55308942 for augmenting the regulatory T cell population (increased % FoxP3 of CD4+ T cells), while IB-MECA and Regadenoson show no discernible influence on the T cell population. Figure 5B shows the effect of IBMECA on the proliferation of CD4+ T, stimulating them with anti-CD3 / CD28, and culturing cells with IL-2 and in combination with IB-MECA. IBMECA was shown to increase populations of non-proliferating cells. Figures 6A-6C show the effects of JNJ-55308942 on inflammation in response to a model contact allergen. Figure 6A shows the experimental setup depicting C57BL / 6 mice were sensitized and challenged with DNFB (2,4-dinitrofluorobenzene) topically applied to the ear. Subsequently, the mice received subcutaneous injections of JNJ-55308942 at the scruff. The experiment included three experimental groups: a vehicle control group receiving PBS injections, a high-dose JNJ group (10 μg), and a low-dose JNJ group (1 μg). Experimental groups were administered daily for one week. Ear swelling was assessed as an indicator of inflammation. Figure 6B shows the quantification of ear swelling post-sensitization and Figure 6C shows the quantification of ear swelling, post-challenge. Daily soluble injections of JNJ- 55308942 led to a reduction in ear swelling during both the sensitization and challenge phases. This reduction in swelling suggests a suppressive effect of JNJ-55308942 on the inflammatory response induced by the contact allergen. Figures 7A-7F show the effect of JNJ-55308942 treatment on dermal and epidermal thickening. Figure 7A shows a representative histological image depicting dermal and epidermal thickening induced by DNFB. Figure 7B and Figure 7C shows representative histological images depicting a reduction in dermal and epidermal thickening in response to daily soluble injections of JNJ-55308942 at high and low dosages, respectively. Figures 7D- 7F correspond to representative fluorescent images displaying CD3+ T cells. Figure 7D reveals the infiltration of CD3+ T cells in the absence of JNJ-55308942, while Figures 7E and 7F ACTIVE 130935777.2 6 072396.1066 PATENT depict the administration of JNJ-55308942 inhibiting CD3+ T cell infiltration. These findings collectively highlight the potential of JNJ-55308942 in mitigating dermal and epidermal thickening, coupled with its impact on modulating CD3+ T cell infiltration in the observed experimental conditions. Figures 8A-8C show microparticles having mathematically predicted release characteristics of compounds for modulating eATP and / or adenosine signaling. Figure 8A shows a scanning electron micrograph (top panel) and in vitro release profile for JNJ-55308942 (bottom panel). Figure 8B shows a scanning electron micrograph (top panel) and in vitro release profile for Regadenoson (bottom panel). Figure 8C shows a scanning electron micrograph (top panel) and in vitro release profile for IB-MECA (bottom panel). Figures 9A-9D show microfluidics can be used to manufacture controlled release systems for modulating eATP and / or adenosine signaling. Figure 9A shows a SEM image of microparticles comprising JNJ-55308942 (JNJ-MPs); scale bar: 30 µm. Figure 9B shows that microfluidic produced microparticles exhibit a uniform diameter size. Figure 9C shows that homogenization-based microparticles display a peak characteristic indicative of a less uniform distribution, contrasting with the monodisperse nature observed in microfluidic microparticles. Figure 9D shows a cumulative release profile (JNJ-55308942), comparing microfluidics-based microparticles with homogenization-based microparticles. Figures 10A-10C show IBMECA reduces expression of co-stimulatory molecules and inflammatory cytokine secretion. Figure 10A shows representative histograms demonstrating expression of co-stimulatory markers (CD40 and CD80) on the surface of LPS-stimulated dendritic cells (DC2.4) cultured for 24 hours in the presence or absence of 10 µM IBMECA. Figure 10B shows the relative expression of co-stimulatory receptors (CD40 and CD80) by dendritic cells. Median fluorescence intensity (MFI) values were normalized to those for unstimulated dendritic cells from the same experiment. Figure 10C shows the concentration of TNF^ in supernatants of LPS-stimulated dendritic cells (DC2.4) and macrophages (J774A.1) in the presence of increasing doses of IBMECA. Groups were compared by unpaired t-tests. *p<0.05, **p<0.01, **p<0.001, ns indicates non-significant difference. Figures 11A-11C show characterization of the IBMECA microparticle (IBMECA- MP). Figure 11A shows scanning electron microscopy image of IBMECA-MPs taken at 1000x. Scale bar = 10 μm. Figure 11B shows volume-weighted size distribution of IBMECA-MPs (n= 10,000 particles). Figure 11C shows cumulative release profile (μg IBMECA / mg MP) of IBMECA-MPs (n= 3). ACTIVE 130935777.2 7 072396.1066 PATENT Figures 12A-12E show IBMECA-MPs alter co-stimulatory marker expression on the surface of migratory and lymph node resident dendritic cells 24 hours following allergen sensitization. Figure 12A shows the experimental timeline. Figure 12B shows the change in ear thickness (Δ Ear Thickness) for Blank vs. IBMECA-MPs (n= 5). Figure 12C shows the gating strategy for migratory (CD11c+ MHCIIhigh) and lymph node resident dendritic cells (CD11chighMHCII+). Figures 12D-12E show the relative expression of co-stimulatory receptors (CD40, CD86, or PDL1) by (D) migratory and (E) lymph node resident dendritic cells (n= 5). Median fluorescence intensity (MFI) values are displayed for each marker. *p<0.05, **p<0.01, *** p<0.001, ns indicates non-significant difference. Figures 13A-13E show IBMECA-MPs alter T-cell frequencies in cervical draining lymph nodes following sensitization. Figure 13A shows the experimental timeline. Figure 13B shows the change in ear thickness (Δ Ear Thickness) over time for Blank- and IBMECA-MPs (n= 5). Figure 13C shows flow plots illustrating populations of effector T cells (CD4+Tbet+Th1) and regulatory T cells (CD4+Foxp3+Treg) for Blank- and IBMECA-MPs. Figure 13D shows the relative frequency of cytotoxic T cells (CD8+Tbet+Tc1) in cervical draining lymph nodes (n= 5). Figure 13E shows ratios of regulatory T cells to effector T cells (Treg / Th1) and regulatory T cells to effector and cytotoxic T cells (Treg / Th1+Tc1) in draining lymph nodes (n= 5). *p<0.05, **p<0.01, ***p<0.001, ns indicates non-significant difference. Figures 14A and 14B show IBMECA-MPs alter T-cell proliferation in cervical draining lymph nodes following sensitization. Figure 14A shows flow plots and relative frequencies displaying populations of effector T cells (CD4+Tbet+Th1) and regulatory T cells (CD4+Foxp3+Treg) for Blank- and IBMECA-MPs in cervical draining lymph nodes (n= 5). Figure 14B shows flow plots and relative frequencies of cytotoxic T cells (CD8+Tbet+Tc1) for Blank- and IBMECA-MPs in cervical draining lymph nodes (n= 5). *p<0.05, **p<0.01, ns indicates non-significant difference. Figures 15A-15G show IBMECA-MPs reduced ear swelling and T-cell responses after allergen challenge. Figure 15A shows the experimental timeline. Figure 15B shows the change in ear thickness (Δ Ear Thickness) for Blank- and IBMECA-MPs after allergen challenge (n= 5). Figure 15C shows representative ear skin histology (H&E) from 2 days post-challenge or naïve (no allergen exposures) skin. Scale bar = 50 μm. Figure 15D shows the average epidermal thickness (μm) measured from histology images shown in Figure 15B (n= 3). Figure 15E shows the relative frequencies of Th1 (Tbet+ of CD4+), Treg (Foxp3+ of CD4+), and Tc1 (Tbet+ of CD8+) populations (n= 5) in draining lymph nodes. Figure 15F shows the representative relative frequencies of CD4+ (of Live CD45+) and CD8+ (of Live CD45+) T cell populations ACTIVE 130935777.2 8 072396.1066 PATENT in ear skin. Figure 15G shows the ratio of CD4 / CD8 T cells in ear skin (n= 5). *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, ns indicates non-significant difference. Figures 16A and 16B show contact allergen DNFB (dinitrofluorobenzene) induced eATP release in a dose-dependent manner from antigen-presenting cells. Figure 16A shows levels of eATP secreted by J774A.1 macrophages treated with an increasing dosage of DNFB. Figure 16B shows levels of eATP secreted by DC2.4 dendritic cells treated with an increasing dosage of DNFB (n= 3). Figures 17A and 17B show adenosine agonists reduced TNF^ secretion in a dose- dependent manner from LPS-stimulated J774A.1 macrophages without impacting viability. Figure 17A shows TNF^ secretion levels in LPS-stimulated J774A.1 macrophages treated with increasing dosages of JNJ-55308942, IBMECA, or Regadenoson. Figure 17B shows the cell viability of LPS-stimulated J774A.1 macrophages treated with increasing dosages of JNJ- 55308942, IBMECA, or Regadenoson (n= 3). Figures 18A and 18B show adenosine agonists reduced TNF^ secretion in a dose- dependent manner from LPS-stimulated DC2.4 dendritic cells without impacting viability. Figure 18A shows TNF^ secretion levels in LPS-stimulated DC2.4 dendritic cells treated with JNJ-55308942, IBMECA, or Regadenoson. Figure 18B shows the cell viability of LPS- stimulated DC2.4 dendritic cells treated with JNJ-55308942, IBMECA, or Regadenoson (n= 3). Figure 19 shows P2X7R antagonist reduced IL-1β secretion, increases IL-10 secretion in a dose dependent manner in LPS+ ATP+ mouse macrophages. Levels of IL-1β and IL-10 were measured in LPS+ ATP+ mouse macrophages treated with increasing doses of JNJ- 55308942 (n= 3). Figures 20A-20C show small molecule drugs JNJ-55308942 and Regadenoson decreased expression of maturation markers on surface of mouse dendritic cells. Figure 20A shows representative histograms demonstrating expression of maturation markers (CD40, CD80, and CD86) on the surface of LPS-stimulated dendritic cells (DC2.4) cultured in the presence or absence of 10 µM Regadenoson. Figure 20B-20C shows the relative expression of maturation markers (CD40, CD80, and CD86) by dendritic cells cultured in the presence or absence of 10 µm JNJ-55308942 (Figure 20B) or 10 µm Regadenoson (Figure 20C, n= 3). Figures 21A and 21B show JNJ-55308942 increased the percentage of Foxp3+CFSElowin CD4+ T cells (Figure 21A) and impacted the percentage of Tbet+ CFSElowin CD4+ T cells (Figure 21B, n= 3). ACTIVE 130935777.2 9 072396.1066 PATENT Figures 22A and 22B show small molecules JNJ-55308942, IBMECA, and Regadenoson did not impact Th1 differentiation or proliferation in the presence of the polarizing cytokines IL-2 and IL-12. Shown are measurements for the percentage of Tbet+ cells in live CD4+ cells (Figure 22A) and the percentage of Tbet+CFSElowcells in live CD4+ cells (Figure 22B) after Th1 cells were treated with increasing doses of JNJ-55308942, IBMECA, or Regadenoson (n= 3). Figure 23 shows large microparticles were not trafficked to draining lymph nodes within 96 hours. SEM images demonstrate the size distribution of small and large microparticles. Histological sections of draining lymph nodes immunostained for CD11c and counterstained with DAPI show few small diameter microparticle and no large microparticles present in the lymph node. Scale bars: 50 µm. Figures 24A and 24C show migratory dendritic cells (CD11c+ MHCIIhigh) and lymph node resident dendritic cells (CD11chighMHCII+) can be identified after sensitization with DNFB. Figure 24A shows the experimental timeline. Figure 24B shows the gating strategy to analyze single cells. Figure 24C shows the gating strategy to quantify migratory dendritic cells and lymph node resident dendritic cells. Figures 25A and 25B show JNJ-55308942 microparticles (JNJ-MPs) did not reduceear swelling or modulate expression of surface markers on dendritic cells 24 hours after sensitization with DNFB. Figure 25A shows change in ear thickness (Δ Ear Thickness) for Blank- and JNJ-MPs after sensitization with DNFB. Figure 25B shows the level of cell surface markers CD40, CD80, CD86, PDL1, and CD83 in migratory dendritic cells and lymph node resident dendritic cells isolated from animals that were treated with Blank- or JNJ-MPs (n= 5). Figures 26A-26D show JNJ-MPs did not reduce ear swelling but do impact T cells during sensitization with DNFB. Figure 26A shows the experimental timeline. Figure 26B shows change in ear thickness (Δ Ear Thickness) for Blank- and JNJ-MPs during sensitization with DNFB. Figure 26C shows the percentage of CD4+ cells of all live cells measured and of those CD4+ cells, the percentage of Foxp3+ cells, the percentage of Tbet+ cells, and the ratio of Treg / Teff cells isolated from animals that were treated with Blank- or JNJ-MPs (n= 5). Figure 26D shows the percentage of Ki67+Foxp3+ cells and Ki67+Tbet+ cells in CD4+ cell populations and CD8b+ cell populations isolated from animals that were treated with Blank- or JNJ-MPs (n= 5). Figures 27A-27C show JNJ-MPs did not show reduce ear swelling but do impact T- cell responses after allergen challenge. Figure 27A shows the experimental timeline. Figure 27B shows the change in ear thickness (Δ Ear Thickness) for Blank- and JNJ-MPs after allergen ACTIVE 130935777.2 10 072396.1066 PATENT challenge (n= 5). Figure 27C shows gene expression levels of Nfkb1, Tnfa, and Il1b in ear skin after allergen challenge (n= 5). Figures 28A-28C show Regadenoson microparticles (REG-MPs) did not reduce earswelling but reduced the expression of CD40 surface marker on lymph node resident dendritic cells within 24 hours after sensitization with DNFB. Figure 28A shows the experimental timeline. Figure 28B shows the change in ear thickness (Δ Ear Thickness) for Blank- and REG- MPs after sensitization with DNFB. Figure 28C shows the level of cell surface markers CD40, CD80, CD86, PDL1, and CD83 in migratory dendritic cells and lymph node resident dendritic cells isolated from animals that were treated with Blank- or REG-MPs (n= 5). Figures 29A-29D show REG-MPs did not reduce ear swelling but do impact T cells during sensitization with DNFB. Figure 29A shows the experimental timeline. Figure 29B shows change in ear thickness (Δ Ear Thickness) for Blank- and REG-MPs during sensitization with DNFB. Figure 29C shows the percentage of CD4+ cells of all live cells measured and of those CD4+ cells, the percentage of Foxp3+ cells, the percentage of Tbet+ cells isolated from animals that were treated with Blank- or REG-MPs. Figure 29C also shows the percentage of CD8b+ cells of all live cells measured and of those CD8b+ cells, the percentage Tbet+ cells isolated from animals treated with Blank- or REG-MPs (n= 5). Figure 29D shows the ratio of Treg / Th1 cell populations and Treg / (Th1+Tc1) cell populations isolated from animals that were treated with Blank- or REG-MPs (n= 5). Figures 30A-30C show IBMECA-MPs do not modulate frequencies of dendritic cell populations or alter expression of certain co-stimulatory markers. Figure 30A shows the relative frequencies of migratory DCs (CD11c+MHCIIhigh) and lymph node resident DCs (CD11chighMHC+). Figure 30B shows median fluorescent intensities (MFI) for CD80 and CD83 for migratory DCs (N = 5). Figure 30C shows median fluorescent intensities (MFI) for CD80 and CD83 for lymph node resident DCs (N = 5). ns = non-significant difference. Figures 31A and 31B show IBMECA-MPs do not modulate frequencies of certain T- cell populations in draining lymph nodes and ear skin. Figure 31A shows the relative frequency of Tregs (Foxp3+ of CD4+) in draining lymph nodes (N = 5). Figure 31B shows the relative frequencies of Tregs (Foxp3+ of CD4+), Th1 (Tbet+ of CD4+), and Tc1 (Tbet+ of CD8b+) cells in ear skin. ns = non-significant difference. Figures 32A and 32B show IBMECA-MPs reduce % CD8b+ of CD45+ T cells, but do not alter other T-cell subtypes. Figure 32A shows the relative frequency of C8b+ T cells and CD4+ T cells in ear skin (N = 5). Figure 32B shows the relative frequencies of Tregs (Foxp3+ of CD4+), Th1 (Tbet+ of CD4+), and Tc1 (Tbet+ of CD8b+) cells in ear skin (N = 5). ACTIVE 130935777.2 11 072396.1066 PATENT ns = non-significant difference. 5. DETAILED DESCRIPTION The ATP / adenosine signaling axis is implicated in the etiopathogenesis of a variety of inflammatory diseases and conditions. As depicted in Figures 1A and 1B, inflammation can be initiated by the release of extracellular ATP (eATP) from activated or dying cells, leading to its local accumulation. Acting through purinergic signaling receptors, eATP functions as a pro- inflammatory danger signal, triggering the secretion of inflammatory cytokines (e.g., IL-18, IL-1β) and the differentiation of pro-inflammatory T cell subtypes (Th1, Th17). This eATP is then converted to adenosine (Ado) by CD39 and CD73, enzymes expressed on regulatory T cells’ surface. Ado, in turn, serves as an anti-inflammatory signal, prompting the secretion of anti-inflammatory cytokines (e.g., IL-10) and preventing the differentiation of pro- inflammatory T cell subtypes (Th17). As shown in Figure 1B, local delivery of eATP signaling antagonists (such as P2X7R antagonists) or adenosine receptor agonists (AR) can promote immunosuppression in models of inflammation. The present disclosure provides compositions and methods that can be used to treat inflammatory diseases and conditions (e.g., dermatitis). The present disclosure is based, in part, on the demonstration that controlled release systems that encapsulate and release Ado signaling agonists and / or ATP signaling antagonists can treat inflammatory diseases and conditions. Surprisingly, the presently disclosed compositions and methods reduce the risk of side effects and overimmunosuppression observed with the currently available therapies. For clarity, and not by way of limitation, the detailed description of the invention is divided into the following subsections: 5.1 Definitions;5.2 Controlled Release Microparticles;5.3 Therapeutic Agents;5.4 Pharmaceutical Compositions;5.5 Methods of Treatment; and5.6 Kits.5.1. Definitions The terms used in this specification generally have their ordinary meanings in the art, within the context of this disclosure and in the specific context where each term is used. Certain terms are discussed below, or elsewhere in the specification, to provide additional guidance to ACTIVE 130935777.2 12 072396.1066 PATENT the practitioner in describing the compositions and methods of the disclosure and how to make and use them. As used herein, the use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification can mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” As used herein, the terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The present disclosure also contemplates other embodiments “comprising,” “consisting of,” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not. As used herein, the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within three, or more than three standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2- fold, of a value. As used herein, the term “individual” or “subject” refers to a vertebrate, such as a human or non-human animal, for example, a mammal. Mammals include, but are not limited to, humans, non-human primates, farm animals, sport animals, rodents, and pets. Non-limiting examples of non-human animal subjects include rodents such as mice, rats, hamsters, and guinea pigs; rabbits; dogs; cats; sheep; pigs; goats; cattle; horses; and non-human primates such as apes and monkeys. As used herein, the terms “pharmaceutically” or “pharmacologically acceptable” refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human. As used herein, the term, “pharmaceutically acceptable carrier” includes any and all solvents, or a dispersion medium including, but not limited to, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils, coatings, isotonic and absorption delaying agents, liposome, commercially available cleansers, and the like. Supplementary bioactive ingredients ACTIVE 130935777.2 13 072396.1066 PATENT also can be incorporated into such carriers. As used herein, the term “derivative” refers to a chemical compound with a similar core structure. For example, trichloromethane (chloroform) is a derivative of methane. As used herein, the term “administered” or “administering” a drug, refers to any method of providing a compound or drug to a patient such that the compound or drug has its intended effect on the patient. For example, one method of administering is by an indirect mechanism using a medical device such as, but not limited to a catheter, spray gun, syringe, etc. A second exemplary method of administering is by a direct mechanism such as, oral ingestion, transdermal patch, topical, inhalation, suppository, etc. As used herein, the term “effective amount” or “therapeutically effective amount” refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, a therapeutically effective amount of an agent is an amount sufficient to inhibit or treat the disease or condition without causing a substantial cytotoxic effect in the subject. The therapeutically effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition. In certain embodiments, an effective amount can be formulated and / or administered in a plurality of doses, for example, as part of a dosing regimen. As used herein, the term “treatment” refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop, or administering a compound or composition to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing a pathology or condition, or diminishing the severity of a pathology or condition. As used herein, the term “ameliorating,” with reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. As used herein, “preventing” a disease or condition refers to prophylactic administering a composition to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing a pathology or condition or diminishing the severity of a pathology or condition. As used herein, the terms “reduce,” “inhibit,” “diminish,” “suppress,” “decrease,” “prevent,” “eliminate,” or any variation of these terms includes any measurable decrease or ACTIVE 130935777.2 14 072396.1066 PATENT complete inhibition to achieve a desired result. The terms “reduce,” “inhibit,” “diminish,” “suppress,” “decrease,” “prevent,” “eliminate,” and grammatical equivalents (including “lower,” “smaller,” etc.) when in reference to the expression of any symptom in an untreated subject relative to a treated subject, mean that the quantity and / or magnitude of the symptoms in the treated subject is lower than in the untreated subject by any amount that is recognized as clinically relevant by any medically trained personnel. In one embodiment, the quantity and / or magnitude of the symptoms in the treated subject is at least 10% lower than, at least 25% lower than, at least 50% lower than, at least 75% lower than, and / or at least 90% lower than the quantity and / or magnitude of the symptoms in the untreated subject. As used herein, the term “microparticle” as used herein, refers to any microscopic carrier to which a compound or drug can be attached. Microparticles generally refer to the general categories comprising liposomes, nanoparticles, microspheres, nanospheres, microcapsules, and nanocapsules. In certain embodiments, microparticles contemplated by this present disclosure are capable of formulations having controlled release properties. As used herein, the term “biocompatible” refers to any material does not elicit a substantial detrimental response in the host. There is always concern, when a foreign object is introduced into a living body, that the object will induce an immune reaction, such as an inflammatory response that will have negative effects on the host. In the context of this invention, biocompatibility is evaluated according to the application for which it was designed: for example; a bandage is regarded a biocompatible with the skin, whereas an implanted medical device is regarded as biocompatible with the internal tissues of the body. In certain embodiments, biocompatible materials include, but are not limited to, biodegradable and biostable materials. As used herein, the term “biodegradable” refers to any material that can be acted upon biochemically by living cells or organisms, or processes thereof, including water, and broken down into lower molecular weight products such that the molecular structure has been altered. As used herein, the term “polymer” refers to any unit-based chain of molecules. For example, such molecules can include but are not limited to gelatin, collagen, cellulose esters, dextran sulfate, pentosan polysulfate, chitin, saccharides, albumin, synthetic polyvinyl pyrrolidone, polyethylene oxide, polypropylene oxide, block polymers of polyethylene oxide and polypropylene oxide, polyethylene glycol, acrylates, acrylamides, methacrylates including, but not limited to, 2-hydroxyethyl methacrylate, poly(ortho esters), cyanoacrylates, gelatin- resorcin-aldehyde type bioadhesives, polyacrylic acid and copolymers and block copolymers thereof. ACTIVE 130935777.2 15 072396.1066 PATENT As used herein, the term “PLGA” refers to mixtures of polymers or copolymers of lactic acid and glycolic acid. As used herein, lactide polymers are chemically equivalent to lactic acid polymer and glycolide polymers are chemically equivalent to glycolic acid polymers. In one embodiment, PLGA contemplates an alternating mixture of lactide and glycolide polymers and is referred to as a poly(lactide-co-glycolide) polymer. As used, herein, the term “controlled release” refers to the escape of any attached or encapsulated factor at a predetermined rate. For example, a controlled release of a factor can occur resulting from the predicable biodegradation of a polymer particle (i.e., for example, an artificial antigen presenting cell). The rate of biodegradation can be predetermined by altering the polymer composition and / or ratio comprising the particle. Consequently, the controlled release can be short term, or the controlled release can be long term. In one embodiment, the short-term release is between about 30 minutes and about 1 hour. In one embodiment, the short- term release is between about 1 hour and about 3 hours. In one embodiment, the short-term release is between about 3 hours and about 10 hours. In one embodiment, the short-term release is between 10 hours-24 hours. In one embodiment, the long-term release is between about 24 hours and about 36 hours. In one embodiment, the long-term release is between about 3 days and about 7 days. In one embodiment, the long-term release is between about 7 days and about 1 month. In one embodiment, the long-term release is between about 1 month and about 6 months. In one embodiment, the long-term release is between about 6 months and about 1 year. In one embodiment, the long-term release is at least one year. As used herein, the term “sustained release” refers to a microparticle that provides for gradual release of a therapeutic agent over an extended period of time. In certain embodiments, sustained release results in constant blood levels of a therapeutic agent over an extended time period. As used herein, the term “delayed release” refers to a microparticle in which there is a time delay between administration of the microparticle and the release of the therapeutic agent. “Delayed release” can involve gradual release of a therapeutic agent over an extended period of time, and thus can be “sustained release.” As used herein, “long-term release” refers to a microparticle capable of delivering therapeutic levels of the agent for at least about 7 days, at least about 15 days, at least about 30 days, or at least about 60 days. As used herein, the term “dermatitis” (also known as eczema) refers to general inflammation of the skin. Specific types of dermatitis include, but are not limited to, atopic dermatitis, contact dermatitis, nummular dermatitis, photo-induced dermatitis, and stasis ACTIVE 130935777.2 16 072396.1066 PATENT dermatitis. These diseases or disorders are characterized by itching, red skin, and rashes. 5.2. Controlled Release Microparticles Microparticles refer to the general categories comprising liposomes, nanoparticles, microspheres, nanospheres, microcapsules, and nanocapsules. Preferably, some microparticles contemplated by the present disclosure comprise poly(lactide-co-glycolide), aliphatic polyesters including, but not limited to, poly-glycolic acid and poly-lactic acid, hyaluronic acid, modified polysaccharides, chitosan, cellulose, dextran, polyurethanes, polyacrylic acids, pseudo-poly(amino acids), polyhydroxybutrate-related copolymers, polyanhydrides, polymethylmethacrylate, poly(ethylene oxide), lecithin and phospholipids. In certain embodiments, the microparticles can have a diameter of less than 1000 μm, e.g., from about 10 μm to about 200 μm. In certain embodiments, the microparticles can have a diameter of from about 10 μm to about 90 μm, from about 20 μm to about 80 μm, from about 60 μm to about 120 μm, from about 70 μm to about 120 μm, from about 80 μm to about 120 μm, from about 90 μm to about 120 μm, from about 100 μm to about 120 μm, from about 60 μm to about 130 μm, from about 70 μm to about 130 μm, from about 80 μm to about 130 μm, from about 90 μm to about 130 μm, from about 100 μm to about 130 μm, from about 110 μm to about 130 μm, from about 60 μm to about 140 μm, from about 70 μm to about 140 μm, from about 80 μm to about 140 μm, from about 90 μm to about 140 μm, from about 100 μm to about 140 μm, from about 110 μm to about 140 μm, from about 60 μm to about 150 μm, from about 70 μm to about 150 μm, from about 80 μm to about 150 μm, from about 90 μm to about 150 μm, from about 100 μm to about 150 μm, from about 110 μm to about 150 μm, or from about 120 μm to about 150 μm. In certain embodiments, the microparticles can have a diameter of from about 1 μm to about 30 μm, from about 2 μm to about 30 μm, from about 5 μm to about 30 μm, from about 7 μm to about 30 μm, from about 10 μm to about 30 μm, from about 12 μm to about 30 μm, from about 15 μm to about 30 μm, from about 20 μm to about 30 μm, from about 5 μm to about 20 μm, from about 8 μm to about 20 μm, from about 10 μm to about 20 μm, from about 12 μm to about 20 μm, from about 15 μm to about 20 μm, or from about 10 μm to about 15 μm. In certain embodiments, the microparticles can have a diameter of from about 10 μm to about 20 μm. In certain embodiments, the microparticles can have a diameter of from about 10 nm to about 1000 nm, from about 50 nm to about 1000 nm, from about 100 nm to about 1000 nm, from about 150 nm to about 1000 nm, from about 200 nm to about 1000 nm, from about 300 nm to about 1000 nm, from about 400 nm to about 1000 nm, from about 500 nm to about 1000 ACTIVE 130935777.2 17 072396.1066 PATENT nm, from about 600 nm to about 1000 nm, from about 700 nm to about 1000 nm, from about 800 nm to about 1000 nm, from about 100 nm to about 500 nm, from about 150 nm to about 500 nm, from about 200 nm to about 500 nm, from about 250 nm to about 500 nm, from about 300 nm to about 500 nm, from about 400 nm to about 500 nm, from about 500 nm to about 900 nm, from about 600 nm to about 900 nm, from about 700 nm to about 900 nm, from about 800 nm to about 900 nm, from about 100 nm to about 200 nm, from about 100 nm to about 300 nm, from about 100 nm to about 400 nm, from about 600 nm to about 800 nm, or from about 700 nm to about 800 nm. In certain embodiments, the microparticles can have a diameter of from about 10 nm to about 100 nm, from about 20 nm to about 100 nm, from about 50 nm to about 100 nm, from about 70 nm to about 100 nm, from about 110 nm to about 200 nm, from about 120 nm to about 100 nm, from about 150 nm to about 200 nm, from about 200 nm to about 300 nm, or from about 250 nm to about 300 nm. In certain embodiments, the microparticle can include one or more lipids. In certain embodiments, the lipids can be neutral, anionic, or cationic at physiological pH. In certain embodiments, the lipids can be sterols. For example, in certain embodiments, the lipid microparticle include cholesterol, phospholipids and sphingolipids. In certain embodiments, the microparticles comprise PEGylated derivatives of the neutral, anionic, and cationic lipids. The incorporation of PEGylated derivatives can improve the stability of the microparticles. Non-limiting examples of PEGylated lipids include distearoylphosphatidylethanlamine- polyethylene glycol (DSPE-PEG), stearyl-polyethylene glycol and cholesteryl-polyethylene glycol. In certain embodiments, the microparticle include substituted or unsubstituted fatty acids. Non-limiting examples of saturated fatty acids include caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachidic acid, heneicosanoic acid, behenic acid, tricosanoic acid, lignoceric acid, pentacosanoic acid, cerotic acid, heptacosanoic acid, montanic acid, nonacosanoic acid, melissic acid, henatriacontanoic acid, lacceroic acid, psyllic acid, geddic acid, ceroplastic acid, hexatriacontanoic acid, and combinations thereof. Non-limiting examples of unsaturated fatty acids include hexadecatrienoic acid, alpha-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo-gamma-linolenic acid, arachidonic acid, docosadienoic acid, adrenic acid, docosapentaenoic acid, tetracosatetraenoic acid, tetracosapentaenoic acid, oleic acid, eicosenoic acid, mead acid, erucic acid, nervonic acid, ACTIVE 130935777.2 18 072396.1066 PATENT rumenic acid, α-calendic acid, β-calendic acid, jacaric acid, α-eleostearic acid, β-eleostearic acid, catalpic acid, punicic acid, rumelenic acid, α-parinaric acid, β-parinaric acid, bosseopentaenoic acid, pinolenic acid, podocarpic acid, palmitoleic acid, vaccenic acid, gadoleic acid, erucic acid, and combinations thereof. In certain embodiments, the microparticles include polymers. In certain embodiments, the polymer can be amphiphilic, hydrophilic, or hydrophobic. In certain embodiments, the polymer can be biocompatible, e.g., the polymer does not induce an adverse and / or inflammatory response when administered to a subject. For example, without limitation, a polymer can be selected from polydioxanone (PDO), polyhydroxyalkanoate, polyhydroxybutyrate, poly(glycerol sebacate), polyglycolide (i.e., poly(glycolic) acid) (PGA), polylactide (i.e., poly(lactic) acid) (PLA), poly(lactic) acid-co-poly(glycolic) acid (PLGA), poly(lactide-co-glycolide) (PLG), polycaprolactone, copolymers, or derivatives including these and / or other polymers. In certain embodiments, the polymer includes PEG. In certain embodiments, the polymer includes poly(lactide-co-glycolide) (PLG). In certain embodiments, the microparticles include cationic polymers. In certain embodiments, the cationic polymers can be branched or linear. Cationic polymers can condense and protect negatively charged molecules such as DNA or RNA. In certain embodiments, without limitation, the cationic polymers can be polyethylenimines, poly-histidyl polymers, chitosan, poly(amino ester glycol urethane), polylysines, or amino cyclodextrin derivatives. In certain embodiments, the microparticle comprises linear polyethylenimine. In certain embodiments, the microparticle comprises chitosan. In certain embodiments, the microparticles include anionic polymers. In certain embodiments, the anionic polymers can be branched or linear. Anionic polymers can condense and protect positively charged molecules such as metals (e.g., Ca++) and positively charged proteins. In certain embodiments, without limitation, the anionic polymers can be polyacrylic acid cystamine conjugates and derivatives thereof, sodium carboxy methyl starch (CMS) and derivatives thereof, carboxy methyl guar gum (CMG) and derivatives thereof, carboxymethyl cellulose and derivatives thereof, or alginate and derivative thereof. In certain embodiments, the microparticle comprises alginate or a derivative thereof. In certain embodiments, the microparticle can show organ tropism and can have an organ-specific distribution. In certain embodiments, the microparticles include molecules providing for organ tropism or organ-specific distribution. For example, but without any limitation, the surface of the microparticles can be functionalized to bind biological molecules (e.g., a ligand or an antibody) targeting a specific tissue (e.g., epithelial cells). The surface ACTIVE 130935777.2 19 072396.1066 PATENT functionalization of microparticles can be based on the use of homo- or hetero-bifunctional cross linkers to the aim to add an organic functional group (e.g., R-NH2, R-COOH, etc.), useful to bind biological molecules (e.g., a ligand or an antibody). In certain embodiments, the functionalization of the surface of the microparticles can be achieved using non-covalent conjugation. In certain embodiments, the functionalization of the surface of the microparticles can be achieved using non-covalent conjugation. The covalent conjugation allows modifications at several levels using sequential functionalization and can be exploited to achieve structures with multiple functions. For example, without any limitation, the microparticle can include a PEG molecule synthesized with specific functional groups at the ends which can be used as homo-bifunctional or hetero-bifunctional linkers to perform a wide range of functionalization processes. In certain embodiments, the biological molecule is an antibody targeting an epithelial cell surface molecule. Non-limiting examples of epithelial cell surface molecules include A33, ACE / CD143, ALCAM / CD166, Aminopeptidase B / RNPEP, Aminopeptidase Inhibitors, Aminopeptidase N / CD13, Amnionless, B7-H2, B7-H3, CA125 / MUC16, CA15-3 / MUC-1, E-Cadherin, CD1a, CD1d, CD1d1, CD46, CD74, CEACAM-1 / CD66a, CEACAM-3 / CD66d, CEACAM-4, CEACAM-5 / CD66e, CEACAM- 6 / CD66c, CEACAM-7, Collagen I, CTRP5 / C1qTNF5, Cubilin, DDR1, DDR1 / DDR2, beta- Defensin 2, beta-Defensin 3, alpha-Defensin 1, alpha-Defensin 5, Endorepellin / Perlecan, EpCAM / TROP1, Fas Ligand / TNFSF6, Gastrokine 1, HIN-1 / SCGB3A1, Hyaluronan, IGSF4C / SynCAM4, Integrin alpha 4 / CD49d, Integrin alpha 4 beta 1, Integrin alpha 4 beta 7 / LPAM-1, JAM-A, JAM-B / VE-JAM, JAM-C, L1CAM, Laminin-1, MFG-E8, MSPR / Ron, MUC-1, MUC-19, MUC-4, Nectin-1, Nectin-2 / CD112, Nectin-3, Nectin-4, Nidogen- 1 / Entactin, Occludin, PD-L1 / B7-H1, PLET-1, PlGF, Prostasin / Prss8, SLURP2, TfR (Transferrin R), and UGRP1 / SCGB3A2. In certain embodiments, the microparticle can adhere to specific tissues. In certain embodiments, the microparticles can be biodegradable or non-biodegradable. In certain embodiment, the microparticle can be comprised in a pharmaceutical composition. In certain embodiments, the microparticles include a therapeutic agent. Microspheres and microcapsules are useful due to their ability to maintain a generally uniform distribution, provide stable controlled compound release and are economical to produce and dispense. Microspheres are obtainable commercially (Prolease®, Alkerme’s: Cambridge, Mass.). For example, a freeze-dried medium comprising at least one therapeutic agent is homogenized in a suitable solvent and sprayed to manufacture microspheres in the range of about 20 to about 90 μm. Techniques are then followed that maintain sustained release ACTIVE 130935777.2 20 072396.1066 PATENT integrity during phases of purification, encapsulation, and storage. Scott et al., Improving Protein Therapeutics with Sustained Release Formulations, Nature Biotechnology, Volume 16:153-157 (1998). Modification of the microsphere composition using biodegradable polymers can provide an ability to control the rate of therapeutic agent release. Miller et al., Degradation Rates of Oral Resorbable Implants (Polylactates and Polyglycolates): Rate Modification and Changes in PLA / PGA Copolymer Ratios, J. Biomed. Mater. Res., Vol. II:711-719 (1977). In certain embodiments, a sustained or controlled release microsphere preparation is prepared using a single emulsion-evaporation technique, where an organic solvent solution of a biodegradable polymer is first prepared. Subsequently, a dissolved or dispersed medium of a therapeutic agent is added to the biodegradable polymer solution. The weight ratio of a therapeutic agent to the biodegradable polymer can for example be about 1:100000 to about 1:1, preferably about 1:20000 to about 1:500 and more preferably about 1:10000 to about 1:500. Next, the organic solvent solution containing the biodegradable polymer and therapeutic agent is poured into an aqueous phase to prepare a primary oil / water emulsion. The solvent in the oil phase is then evaporated off to provide microspheres. Finally, these microspheres are then recovered, washed, and lyophilized. Thereafter, the microspheres can be heated under reduced pressure to remove the residual water and organic solvent. In certain embodiments, a sustained or controlled release microsphere preparation is prepared using a double emulsion-evaporation technique. For double emulsion, the primary emulsion can be combined with an alcohol containing solution, e.g., polyvinyl-alcohol (PVA), under homogenization resulting in the formation of a double emulsion. The utilization of a double emulsion approach can be beneficial for the production of microparticles laden with hydrophilic compounds. Moreover, in emulsion-evaporation techniques, the inclusion of a salt in either the organic or aqueous phases can serve to modulate the release kinetics of the loaded therapeutic agent. In certain embodiments, a sustained or controlled release microparticle can be prepared by droplet microfluidics. Microparticles can be produced using a pump system coupled with hydrophilic flow-focusing microfluidic chips. Within the chip, droplets incorporating a selected polymer and therapeutic agent (e.g., JNJ, IBMECA, Regadenoson, etc.) are emulsified in an organic solvent, such as dimethyl sulfoxide (DMSO) and / or dichloromethane (DCM). These droplets then constitute a continuous aqueous phase within the microfluidic system. Other methods useful in producing microspheres that are compatible with a ACTIVE 130935777.2 21 072396.1066 PATENT biodegradable polymer metal salt and therapeutic agent mixture are: i) phase separation during a gradual addition of a coacervating agent; ii) an in-water drying method or phase separation method, where an antiflocculant is added to prevent particle agglomeration and iii) by a spray- drying method. Microparticles can also comprise a gelatin, or other polymeric cation having a similar charge density to gelatin (i.e., poly-L-lysine) and is used as a complex to form a primary microparticle. A primary microparticle is produced as a mixture of the following composition: i) Gelatin (60 bloom, type A from porcine skin), ii) chondroitin 4-sulfate (0.005%-0.1%), iii) glutaraldehyde (25%, grade 1), and iv) 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC hydrochloride), and ultra-pure sucrose (Sigma Chemical Co., St. Louis, Mo.). The source of gelatin is not thought to be critical; it can be from bovine, porcine, human, or other animal source. Typically, the polymeric cation is between 19,000-30,000 daltons. Chondroitin sulfate is then added to the complex with sodium sulfate, or ethanol as a coacervation agent. Controlled release microcapsules can be produced by using known encapsulation techniques such as centrifugal extrusion, pan coating and air suspension. Such microspheres and / or microcapsules can be engineered to achieve desired release rates. For example, Oliosphere® (Macromed) is a controlled release microsphere system. These particular microspheres are available in uniform sizes ranging between about 5 and about 500 μm and composed of biocompatible and biodegradable polymers. Specific polymer compositions of a microsphere can control the therapeutic agent release rate such that custom-designed microspheres are possible, including effective management of the burst effect. ProMaxx® (Epic Therapeutics, Inc.) is a protein-matrix delivery system. The system is aqueous in nature and is adaptable to standard pharmaceutical delivery models. In particular, ProMaxx® are bioerodible protein microspheres that deliver both small and macromolecular drugs and can be customized regarding both microsphere size and desired release characteristics. A microsphere or microparticle can comprise a pH sensitive encapsulation material that is stable at a pH less than the pH of the internal mesentery. The typical range in the internal mesentery is pH about 7.6 to pH about 7.2. Consequently, the microcapsules should be maintained at a pH of less than about 7. However, if pH variability is expected, the pH sensitive material can be selected based on the different pH criteria needed for the dissolution of the microcapsules. The encapsulated compound, therefore, will be selected for the pH environment in which dissolution is desired and stored in a pH preselected to maintain stability. Examples of pH sensitive material useful as encapsulants are Eudragit® L-100 or S-100 (Rohm GMBH), ACTIVE 130935777.2 22 072396.1066 PATENT hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate. In one embodiment, lipids comprise the inner coating of the microcapsules. In these compositions, these lipids can be, but are not limited to, partial esters of fatty acids and hexitiol anhydrides, and edible fats such as triglycerides. Lew C. W., Controlled-Release pH Sensitive Capsule and Adhesive System and Method. U.S. Pat. No.5,364,634 (herein incorporated by reference). In certain embodiments, the microparticle comprises a biodegradable construct thereby providing a controlled release of encapsulated, incorporated and / or attached factors (i.e., for example, therapeutic agents, antibodies, cytokines, or chemokines). In one embodiment, the particle comprises a degradable polyester including, but not limited to, poly (lactic-co-glycolic) acid (PLGA). PLGA has been used in FDA-approved grafts, sutures, and / or drug delivery microparticulates such as Lupron Depot®. Degradable PLGA polymer microparticles are superior to conventional latex or polystyrene “artificial APCs” because PLGA confers biodegradability. Further, unlike latex and polystyrene polymer particles that only allow surface attachment of proteins, so PLGA polymer particles, allow encapsulation of signaling factor (e.g., ATP / adenosine signaling factors) through a double emulsion / solvent evaporation procedure. Odonnell et al., Advanced Drug Delivery Reviews 28:25-42 (1997). Further, a controlled release of soluble cell factors from PLGA polymers can be engineered to create an appropriate local concentration of these cell factors, which would be accompanied by cell-to- cell contact with immobilized molecules on the particle surface. Such immobilized molecules (i.e., for example, a monoclonal antibody) can be easily bound to the particle through a streptavidin-biotin linkage using several established chemical techniques. In certain embodiments, the releasing is controlled by using different molecular weight PLGA or through other fabrication parameters including, but not limited to, drug distribution, occlusion radius, amorphicity / crystallinity of the polymer, excipients etc. Rothstein et al., J Materials Chem 18:1873-1880 (2008). An empirical process determines the final amounts of factors to be encapsulated given that the appropriate quantity of these factors for optimal stimulation of regulatory T-cells in vivo is yet still unknown. The factors can be encapsulated individually or in any combination. In certain embodiments, the factors have independent and differential release profiles. In other words, the release profile for each factor in the formulation is released with a custom-tailored predetermined kinetic and temporal pattern. Rothstein et al., “A simple model framework for the prediction of controlled release from bulk eroding polymer matrices” J Mater Chem (2008) 18:1873-1880; and Rothstein et al., “A unified mathematical model for the prediction of ACTIVE 130935777.2 23 072396.1066 PATENT controlled release from surface and bulk eroding polymer matrices” Biomaterials (2009) 30:1657-1664. As is shown herein, the specific composition of a microparticle can be determined, in advance, that results in the differential release profiles of each component. Although it is not necessary to understand the mechanism of an invention, it is believed that the interaction of the differential release profiles from these microparticle populations result in Treg cell population induction, attraction, or stimulation. In certain embodiments, microparticles can present incorporated and / or attached factors (i.e., for example, therapeutic agents, antibodies, cytokines, or chemokines). In certain embodiments, the incorporated and / or attached factor release is dependent on degradation of the polymer microparticles. As the polymer chains break up, the agent can diffuse out of the initial polymer microparticle matrix where it will eventually be presented to a targeted cell or tissue. In certain embodiments, the incorporated and / or attached factor release can be linear or non-linear (single or multiple burst release). In certain embodiments, the incorporated and / or attached factors can be released without a burst effect. For example, the sustained release can exhibit a substantially linear rate of release of the therapeutic agent. However, the release rate can change to either increase or decrease depending on the formulation of the polymer microparticle. The desired release rate and target drug concentration can vary depending on the particular therapeutic agent chosen for the drug delivery system, the condition being treated, and the subject’s health. Additional information on the features and components of the microparticles disclosed herein can be found in International Patent Publication Nos. WO2011006029, WO2013112456, and WO2014022685, the contents of each of which is incorporated by reference in their entireties. 5.3. Therapeutic Agents In certain embodiments, the microparticles described herein include one or more therapeutic agents. In certain embodiments, the microparticles disclosed herein provide for a controlled release of the one or more therapeutic agents. In certain embodiments, the therapeutic agents can modulate immune-related responses. In certain embodiments, the therapeutic agents can suppress inflammation. In certain embodiments, the therapeutic agents can regulate ATP signaling. In certain embodiments, the therapeutic agents can regulate adenosine signaling. In certain embodiments, the therapeutic agents can regulate ATP signaling and adenosine signaling. ACTIVE 130935777.2 24 072396.1066 PATENT In certain embodiments, the therapeutic agent is an ATP signaling antagonist. In certain embodiments, the ATP signaling antagonist is a P2X7 receptor antagonist. The P2X7 receptor (previously known as P2Z receptor) is a ligand-gated ion channel present on a variety of cell types, largely those known to be involved in the inflammatory / immune processes (e.g., macrophages, mast cells, B lymphocytes, and T lymphocytes). Activation of the P2X7 receptor by extracellular nucleotides (e.g., extracellular ATP) leads to the release of interleukin-1β (IL- 1β), giant cell formation (macrophages / microglial cells), degranulation (mast cells), and L- selectin shedding (lymphocytes). P2X7 receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells), and hepatocytes. Non-limiting example of P2X7 receptor antagonists encompassed by the present disclosure include JNJ-55308942, A438079, brilliant blue G (BBG), AZ11645373, JNJ- 47965567, CE-224,535, oxidized ATP, Pyridoxal Phosphate-6-Azophenyl-2',4'-Disulfonic Acid, and Suramin. In certain embodiments, the P2X7 receptor antagonist is JNJ-55308942 or a derivative thereof. In certain embodiments, the P2X7 receptor antagonist has formula: . In certain embodiments, the P2X7 receptor antagonist is A438079 or a derivative thereof. In certain embodiments, the P2X7 receptor antagonist has formula: . In certain embodiments, the P2X7 receptor antagonist is BBG or a derivative thereof. In certain embodiments, the P2X7 receptor antagonist has formula: ACTIVE 130935777.2 25 072396.1066 PATENT In certain embodiments, the therapeutic agent is an adenosine signaling agonist. Adenosine, acting on its four known receptors (adenosine A1, A2A, A2B, and A3 receptors), plays a pivotal role in maintaining energy equilibrium within tissues. Notably, adenosine Al receptor agonists exhibit potent analgesic properties, as demonstrated in studies, and adenosine A2A receptor agonists are acknowledged for their anti-inflammatory activity. In experimental settings, A2A receptor agonists have shown effectiveness against diverse conditions, including sepsis, arthritis, and ischemia / reperfusion injuries resulting from artery occlusion. In certain embodiments, the adenosine signaling agonist or derivates thereof. In certain embodiments, adenosine signaling agonist has formula: . In certain embodiments, the adenosine signaling agonist is an adenosine derivative that has a core structure of the formula: . R1 is selected from : , or ACTIVE 130935777.2 26 072396.1066 PATENT . In certain embodiments, R2 is selected from : , or . In certain embodiments, R1 is selected from -H, -OH, -NH2, -SH,-CN, -COOH, - C(O)H, -COH, -C(O)NH, C1-8 alkyl, C1-8 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C3-8 cycloalkyl, C6-14aryl, C1-8heteroalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, wherein R1 is optionally substituted. In certain embodiments, R2 is selected from -H, -OH, -NH2, -SH, -CN, -COOH, - C(O)H, -COH, -C(O)NH, C1-8 alkyl, C1-8 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C3-8 cycloalkyl, C6-14aryl, C1-8heteroalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, wherein R2 is optionally substituted. In certain embodiments, R3 is selected from -H, -OH, -NH2, -SH, -CN, -COOH, - C(O)H, -COH, -C(O)NH, C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynyl, C1-8haloalkyl, C3-8cycloalkyl, C6-14 aryl, C1-8 heteroalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, wherein R3 is optionally substituted. Non-limiting example of adenosine signaling agonists encompassed by the present disclosure include piclidenoson / IB-MECA (N6-(3-iodobenzyl)-adenosine-5'-N- methylcarboxamide), regadenoson, adenosine, Cl-IB-MECA, dipyridamole, CGS-21680, and ACTIVE 130935777.2 27 072396.1066 PATENT 5'-N-ethylcarboxamidoadenosine. In certain embodiments, the adenosine signaling agonist is Piclidenoson (IB-MECA) or a derivative thereof. In certain embodiments, the adenosine signaling agonist has formula: . In certain embodiments, the adenosine signaling agonist is Regadenoson or a derivative thereof. In certain embodiments, the adenosine signaling agonist has formula: . In certain embodiments, the microparticles described herein include an ATP signaling antagonist (e.g., JNJ-55308942, A438079). In certain embodiments, the microparticles described herein include an adenosine signaling agonist (e.g., piclidenoson / IB-MECA, regadenoson). In certain embodiments, the microparticles described herein include an ATP signaling antagonist (e.g., JNJ-55308942, A438079) and an adenosine signaling agonist (e.g., piclidenoson / IB-MECA, regadenoson). In certain embodiments, the microparticles described herein can further include a therapeutic agent that modulates immune-related blood cells, including, but not limited to T cells. In certain exemplary embodiments, the therapeutic agent that modulates immune-related blood cells can be IL-2 (Accession No: NP_000577.2), TGF-β (Accession No: NP_000651.3), CCL22 (Accession No: NP_002981.2), IL-33 (Accession No: NP_001300973.1), or rapamycin. 5.4. Pharmaceutical Compositions The present disclosure further provides pharmaceutical formulations and / or ACTIVE 130935777.2 28 072396.1066 PATENT compositions. In certain embodiments, the pharmaceutical formulations and / or compositions can comprise a compound-loaded microparticle as described herein. In certain embodiments, the pharmaceutical formulation and / or composition is a compound-loaded microparticle population. In certain embodiments, the compound-loaded microparticle population comprises a solid shape. In one embodiment, the solid shape of the compound-loaded microparticle population can include, but is not limited to, transdermal patches, ointments, lotions, creams, gels, suppositories, and powders. In one embodiment, the solid shape of the compound-loaded microparticle population can include, but is not limited to, powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets and / or tablets. In certain embodiments, the pharmaceutical formulation and / or composition further includes a second microparticle comprising a therapeutic agent that modulates immune-related blood cells, including, but not limited to T cells. In certain exemplary embodiments, the therapeutic agent that modulates immune-related blood cells can be IL-2 (Accession No: NP_000577.2), TGF-β (Accession No: NP_000651.3), CCL22 (Accession No: NP_002981.2), IL-33 (Accession No: NP_001300973.1), or rapamycin. In certain embodiments, the pharmaceutical formulation and / or composition further includes a second microparticle comprising a therapeutic agent including, but not limited to IL- 2, TGF-^, and rapamycin. In certain embodiments, the pharmaceutical formulation and / or composition further includes a second microparticle comprising IL-2. In certain embodiments, the pharmaceutical formulation and / or composition further includes a second microparticle comprising TGF-^. In certain embodiments, the pharmaceutical formulation and / or composition further includes a second microparticle comprising rapamycin. In certain embodiments, the pharmaceutical formulation and / or composition further includes a second microparticle comprising IL-2 and a third microparticle comprising TGF-^. In certain embodiments, the pharmaceutical formulation and / or composition further includes a second microparticle comprising IL-2 and a third microparticle comprising rapamycin. In certain embodiments, the pharmaceutical formulation and / or composition further includes a second microparticle comprising TGF-^ and a third microparticle comprising rapamycin. In certain embodiments, the pharmaceutical formulation and / or composition further includes a second microparticle comprising IL-2, a third microparticle comprising TGF-^, and a fourth microparticle comprising rapamycin. ACTIVE 130935777.2 29 072396.1066 PATENT The pharmaceutical formulations and / or compositions of the present disclosure can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. In certain embodiments, the administration of the formulation and / or composition can be topical (including, but not limited to, ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal, and transdermal), oral or parenteral. Local administration can also be topical but can include intraarticular injection into synovial spaces of the body (e.g., articulating bone joints and / or cartilage). Parenteral administration includes, but is not limited to, intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal, or intraventricular, administration. Pharmaceutical compositions and formulations for topical administration can include, but are not limited to, transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like can be necessary or desirable. Compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders can be desirable. Compositions and formulations for parenteral, intrathecal, or intraventricular administration can include sterile aqueous solutions that can also contain buffers, diluents, and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. Pharmaceutical compositions of the present disclosure include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions can be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids, and self-emulsifying semisolids. The pharmaceutical formulations of the present disclosure, which can conveniently be presented in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. ACTIVE 130935777.2 30 072396.1066 PATENT The compositions of the present disclosure can be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present disclosure can also, be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions can further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and / or dextran. The suspension can also contain stabilizers. Dosing is dependent on severity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. The administering physician can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages can vary depending on the relative potency of individual drugs and can generally be estimated based on EC50s found to be effective in in vitro and in vivo animal models or based on the examples described herein. In general, dosage is from 0.01 μg to 100 g per kg of body weight, and can be given once or more daily, weekly, monthly, or yearly. The treating physician can estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. Following successful treatment, it can be desirable to have the subject undergo maintenance therapy to prevent the recurrence of the disease state, wherein the compound is administered in maintenance doses, ranging from about 0.01 μg to about 100 g per kg of body weight, from once or more daily to once every 20 years, for example, such dosing can be weekly, monthly, or yearly as necessary for maintenance therapy. In certain embodiments, the pharmaceutical compositions can be formulated and used as foams. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies, and liposomes. While basically similar in nature, these formulations vary in the components and the consistency of the final product. The compositions of the present disclosure can additionally contain other adjunct components conventionally found in pharmaceutical compositions. Thus, for example, the compositions can contain additional, compatible, pharmaceutically active materials such as, for example, antipruritics, astringents, local anesthetics, or anti-inflammatory agents, or can contain additional materials useful in physically formulating various dosage forms of the compositions of the present disclosure, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the ACTIVE 130935777.2 31 072396.1066 PATENT compositions of the present disclosure. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and / or aromatic substances and the like which do not deleteriously interact with the components of the formulation. In certain non-limiting embodiments, the present disclosure provides a composition comprising a controlled release microparticle comprising an adenosine receptor agonist. In certain embodiments, the adenosine receptor agonist is piclidenoson (IB-MECA) or a derivative thereof. In certain embodiments, the composition is a pharmaceutical composition for subcutaneous administration. In certain non-limiting embodiments, the present disclosure provides a composition comprising a controlled release microparticle comprising an adenosine receptor agonist. In certain embodiments, the adenosine receptor agonist is regadenoson or a derivative thereof. In certain embodiments, the composition is a pharmaceutical composition for subcutaneous administration. In certain non-limiting embodiments, the present disclosure provides a composition comprising a controlled release microparticle comprising an ATP signaling antagonist. In certain embodiments, the ATP signaling antagonist is JNJ-55308942 or a derivative thereof. In certain embodiments, the composition is a pharmaceutical composition for subcutaneous administration. In certain non-limiting embodiments, the present disclosure provides a composition comprising a controlled release microparticle comprising an adenosine receptor agonist. In certain embodiments, the adenosine receptor agonist is piclidenoson (IB-MECA) or a derivative thereof. In certain embodiments, the composition is a pharmaceutical composition for topical administration. In certain non-limiting embodiments, the present disclosure provides a composition comprising a controlled release microparticle comprising an adenosine receptor agonist. In certain embodiments, the adenosine receptor agonist is regadenoson or a derivative thereof. In certain embodiments, the composition is a pharmaceutical composition for topical administration. In certain non-limiting embodiments, the present disclosure provides a composition comprising a controlled release microparticle comprising an ATP signaling antagonist. In certain embodiments, the ATP signaling antagonist is JNJ-55308942 or a derivative thereof. In certain embodiments, the composition is a pharmaceutical composition for topical ACTIVE 130935777.2 32 072396.1066 PATENT administration. 5.5. Methods of Treatment In certain embodiments, the present disclosure provides methods for treating inflammation and / or immune reactions in a subject in need thereof by administering a microparticle or a pharmaceutical composition thereof described herein. In certain embodiments, the presently disclosed methods can be used to treat conditions, diseases, or disorders involving immune-mediated hypersensitivity reactions. These reactions occur when the immune system responds excessively or inappropriately to certain triggers, leading to various manifestations like skin irritation in the case of dermatitis or rejection of transplanted tissue. These reactions can entail an inflammatory response, contributing to the observed symptoms and tissue damage. Exemplary inflammatory conditions and / or immune reactions that can be treated using the disclosed methods are organ preservation for transplantation, allograft rejection, post- transplantation organ protection, organ transplant rejection, viral or bacterial infections, periodontal disease, graft vs. host disease, postsurgical inflammation, burns, dermatitis atopic dermatitis (eczema), contact dermatitis, dermatitis herpetiformis hives (urticaria), allergic rhinitis, acne, psoriasis, pruritus, rosacea, cutaneous lupus erythematosus, or molluscum contagiosum. In certain embodiments, the present disclosure provides methods for treating inflammatory diseases and conditions. Non-limiting example of inflammatory diseases include an inflammatory disease associated with an autoimmune disease, a central nervous system (CNS) inflammatory disease, a joint inflammation disease, an inflammatory digestive tract disease, inflammatory skin and other inflammatory diseases related to epithelial cells (e.g., bronchitis), inflammation associated with cancer (e.g., colon carcinoma), inflammation associated with irritation, and inflammation associated with injury. In certain embodiments, the inflammatory disease can be an inflammatory disease associated with an autoimmune disease, a central nervous system (CNS) inflammatory disease, a joint inflammation disease, an inflammatory digestive tract disease, inflammatory skin and other inflammatory diseases related to epithelial cells, inflammation associated with cancer, inflammation associated with irritation, or inflammation associated with injury. In certain embodiments, the inflammatory disease is selected from inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Alzheimer's disease, Parkinson, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, ACTIVE 130935777.2 33 072396.1066 PATENT Sjogren's syndrome, bronchitis, asthma, or inflammation associated with cancer (e.g., colon carcinoma). In certain embodiments, the presently disclosed methods can be used to treat a subject that has a dermatological condition, including but not limited to allergic contact dermatitis. In certain embodiments, the presently disclosed methods can be used to treat a subject that has received or is receiving a transplant (e.g., a tissue transplant), including but not limited to a skin transplant, a vascularized composite transplant, or a solid organ transplant. In certain embodiments, the subject is at risk of transplant rejection. In certain embodiments, the subject is at risk of tissue transplant rejection. In certain embodiments, the presently disclosed methods can effectively target immune cells, addressing processes such as recruitment, induction, activation, or engagement of immune cells, including but not limited to T cells. In certain embodiments, the presently disclosed methods can be used to treat a targeted tissue affected by inflammation and / or immune reactions, wherein the treatment results in: (a) a reduction in the amount of immune cells at the tissue target site; (b) an induction of T cells, for example regulatory T cells (Tregs) at the tissue target site; (c) a reduction of pro- inflammatory cytokines at the tissue target site, for example, the secretion of IL-1β; and / or (d) the induction of anti-inflammatory cytokines at the tissue target site, for example, IL-10 secretion. In certain embodiments, treating inflammation and / or immune reactions can alleviate, prevent, or impede tissue damage, manifested, for instance, by the reduction of inflammation-associated thickening and / or swelling in the target tissue. In certain embodiments, the presently disclosed methods involve the administration of one or more microparticle populations to provide a controlled release formulation of one or more therapeutic agent. In certain embodiments, the presently disclosed methods can be used to suppress inflammation. In certain embodiments, the presently disclosed methods can regulate ATP and adenosine signaling. In certain embodiments, the presently disclosed methods can be used to deliver a therapeutic agent that is an ATP signaling antagonist, including but not limited to JNJ-55308942 and A438079. In certain embodiments, the presently disclosed methods can be used to deliver a therapeutic agent that is an adenosine signaling agonist, including but not limited to Piclidenoson (IB-MECA) and Regadenoson. In certain embodiments, the presently disclosed methods can be used to modulate specific immune-related blood cells, including but not limited to T cells. In certain embodiments, the presently disclosed methods can be used to deliver a therapeutic agent that is a T cell chemoattractant factor, a T cell inducing factor, and / or a T cell stimulatory factor ACTIVE 130935777.2 34 072396.1066 PATENT (e.g., IL-2, TGF-β, CCL22, IL-33, or rapamycin). In certain embodiments, the presently disclosed methods effectively treat tissue affected by inflammation and / or immune reactions related to a dermatological condition or a tissue that has received or is receiving a transplant is treated by the administration of the microparticle composition and / or pharmaceutical composition. In certain embodiments, the administration can be topical (including, but not limited to, ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Local administration can also be topical, but includes as well intraarticular injection into synovial spaces of the body (i.e., for example, into articulating bone joints and / or cartilage). Parenteral administration includes, but is not limited to, intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. In certain non-limiting embodiments, the present disclosure provides a method of treating dermatitis in a subject in need thereof, the method comprising administering an effective amount of a controlled release microparticle comprising an adenosine receptor agonist. In certain embodiments, the dermatitis is a contact dermatitis. In certain embodiments, the adenosine receptor agonist is piclidenoson (IB-MECA) or a derivative thereof. In certain embodiments, the microparticle is subcutaneously administered. In certain non-limiting embodiments, the present disclosure provides a method of treating dermatitis in a subject in need thereof, the method comprising administering an effective amount of a controlled release microparticle comprising an adenosine receptor agonist. In certain embodiments, the dermatitis is a contact dermatitis. In certain embodiments, the adenosine receptor agonist is regadenoson or a derivative thereof. In certain embodiments, the microparticle is subcutaneously administered. In certain non-limiting embodiments, the present disclosure provides a method of treating dermatitis in a subject in need thereof, the method comprising administering an effective amount of a controlled release microparticle comprising an ATP signaling antagonist. In certain embodiments, the dermatitis is a contact dermatitis. In certain embodiments, the ATP signaling antagonist is JNJ-55308942 or a derivative thereof. In certain embodiments, the microparticle is subcutaneously administered. In certain non-limiting embodiments, the present disclosure provides a method of treating dermatitis in a subject in need thereof, the method comprising administering an effective amount of a controlled release microparticle comprising an adenosine receptor ACTIVE 130935777.2 35 072396.1066 PATENT agonist. In certain embodiments, the dermatitis is a contact dermatitis. In certain embodiments, the adenosine receptor agonist is piclidenoson (IB-MECA) or a derivative thereof. In certain embodiments, the microparticle is topically administered. In certain non-limiting embodiments, the present disclosure provides a method of treating dermatitis in a subject in need thereof, the method comprising administering an effective amount of a controlled release microparticle comprising an adenosine receptor agonist. In certain embodiments, the dermatitis is a contact dermatitis. In certain embodiments, the adenosine receptor agonist is regadenoson or a derivative thereof. In certain embodiments, the microparticle is topically administered. In certain non-limiting embodiments, the present disclosure provides a method of treating dermatitis in a subject in need thereof, the method comprising administering an effective amount of a controlled release microparticle comprising an ATP signaling antagonist. In certain embodiments, the dermatitis is a contact dermatitis. In certain embodiments, the ATP signaling antagonist is JNJ-55308942 or a derivative thereof. In certain embodiments, the microparticle is topically administered. In certain non-limiting embodiments, the present disclosure provides a method of treating a transplant rejection in a subject in need thereof, the method comprising administering an effective amount of a controlled release microparticle comprising an adenosine receptor agonist. In certain embodiments, the transplant rejection is a skin transplant rejection. In certain embodiments, the adenosine receptor agonist is piclidenoson (IB-MECA) or a derivative thereof. In certain embodiments, the microparticle is subcutaneously administered. In certain non-limiting embodiments, the present disclosure provides a method of treating a transplant rejection in a subject in need thereof, the method comprising administering an effective amount of a controlled release microparticle comprising an adenosine receptor agonist. In certain embodiments, the transplant rejection is a skin transplant rejection. In certain embodiments, the adenosine receptor agonist is regadenoson or a derivative thereof. In certain embodiments, the microparticle is subcutaneously administered. In certain non-limiting embodiments, the present disclosure provides a method of treating a transplant rejection in a subject in need thereof, the method comprising administering an effective amount of a controlled release microparticle comprising an ATP signaling antagonist. In certain embodiments, the transplant rejection is a skin transplant rejection. In certain embodiments, the ATP signaling antagonist is JNJ-55308942 or a derivative thereof. In certain embodiments, the microparticle is subcutaneously administered. In certain non-limiting embodiments, the present disclosure provides a method of ACTIVE 130935777.2 36 072396.1066 PATENT treating a transplant rejection in a subject in need thereof, the method comprising administering an effective amount of a controlled release microparticle comprising an adenosine receptor agonist. In certain embodiments, the transplant rejection is a skin transplant rejection. In certain embodiments, the adenosine receptor agonist is piclidenoson (IB-MECA) or a derivative thereof. In certain embodiments, the microparticle is topically administered. In certain non-limiting embodiments, the present disclosure provides a method of treating a transplant rejection in a subject in need thereof, the method comprising administering an effective amount of a controlled release microparticle comprising an adenosine receptor agonist. In certain embodiments, the transplant rejection is a skin transplant rejection. In certain embodiments, the adenosine receptor agonist is regadenoson or a derivative thereof. In certain embodiments, the microparticle is topically administered. In certain non-limiting embodiments, the present disclosure provides a method of treating a transplant rejection in a subject in need thereof, the method comprising administering an effective amount of a controlled release microparticle comprising an ATP signaling antagonist. In certain embodiments, the transplant rejection is a skin transplant rejection. In certain embodiments, the ATP signaling antagonist is JNJ-55308942 or a derivative thereof. In certain embodiments, the microparticle is topically administered. 5.6. Kits In another embodiment, the present disclosure provides kits comprising a composition disclosed herein and / or for practicing any one of the above-listed methods. In certain embodiments, the kit can include a composition comprising a microparticle component. In certain embodiments, the kit can include a composition comprising one or more controlled released microparticle population. In certain embodiments, the kit can include a composition comprising one or more therapeutic agent. In certain embodiments, the one or more therapeutic agent comprises an immune- modulating agent. In certain embodiments, the one or more therapeutic agent comprises an inflammatory suppressing agent. In certain embodiments, the one or more therapeutic agent comprises an agent that modulates ATP and / or adenosine signaling. In certain embodiments, the one or more therapeutic agent comprises an ATP signaling antagonist including, but not limited to JNJ-55308942 and A438079. In certain embodiments, the one or more therapeutic agent comprises an adenosine signaling agonist including, but not limited to Piclidenoson (IB- MECA) and Regadenoson. In certain embodiments, the one or more therapeutic agent comprises an agent that ACTIVE 130935777.2 37 072396.1066 PATENT modulate specific immune-related blood cells including, but not limited to T cells. In certain embodiments, the one or more therapeutic agent can include a T cell chemoattractant factor, a T cell inducing factor, and / or a T cell stimulatory factor. In certain embodiments, the one or more T cell factor can include, but are not limited to, IL-2, TGF-β, CCL22, IL-33, and rapamycin. The kit can include a pharmaceutically acceptable excipient and / or a delivery vehicle. The reagents can be suspended in the excipient and / or delivery vehicle or may be provided as a separate component which can be later combined with the excipient and / or delivery vehicle. The kit can contain additional therapeutics to be co-administered with the composition(s). The kits can also optionally include appropriate systems (e.g., opaque containers) or stabilizers (e.g., antioxidants) to prevent degradation of the reagents by light or other adverse conditions. The kits can optionally include instructional materials containing directions (i.e., protocols) providing for the use of the reagents in the performance of the methods described herein. In particular, the disease can include any one or more of the disorders described herein. While the instructional materials typically comprise written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media can include addresses to internet sites that provide such instructional materials. In certain embodiments, the present disclosure contemplates a kit comprising a hydrogel-coupled microparticle composition(s) to provide an ‘off-the-shelf’ therapeutic for creating a local immunosuppressive environment and increasing the presence of Treg cells at sites of inflammation. In one embodiment, the kits can be used to treat various medical conditions including, but not limited to, ischemia or ischemia-reperfusion injury. Although it is not necessary to understand the mechanism of the present disclosure, it is believed that compound-coupled microparticle composition, including a therapeutic agent(s), can be administered to treat diseases and disorders while the systemic immune system integrity such that the immune system can continue to fight infections and inhibit malignancies. 6. EXAMPLES The present disclosure will be better understood by reference to the following Example, ACTIVE 130935777.2 38 072396.1066 PATENT which are provided as exemplary of the present disclosure, and not by way of limitation. Example 1: Sustained delivery formulations of ATP signaling antagonists and adenosine signaling agonists for immune modulation The present Example is directed to novel controlled release systems (e.g., microparticle-based systems) that encapsulate and release (1) Ado signaling agonists (e.g., Piclidenoson / IB-MECA, Regadenoson) or (2) ATP signaling antagonists (e.g., JNJ- 55308942). These microparticle-based systems allow sustained release of picogram / nanogram quantities of the encapsulated therapeutic agents over a period of days to weeks. Notably, these microparticle-based systems were able to improve inflammation-related symptoms. Methods DNCB-induced eATP release To examine the ability for contact allergens to induce eATP release from APCs, THP1 cells (human monocytes) were cultured in the presence of DNCB (model allergen) for 4 hours. After 4 hours, cell supernatants were collected and eATP release was assessed using Cell Titer Glo. DNCB induced eATP release in a dose-dependent manner. In Vitro Cytokine Assays To assess the effect of P2X7R antagonists on IL-1β and IL-10 secretion, murine macrophages (J774A.1) were activated with lipopolysaccharide (1 ug / mL) and eATP (2 mM) in the presence of P2X7R antagonists (JNJ55308942, Brilliant Blue, A438079). After 4 to 24 hours, supernatants were collected and IL-1β or IL-10 concentrations were assessed using ELISAs. Soluble P2X7R antagonists reduced IL-1β secretion in a dose-dependent manner. Multiple P2X7R antagonists (JNJ55308942, A438079) also increased IL-10 secretion. In Vitro CD4+ T Cell Assays To evaluate ATP / Ado signaling modulation for Tregs induction, murine naïve CD4+ T cells were isolated from spleens of C57BL / 6 mice. Isolated CD4+ T cells were stimulated with anti-CD3 / CD28 antibodies in the presence of IL-2, TGFβ1, and / or receptor antagonists / agonists for 72 hours. After 72 hours, differentiation of Treg from naïve T cells was assessed through flow cytometry by staining cells to identify live CD4+ Foxp3+ Tregs. Percentages of live CD4+ Foxp3+ Tregs induced with TGFβ1 was compared to percentages of live CD4+ Foxp3+ Tregs induced with TGF1 plus receptor antagonists / agonists to determine if the presence of antagonist / agonists has an effect. Soluble JNJ-55308942 was found to increase % Foxp3+ of CD4+ T cells. The proliferative responses of Tregs or effector T cells in response to TCR stimulation in the presence of the drugs was assessed. To do so, isolated ACTIVE 130935777.2 39 072396.1066 PATENT murine CD4+ and CD8+ T cells were stained with CFSE and stimulated as described above. Cells were cultured for 72 hours, following which proliferation (CFSE dilution) was assessed using flow cytometry. IB-MECA was found to reduce proliferation of CD4+ T cells. In Vivo CHS Model Mice were sensitized with DNFB alone as a control. Daily soluble injections of experimental groups (e.g., JNJ-55308942 doses) were given subcutaneously at the base of the ear for one week (-2 to 5 days). On day 0 (D0), mice were sensitized by topical application of DNFB to both ears. On D10, mice were challenged at both ears with DNFB. Therapeutic efficacy, evidenced by reduced cutaneous inflammation, was assessed using ear thickness measurements taken throughout. Ear skin histology was evaluated to confirm ear thickness measurements. CD3 staining For CD3 staining, 7 μm thick sections were fixed with ethanol for 10 minutes and then washed with PBS. Slides were then blocked with PBS containing donkey serum. Blocked sections were incubated overnight at 4 °C with a primary antibody for CD3. Sections were then washed with PBS and counterstained with DAPI for 1 hour. Slides were then washed and imaged using a fluorescent microscope. Microparticle manufacturing and characterization Batch manufacturing: to manufacture MPs via homogenization, a well-documented single emulsion solvent evaporation method was used. Briefly, DMSO containing the drug of choice (e.g., JNJ) was added to dichloromethane containing PLGA. The organic phase was then added to an aqueous phase containing PVA and homogenized for 1 minute. Following homogenization, the solution was transferred to a stir plate, where it was stirred for 3 hours to allow for DCM to evaporate. Particles were then washed 4 times using deionized water, flash frozen in liquid nitrogen, and lyophilized for 72 hours. Continuous manufacturing / microfluidics: to manufacture MPs (e.g., JNJ, IBMECA, Regadenoson) via microfluidics, a three-pump system with a hydrophilic flow-focusing microfluidics chip with a 100-um channel was used. Within the chip, droplets containing PLGA and drug of choice (JNJ, etc.) dissolved in DMSO and DCM within a continuous aqueous phase were formed. Droplets were collected in 1% PVA and stirred for 3 hours to allow for solidification of the particles and solvent evaporation. Particles were then washed 4 times using deionized water, flash frozen in liquid nitrogen, and lyophilized for 72 hours. Characterization: following lyophilization, microparticle surface morphology, size distribution, and release kinetics were characterized. Surface morphology and size distribution were assessed through scanning ACTIVE 130935777.2 40 072396.1066 PATENT electron microscopy and volume impedance measurements, respectively. To characterize release, 5 mg of microparticles were weighed in microcentrifuge tubes in triplicate and resuspended in phosphate buffer saline containing 0.20% Tween 20. Samples were then incubated at 37C on an end-over-end rotator. Supernatant release media was sampled and replaced daily. Small molecule concentrations were determined by spectrophotometry (absorbance at JNJ – 260 nm; Regadenoson – 240 nm; IBMECA – 268 nm). Results Contact allergens are known to trigger allergic contact dermatitis. The present disclosure demonstrated that contact allergens can induce the release of extracellular eATP. As shown in Figure 2, THP1 monocytes, upon exposure to a contact allergen, exhibited a substantial release of eATP, thereby revealing a direct link between allergen exposure and heightened extracellular ATP levels. This observation underscores the potential involvement of ATP signaling in the cellular responses associated with allergic contact dermatitis induced by contact allergens. The present disclosure investigated the ability of P2X7R antagonists to suppress inflammatory cytokine secretion. Figures 3A-3C demonstrated that the P2X7R antagonist JNJ- 55308942, Brilliant Blue G, and A438079 suppressed IL-1β secretion in macrophages (LPS+ATP+ J774A.1 cells) in a dose-dependent manner. Interestingly, JNJ-55308942 and A438079, as depicted in Figures 4A and 4B, not only exhibited suppression of IL-1β but also promoted the secretion of the anti-inflammatory cytokine IL-10. This dual functionality positions JNJ-55308942 and A438079 as compounds with a unique ability to modulate inflammation, acting both as suppressors of pro-inflammatory responses and promoters of anti- inflammatory signaling. Moreover, the present disclosure investigated the effects of modulating ATP / Ado signaling in T cells. Here, it is demonstrated that JNJ-55308942 treatment increased the percent FoxP3+ of CD4+ T cells, compared to IB-MECA, a compound that is a specific agonist (activator) for the adenosine A3 receptor, and Regadenoson, a compound that is a selective A2A adenosine receptor agonist and is primarily utilized to induce stress during cardiac imaging procedures to assess blood flow to the heart (Figure 5A). However, IBMECA was shown to affect CD4+ T cell proliferation, leading to an increase in the population of non- proliferating cells (Figure 5B). This comparative analysis provided insights into the differences in their efficacy or mechanisms of action in regulating inflammatory processes. The present disclosure explored the impact of JNJ-55308942 on modulating inflammation in response to a model contact allergen (Figures 6A-6C). C57BL / 6 mice were ACTIVE 130935777.2 41 072396.1066 PATENT sensitized and challenged with DNFB, resulting in ear swelling. Subsequent subcutaneous injections of JNJ-55308942 revealed a discernible suppressive effect on inflammation, as evidenced by a reduction in ear swelling measurements. These results were confirmed by histological assessment demonstrating JNJ-55308942 reduced dermal and epidermal thickening, (Figure 7A-7C). Figures 7D-7F correspond to representative fluorescent images displaying CD3+ T cells. Figure 7D reveals the infiltration of CD3+ T cells in the absence of JNJ-55308942, while Figures 7E and 7F depict the administration of JNJ-55308942, as low and high dosages, respectively, inhibited CD3+ T cell infiltration. Microparticles containing JNJ-55308942, Regadenoson, or IB-MECA were developed to provide a controlled release delivery system for modulating eATP / adenosine signaling (Figures 8A-8C). These microparticles exhibited a spherical morphology and provided a sustained release profile for at least 2 weeks. Additionally, microfluidic can be used to manufacture controlled release systems for modulating eATP and / or adenosine signaling (Figures 9A-9D). Microfluidic-based microparticles exhibit a uniform diameter size, exhibiting a peak characteristic of more monodisperse microparticles, compared to homogenization-based microparticles, and provided a sustained release profile of JNJ-55308942 for over 10 days. Discussion The present disclosure involved the manipulation of ATP / Ado signaling using controllable release systems. The controlled release systems encapsulated and released (1) Ado signaling agonists (e.g., Piclidenoson / IB-MECA, Regadenoson) or (2) ATP signaling antagonists (e.g., JNJ-55308942 and A438079). These microparticle-based systems enabled sustained release of picogram / nanogram quantities of the encapsulated active pharmaceutical ingredients over a period of days to weeks. The present disclosure provided the first demonstration that such molecules can be encapsulated and released via controllable release systems. The present disclosure also explored the use of these drugs in novel conditions. The present disclosure demonstrated the therapeutic efficacy of sustained release delivery method for JNJ-55308942 in an in vivo murine model of allergic contact dermatitis, an inflammatory skin condition. Given that ATP signaling is implicated in a variety of inflammatory conditions, these delivery systems, which either inhibit ATP signaling or enhance Ado signaling, can be used as therapeutics for many disease indications (e.g., skin transplant rejection, vascularized composite allotransplant rejection, etc.). Example 2: Local delivery of an adenosine receptor agonist reduces inflammation ACTIVE 130935777.2 42 072396.1066 PATENT associated with contact hypersensitivity Allergic contact dermatitis (ACD), a T-cell mediated inflammatory skin condition, impacts about 20% of the adult population (Balmert et al., 2017; Martin et al., 2018; Brites et al., 2020). In ACD, cutaneous exposure to chemical allergens, such as metals (e.g., nickel, chromate, etc.), cosmetics, or topical medications (e.g., corticosteroids), causes inflammation, resulting in clinical manifestation of symptoms such as erythema (redness), pruritus (itchiness), and edema (swelling) (Saint-Mezard et al., 2004; Brites et al., 2020; Tramontana et al., 2023). Given that many of the aforementioned allergens are found abundantly in everyday life, ACD is a significant occupational health hazard, resulting in an estimated 4 million lost workdays per year in the United States alone (Kaplan et al., 2012; Martin et al., 2018; Brites et al., 2020). While it originally presents at the site of contact, ACD can propagate to other locations, causing a widespread reaction (Saint-Mezard et al., 2004; Tramontana et al., 2023). Mechanistically, ACD consists of two phases: sensitization, which occurs after first allergen contact, and elicitation / challenge, which occurs after re-exposure (Brites et al., 2020). During sensitization, chemical allergens, otherwise known as haptens, penetrate the skin and bind to self-proteins, resulting in the formation of antigenic self-hapten complexes in a process known as haptenization (Saint-Mezard et al., 2004; Kaplan et al., 2012; Martin et al., 2018; Brites et al., 2020; Tramontana et al., 2023). These complexes activate the innate immune response, resulting in migration of a variety of antigen-presenting cells (APCs) (e.g., dendritic cells, Langerhans cells) from the skin to draining lymph nodes. In the draining lymph nodes, APCs present self-hapten complexes to T cells, resulting in the generation and activation of antigen-specific T cells. Upon re-exposure to an allergen, known as elicitation, a delayed type IV hypersensitivity (DTH) response occurs, resulting in the activation of antigen-specific T cells and clinical manifestation of ACD within 24 to 72 hours. To prevent and / or treat ACD, individuals are first encouraged to remove and / or avoid environmental allergens (Saint-Mezard et al., 2004; Brites et al., 2020; Tramontana et al., 2023). Otherwise, ACD can be treated through repetitive application of topical anti-inflammatory agents such as corticosteroids (Saint-Mezard et al., 2004; Kaplan et al., 2012; Martin et al., 2018; Brites et al., 2020). In the case of a widespread reaction, systemic immunosuppressants (e.g., methotrexate, cyclosporine, etc.) may be used (Saint-Mezard et al., 2004; Kaplan et al., 2012; Martin et al., 2018). Nonetheless, these approaches have a variety of limitations. Topical application of corticosteroids can result in skin atrophy, striae, and telangiectasia (Coondoo et al., 2014; Tramontana et al., 2023). Systemic approaches place individuals at risk for other side effects, including osteoporosis and type 2 diabetes (Brites et al., 2020). In addition, many of ACTIVE 130935777.2 43 072396.1066 PATENT these approaches act broadly to suppress inflammation, failing to address the specific underlying mechanisms responsible for disease (Balmert et al., 2017; Bentley and Little, 2021). To address these limitations, there is a clinical need to develop novel approaches that more specifically target the underlying immune mechanisms responsible for ACD. For instance, one mechanism that contributes to efficient sensitization is the release and action of danger- associated molecular patterns (DAMPs), such as extracellular ATP (eATP). In ACD, exposure to contact allergens can trigger eATP release from dying cells, as well as activated keratinocytes and skin APCs (Weber et al., 2010; Sebastião et al., 2020; Chen et al., 2024). eATP signaling through its receptor, P2X7, can promote inflammasome activation and inflammatory cytokine secretion (e.g., IL-2, IFNg, IL-1b, etc.), leading to proliferation and differentiation of effector T cells (e.g., Th1, Tc1, etc.). However, eATP can be converted to anti-inflammatory adenosine (Ado) by CD39 and CD73, two ectoenzymes expressed on the surface of regulatory T cells (Tregs). Contrary to eATP, Ado signaling through its receptors (e.g., A3) promotes immunosuppression. Ado signaling can stimulate secretion of anti- inflammatory cytokines (e.g., IL-10, TGFβ1) while reducing secretion of inflammatory cytokines (e.g., TNFa, IL-6), induce Treg differentiation, and prevent effector T cell differentiation (Faas et al., 2017; Silva-Vilches et al., 2018; Effendi et al., 2020; Chen et al., 2024). Altogether, these studies illustrate the potential to target the eATP / Ado axis as a therapeutic approach for ACD. To this end, the present disclosure sought to enhance Ado signaling in ACD as a method to induce immunosuppression through local administration of IBMECA (Piclidenoson), an A3 adenosine receptor (A3AR) agonist. Systemic administration of IBMECA has been tested in clinical trials for a variety of inflammatory4 conditions, including rheumatoid arthritis, uveitis, keratoconjunctivitis sicca, and psoriasis (Chen et al., 2024). In several of these trials, IBMECA, which has a half-life of 9 hours, was administered orally twice a day, suggesting repetitive dosing was needed to maintain sufficient systemic drug levels (Smith et al., 2018; Fishman, 2022). Nonetheless, in clinical trials for psoriasis, oral IBMECA resulted in improvement in Psoriasis Area and Severity Index (PASI), a scoring system used to measure disease severity (David et al., 2012, 2016; Papp et al., 2024). Despite its efficacy, some of these studies reported adverse events, including infections, moderate hepatic dysfunction, and gastrointestinal issues (David et al., 2016; Chen et al., 2024). These adverse effects were likely a result of the frequent dosing and systemic administration of IBMECA via the oral route, thereby motivating a more localized delivery approach to enable sequestration of low doses of IBMECA in specific tissues of interest over extended periods of time. ACTIVE 130935777.2 44 072396.1066 PATENT To address these limitations, as well as those associated with topical and systemic immunosuppressants typically used for ACD, a biodegradable polymeric microparticles (MPs) that controllably release IBMECA over time in a local environment (IBMECA-MPs) was developed. Given success of systemically administered IBMECA in clinical trials for treating inflammation, local delivery of IBMECA-MPs could be effective at suppressing inflammation in a model of contact hypersensitivity (CHS), an in vivo model of ACD. First, in vitro effects of IBMECA on APC phenotype were demonstrated. In further embodiments, the therapeutic efficacy of IBMECA-MPs in a murine CHS model was evaluated, demonstrating that locally administered IBMECA-MPs effectively suppressed cutaneous inflammation during sensitization and elicitation phases. Ultimately, this novel approach can have potential therapeutic implications for other T-cell mediated inflammatory conditions, including as transplant rejection. Methods In vitro cytokine assays DC2.4 cells (murine dendritic cells) were cultured in RPMI-1640 containing 10% FBS, 1x L-Glutamine, 1x non-essential amino acids, 1x HEPES Buffer Solution, and 0.0054x b- Mercaptoethanol at 37^C with 5% CO2. J774A.1 (murine macrophages) were cultured in DMEM containing 10% FBS at 37^C with 5% CO2. Cells were added to a 12-well plate at 5x105cells / well. Cells were stimulated with lipopolysaccharide (LPS, 1 μg / mL) in the presence of various doses of IBMECA for 24 hours in a total volume of 500 μL. After 24 hours, supernatants were extracted and analyzed for TNF^ concentrations using a Mouse TNF^ DuoSet enzyme-linked immunosorbent assay. In vitro surface expression assays DC2.4 cells were cultured as previously described above. 2x105cells were added to each well of a flat-bottom 96-well plate and stimulated with LPS (1 μg / mL) in the presence of various doses of IBMECA for 24 hours at 37^C with 5% CO2. Unstimulated DC2.4s (without LPS) were used as a control. After 24 hours, cells were collected and stained with fluorescently labeled antibodies for CD40, CD80, and fixable viability dye (FVD). Isotype controls were also used for each marker: PE and BV421. Stained cells were fixed with 1x BD Stabilizing Fixative, and flow cytometry analysis was performed using a BD LSR II flow cytometer. FlowJo software was used to quantify median fluorescence intensities (MFI) for each marker. Microparticle fabrication IBMECA-MPs were fabricated using a well-documented single emulsion solvent ACTIVE 130935777.2 45 072396.1066 PATENT evaporation method (McGinity and O’Donnell, 1997; Jhunjhunwala et al., 2012). 2 mg IBMECA was dissolved in 100 μL dimethylsulfoxide (DMSO) and added to 4 mL of dichloromethane containing 200 mg poly (lactic-co-glycolic acid) (PLGA; RG502H; 50:50 lactic:glycolic acid, MW: 7-17 kDa). The resulting solution was transferred to 60 mL of 2% (wt / vol) poly (vinyl alcohol) (PVA, MW -25 kDa, 98% hydrolyzed) in diH2O (deionized water) and homogenized at 3,000 rpm for 1 minute, resulting in a single emulsion. The single emulsion was then added to 80 mL of 1% PVA (wt / vol) and stirred at room temperature for 3 hours at 600 rpm, enabling dichloromethane to evaporate. Following evaporation, the resulting microparticles were then washed four times (1,000 rpm, 5 mins, 4^C) with diH2O to remove residual PVA. After washing, microparticles were resuspended in 10 mL diH2O, flash frozen in liquid nitrogen, lyophilized for 72 hours, and stored at -20^C until use / analysis. Blank (unloaded) MPs were fabricated as described above, but with no drug in the 100 μL DMSO. Microparticle characterization Particle size distribution measurements were assessed via volume impedance measurements using a Multisizer-3. Surface morphology was examined using scanning electron microscopy after sputter coating. To assess IBMECA release kinetics, approximately 5 mg of MPs was suspended in 1 mL of phosphate buffer saline (PBS) containing 0.20% Tween20 to increase drug solubility. Samples were incubated at 37^C with end-over-end rotation and sampled periodically for two weeks. To collect releasate, samples were centrifuged at 2500 rpm for 5 minutes and supernatants were extracted and stored at -20^C until analysis via spectrophotometry. To determine the maximum absorbance wavelength of IBMECA, a spectrum scan was performed using a SpectaMax M2 spectrophotometer. IBMECA concentrations in supernatants were then determined by spectrophotometry (absorbance at 268 nm). Cumulative release over time (mass drug release / mass of particles) was calculated and plotted. Mice Female C57BL / 6 mice were used at 6-12 weeks of age. All institutional and national guidelines for the care and use of laboratory animals were followed, and experiments were performed with approval from the Institutional Animal Care and Use Committee (IACUC) at the University of Pittsburgh. Contact hypersensitivity (CHS) model Dinitrofluorobenzene (DNFB) was dissolved in a 4:1 (v / v) solution of acetone to olive oil, as previously described (Balmert et al., 2017). Female C57BL / 6 mice were then sensitized ACTIVE 130935777.2 46 072396.1066 PATENT by topical application of 10 μL of 0.5% DNFB to both the ventral and dorsal side of each ear. Ear thickness measurements were taken using a digital caliper immediately prior to sensitization and every 24 hours following sensitization for 5 days. To elicit a delayed-type hypersensitivity (DTH), mice were challenged with 0.2% DNFB 10 days after sensitization. Ear thickness measurements were taken immediately prior to challenge and 24 and 48h post- challenge. Change in ear thickness measurements (Δ Ear Thickness) were calculated by subtracting starting ear thickness measurements (taken prior to sensitization or challenge) from ear thickness measurements taken on the day of interest. Suppression of skin inflammation with IBMECA-MPs Microparticles were resuspended in sterile PBS at a concentration of 50 mg / mL. Microparticles were then subcutaneously injected at the base of each ear with a 25-gauge needle one day prior to sensitization. Each injection contained 5 mg of Blank (unloaded) or IBMECA- MPs in 100 pL sterile PBS. Phenotypical analysis of dendritic cell populations in skin draining lymph nodes Cervical skin draining lymph nodes from mice sacrificed 24 hours after sensitization were harvested and enzymatically digested using DNAse and Collagenase D. More specifically, lymph nodes were incubated in 500 pL of RMPI-1640 supplemented with DNase (0.1 mg / mL) and Collagenase D (2 mg / mL) for 1 hour at 37^C using a thermomixer (300 rpm). After 1 hour, lymph nodes were manually resuspended by pipetting. Lymph node suspensions were then placed back in the thermomixer (300 rpm) for 30 minutes of additional enzymatic digestion, during which suspensions were manually mixed two additional times to ensure complete digestion. After 1.5 hours, 500 pL of stop solution (1% FBS and 2 mM EDTA in RPMI-1640) was added to each tube and samples were filtered through 35 pm filters to create single cell suspensions. Samples were then washed with MACS buffer and stained with fluorescently labeled antibodies for the following surface markers: CD83, CD80, CD86, CD11c, CD40, IAb / MHCII, and PDL1. Fixable viability dye (FVD) was used to gate live cells. FlowJo software (Ashland, OR, USA) was used to identify all dendritic cells (Live (FVD–) CD11c+ MHCII+). Lymph node resident dendritic cells (DCs) and migratory DCs were then identified as CD11chiMHCII+ and CD11c+ MHCIIhi, respectively (Gerner et al., 2012; Eisenbarth, 2019; Mani et al., 2019). Median fluorescence intensities (MFI) for each surface marker were then identified for each subpopulation. Phenotypic analysis of T-cell populations in skin draining lymph nodes Cervical skin draining lymph nodes from mice sacrificed 5 days after sensitization or 2 ACTIVE 130935777.2 47 072396.1066 PATENT days after challenge were harvested and processed through 70 pm filters to form single cell suspensions. Cells were blocked with anti-CD16 / 32 and stained with fluorescently labeled antibodies for the following T-cell markers: CD4, CD8b, Tbet, and Foxp3. Fixable viability dye (FVD) was used to identify living cells. An antibody for Ki67 was used to assess proliferating cells. FlowJo software was used for analysis. Phenotypical analysis of T-cell populations in ear skin Ear skin from mice sacrificed 5 days after sensitization or 2 days after challenge was harvested. Harvested ear skin was enzymatically digested with Liberase TL (0.25 mg / mL) and DNase I (10 µg / mL) in Iscove’s Modified Dulbecco’s Medium (IMDM) for 1.5 hours at 37^C on a shaker set to 125 rpm. After 1.5 hours, ear skin was processed through 70 pm filters to form single cell suspensions. Cells were then washed with MACS, blocked with anti-CD16 / 32 and stained with fluorescently labeled antibodies for the following T-cell markers: CD45.2, CD4, CD8b, Tbet, Foxp3, and FVD. Stained cells were fixed with 1x BD Stabilizing Fixative, and flow cytometry analysis was performed using a BD LSR II flow cytometer. FlowJo software was used to identify T-cell subtypes. Cutaneous histology Ears from mice sacrificed 2 days following challenge were removed and flash frozen in OCT. Skin cryosections (7 μm thick) were stained with hematoxylin and eosin and imaged with a Keyence BZ-X800 microscope. Epidermal thickness measurements were taken in ImageJ. Statistical analyses Statistical analyses were performed with GraphPad Prism v10. For analyses of two groups with equal standard deviations, unpaired t tests were performed. For analyses with three or more groups, one-way ANOVAs were performed with Tukey HSD post-hoc tests to identify significant differences. Ear thickness measurements taken across multiple time points were analyzed using repeated-measure two-way ANOVAs. Ear thickness measurements taken at one time point were analyzed using unpaired t tests. Outliers were identified using the ROUT method or Grubb’s method, when appropriate. Data is represented as mean ± standard error of the mean (SEM). Results Antigen-presenting cells treated with IBMECA exhibit reduced costimulatory receptor expression and inflammatory cytokine secretion Prior to assessing the impact of IMBECA in vivo, the effects of IBMECA on antigen- ACTIVE 130935777.2 48 072396.1066 PATENT presenting cells were studied. Antigen-presenting cells, including dendritic cells and macrophages, are crucial players in triggering inflammation by presenting antigens to T cells, resulting in T-cell activation, differentiation, and proliferation. Robust T-cell responses require multiple direct and indirect signals, including co-stimulatory molecule interaction between antigen-presenting cells and T cells, as well as cytokine signaling (Saint-Mezard et al., 2004; Curtsinger and Mescher, 2010). Co-stimulatory molecules expressed on the surface of antigen- presenting cells include CD40 and CD80, to name a few. ATP has previously been shown to increase expression of co-stimulatory molecules on the surface of bone marrow derived dendritic cells (BMDCs) (Furuta et al., 2023). Therefore, adenosine signaling may reduce expression of co-stimulatory molecules on stimulated antigen-presenting cells. To test this hypothesis, the effect of IBMECA on surface expression of co-stimulatory molecules was studied. Murine dendritic cells (DC2.4) were stimulated in the presence of lipopolysaccharide (LPS), a bacteria-derived immune adjuvant, with or without IBMECA. After 24 hours, dendritic cells stimulated in the presence of IBMECA exhibited significantly reduced expression of CD40 when compared to those stimulated in the absence of IBMECA (Figure 10A-B). Although not statistically significant, dendritic cells stimulated in the presence of IBMECA demonstrated slight reduction in expression of CD80 (Figure 10A-B). Altogether, these results demonstrate that IBMECA could be able to reduce the immunostimulatory capacity of dendritic cells. As previously mentioned, another factor which contributes to robust T-cell responses is cytokine signaling. One pleiotropic cytokine known to both support T-cell proliferation and augment naïve CD4+ T-cell differentiation towards effector T cell subtypes is tumor necrosis factor alpha (TNF^) (Croft, 2009; Jiang et al., 2019; Alam et al., 2021). In the context of allergic contact dermatitis, activated keratinocytes and many T cell subtypes secrete TNF^, resulting in increased co-stimulatory molecule expression as well as enhanced migration of lymphocytes and dendritic cells (Saint-Mezard et al., 2004). Though adenosine signaling has been previously shown to reduce TNF^ secretion from a variety of cell types (e.g., epithelial cells, microglial cells, etc.), the specific effects of IBMECA, an A3 receptor agonist, on dendritic cells and macrophages, two crucial cell populations in the pathogenesis of ACD, have yet to be studied (McWhinney et al., 1996; Kreckler et al., 2006; Lee et al., 2006; Ren et al., 2014). To address this knowledge gap, the effect of IBMECA on TNF^ secretion from dendritic cells and macrophages was studied. In individual experiments, APCs were stimulated ACTIVE 130935777.2 49 072396.1066 PATENT with LPS in the absence or presence of IBMECA for 24 hours. After 24 hours, cell supernatants were extracted, and supernatant TNF-a concentrations were analyzed via enzyme-linked immunosorbent assays (ELISAs). As expected, IBMECA reduced TNF^ secretion from both dendritic cells and macrophages in a dose-dependent manner (Figure 10C). Altogether, these results show that IBMECA has the ability to alter both the phenotype and function of antigen- presenting cells, potentially impacting subsequent T-cell responses and proliferation. IBMECA can be encapsulated and released from polymeric microparticles Since IBMECA demonstrated immunosuppressive effects on antigen-presenting cells (APCs) in vitro, it was next encapsulated within poly(lactic-co-glycolic acid) (PLGA) microparticles (IBMECA-MPs), enabling controlled release for in vivo applications. Microparticle-based controllable release systems, such as IBMECA-MPs, are advantageous over other methods of drug delivery (e.g., soluble injections, nanoparticles, etc.) for a variety of reasons. Due to their larger size, polymeric microparticles are often unable to cross biological barriers and provide a depot for sustained release, resulting in increased drug retention within a specific tissue of interest (Balmert and Little, 2012; Fisher et al., 2015; Bentley and Little, 2021). In addition, polymeric microparticles facilitate release of a drug over a period of weeks, reducing dose frequency and systemic concentrations associated with traditional delivery methods (Balmert and Little, 2012; Fisher et al., 2015; Lagreca et al., 2020; Bentley and Little, 2021). In the case of IBMECA, prior studies, in both human clinical trials and murine experiments, have relied upon a high dose frequency (typically twice daily over a period of weeks) and / or concentration (mg / kg) to achieve therapeutic effects (David et al., 2012, 2016; Zeng et al., 2024). The development of a controlled release system for IBMECA could address many of these limitations. Since IBMECA is a hydrophobic compound, IBMECA-MPs were fabricated using a single-emulsion evaporation method (Lagreca et al., 2020; Bentley et al., 2024). Scanning electron microscopy images of the resulting IBMECA-MPs show MPs with a smooth surface morphology, in accordance with previously published single emulsion formulations (Figure 11A) (Balmert et al., 2017; Ratay et al., 2018). IBMECA-MPs were engineered to be approximately 10 μm in diameter to avoid phagocytosis, with their size confirmed by volume impedance measurements (Figure 11B). IBMECA-MPs controllably release IBMECA over a period of one week (Figure 11C). Notably, IBMECA-MPs release small amounts of drug on the order of nanograms per day. In contrast, prior murine studies with IBMECA required daily doses on the order of micrograms to achieve therapeutic effects, highlighting one of the ACTIVE 130935777.2 50 072396.1066 PATENT potential benefits of the sustained release IBMECA-MPs (Hofer et al., 2014; Zeng et al., 2024). IBMECA-MPs alter surface expression of dendritic cell markers following sensitization Since IBMECA demonstrated immunosuppressive effects on various immune cells in vitro, IBMECA-MPs may have a similar effect on dendritic cells undergoing stimulation in vivo. To test this hypothesis, an in vivo model of allergic contact dermatitis (ACD), known as contact hypersensitivity (CHS) was used. Dendritic cells are crucial during the sensitization phase of CHS. In this phase, chemical allergens, known as haptens, activate skin resident dendritic cells, prompting their migration to local lymph nodes where they promote robust T- cell responses through antigen presentation (Kaplan et al., 2012). To this end, the immunosuppressive effects of IBMECA-MPs on dendritic cells during the sensitization phase of ACD were assessed. Similar to a prior study, Blank- (containing no therapeutic drug) or IBMECA-MPs were subcutaneously injected at the base of the ear one day prior to topical sensitization with dinitrofluorobenzene (DNFB), a well-known chemical allergen in CHS (Kaplan et al., 2012; Balmert et al., 2017). Subcutaneous delivery of IBMECA-MPs enables local sequestration of IBMECA, reducing potential adverse systemic effects of the drug, such as increased risk of infection (David et al., 2016; Chen et al., 2024). Ear swelling measurements, indicative of inflammation, were taken immediately prior to sensitization and 24 hours after sensitization (Figure 12A). Overall, IBMECA-MPs reduced ear swelling 24 hours after sensitization when compared to Blank-MPs, indicating a therapeutic effect (Figure 12B). Following endpoint ear swelling measurements, ear draining cervical lymph nodes were harvested and enzymatically digested for flow cytometric analysis of dendritic cell populations (Figure 12A). Two distinct dendritic cell populations were analyzed: skin migratory dendritic cells (mDCs; CD11c+ MHCIIhigh) and lymph node resident dendritic cells (rDCs; CD11chighMHCII+). The gating strategy for these populations was based on previously published works (Gerner et al., 2012; Eisenbarth, 2019; Mani et al., 2019). Though IBMECA-MPs did not alter relative frequencies of mDCs or rDCs when compared to Blank-MPs, IBMECA-MPS did alter their phenotype (Figure 12C-E). For both mDCs and rDCs, IBMECA-MPs reduced CD40 expression (Figure 12D-E). These results are in accordance with in vitro results, where dendritic cells stimulated in the presence of IBMECA reduced expression of CD40 (Figure 10B). The pro-inflammatory role of CD40, and its ligand CD40L, is well-studied in the context of cancer, as many preclinical therapies target CD40 activation to increase anti-tumoral responses (Vonderheide, 2020). In other type IV hypersensitivities (e.g., graft rejection, multiple sclerosis, etc.), disrupting interactions between CD40 and CD40L has resulted in ACTIVE 130935777.2 51 072396.1066 PATENT positive therapeutic outcomes, including prolonged graft survival (graft rejection) and reduced lesions (multiple sclerosis) (Badell et al., 2012; Karnell et al., 2019; Perrin and Magill, 2022; Vermersch et al., 2024). Together, these studies, along with the present study, suggest that reducing CD40 expression could be beneficial in the context of contact hypersensitivity. Although IBMECA-MPs reduced CD40 expression on both dendritic cell subtypes, IBMECA-MPs increased CD86 expression on mDCs and reduced PDL1 expression on rDCs (Figure 12D-E). IBMECA-MPs did not alter expression of other co-stimulatory markers(Figure 30A-C). While increased expression of co-stimulatory molecules (e.g., CD86) andreduced expression of co-inhibitory molecules (e.g., PDL1) are typically associated with semi- mature or mature dendritic cell phenotypes, it is important to note that these populations have been reported to exhibit regulatory functions (e.g., decreased pro-inflammatory cytokine secretion), despite their phenotypical classification (Schmidt et al., 2012; Dudek et al., 2013). Future studies could explore the impact of IBMECA-MPs on the functional maturation status of these dendritic cell populations in vivo in an effort to increase mechanistic understanding. IBMECA-MPs increase ratio of regulatory T cells to effector T cells following sensitization Since subcutaneous administration of IBMECA-MPs impacted dendritic cell populations during sensitization, IBMECA-MPs may reduce ear swelling and T-cell responses during the late-stages of sensitization when compared to Blank-MPs. To test this hypothesis, Blank- or IBMECA-MPs were subcutaneously injected at the base of the ears one day prior to sensitization with DNFB (Figure 13A). Ear thickness measurements, indicative of inflammation, were taken immediately prior to sensitization and every 24 hours following for 5 days. Change in ear thickness (Δ Ear Thickness) was calculated for each time point to reflect differences in initial ear thickness measurements. Surprisingly, IBMECA-MPs significantly reduced ear swelling during the sensitization period when compared to Blank-MPs (Figure 13B), which is in accordance with IBMECA-MPs reducing ear swelling 24 hours after sensitization (Figure 12B). To assess potential differences in T-cell frequencies during sensitization, cervical draining lymph nodes (DLNs) and ear skin were harvested five days following sensitization and processed for flow cytometry. Flow cytometry analysis on DLNs revealed significant effects of IBMECA-MPs on T-cell populations. When compared to Blank-MPs, IBMECA- MPs significantly reduced the frequency of Th1 (CD4+ Tbet+) without changing populations of regulatory T cells (CD4+ Foxp3+) (Figure 13C, Figure 31A). IBMECA-MPs also reduced the frequency of Tc1s (CD8+ Tbet+) when compared to Blank-MPs (Figure 13D). Since ACTIVE 130935777.2 52 072396.1066 PATENT IBMECA-MPs reduced effector T cell populations (Teff; Th1, Tc1) without changing Treg populations, a significant increase in the ratio of Tregs / Teff was observed. More specifically, both Treg / Th1 and Treg / (Th1+Tc1) ratios were increased for IBMECA-MPs when compared to Blank-MPs (Figure 13E). Unlike in DLNs, IBMECA-MPs did not alter relative frequencies of T cell subtypes in ear skin (Figure 31B). One possible explanation for altered T-cell population frequencies is changes in their proliferation. For example, IBMECA-MPs can reduce proliferation of effector T cells in DLNs, leading to an increased ratio of Tregs to Teff. To test this hypothesis, cells from DLNs were stained for Ki67, a protein expressed in dividing cells, in addition to traditional T-cell markers (CD4, CD8, Tbet, Foxp3) (Gerdes et al., 1984). As expected, IBMECA-MPs significantly reduced frequencies of proliferating Th1 (Tbet+ Ki67+ of CD4+) populations when compared to Blank-MPs (Figure 14A). However, IBMECA-MPs did not significantly change proliferation of Tregs (Foxp3+ Ki67+ of CD4+) (Figure 14A). Furthermore, IBMECA-MPs significantly reduced frequencies of proliferating Tc1 (Tbet+ Ki67+ of CD8+) populations when compared to Blank-MPs (Figure 14B). Together, these results show that IBMECA-MPs reduce proliferation of effector T cell populations without changing proliferation of Tregs, leading to increases in the ratios of regulatory T cells to effector T cells during sensitization. IBMECA-MPs reduce ear swelling and inflammation after allergen challenge Since IBMECA-MPs reduced ear swelling and frequencies of effector T cells during sensitization, IBMECA-MPs may be able to reduce inflammation following a second allergen exposure (challenge). To test this hypothesis, previously sensitized mice were challenged with DNFB 10 days after initial sensitization (Figure 15A). Ear thickness measurements were taken immediately prior to challenge as well as daily after challenge. IBMECA-MPs significantly reduced ear swelling following challenge when compared to Blank-MPs (Figure 15B). Furthermore, histological evaluation of ear skin from two days after challenge revealed differences in tissue architecture between the two groups. More specifically, ear skin from Blank-MPs displayed increased epidermal thickness when compared to IBMECA-MPs and naïve skin (Figure 15C). Measurements of the epidermis confirmed these observations, as IBMECA-MPs significantly reduced epidermal thickness when compared to Blank-MPs (Figure 15D). Flow cytometric analysis also revealed differences in frequencies of multiple T-cell populations in DLNs. More specifically, IBMECA-MPs reduced frequencies of both Th1 (CD4+Tbet+) and Treg (CD4+Foxp3+) populations when compared to Blank-MPs (Figure 15E). Although insignificant, Tc1 (CD8+Tbet+) populations also slightly decreased in ACTIVE 130935777.2 53 072396.1066 PATENT response to IBMECA-MPs (Figure 15E). Altogether, IBMECA-MPs significantly reduced all examined T-cell populations when compared to Blank-MPs. In addition to DLNs, flow cytometric analysis of ear skin revealed some differences in frequencies of T-cell subtypes. IBMECA-MPs significantly reduced the relative frequency of CD8+ T cells in ear skin when compared to Blank-MPs (Figure 15F, Figure 32A). On the contrary, IBMECA-MPs did not alter the relative frequency of CD4+ T cells in ear skin (Figure 15F, Figure 32A). As a result, the overall ratio of CD4+ to CD8+ T cells in the skin was significantly increased for mice treated with IBMECA-MPs in comparison to Blank-MPs (Figure 15G). However, the relative frequencies of T cell subtypes within these populations (Treg, Th1, and Tc1) were not statistically different for IBMECA-MPs when compared to Blank-MPs (Figure 32B). While IBMECA-MPs did not reduce relative frequencies of specific T-cell subtypes within the skin (e.g., Th1, Tc1), the finding that IBMECA-MPs reduced overall CD8+ T cells in skin is significant given the role of CD8+ T cells in ACD. While both CD8+ and CD4+ T cells are involved ACD pathogenesis, CD8+ T cells are often recognized as the main effector T-cell population (Saint-Mezard et al., 2004; Vocanson et al., 2006, 2009). Prior studies have demonstrated the importance of CD8+ T cells in CHS. For instance, typical CHS responses (e.g., ear swelling) occurred in an in vivo model of CHS despite depletion of CD4+ T cells by anti-CD4 monoclonal antibody treatment (Vocanson et al., 2006). Therefore, by reducing the frequency of CD8+ T cells and increasing the ratio of CD4+ to CD8+ T cells, IBMECA-MPs reduced the main effector response in ear skin in CHS. Discussion Altogether, these results show that IBMECA and IBMECA-MPs exhibit immunosuppressive effects in vitro and in vivo in CHS, a murine model of ACD. In vitro, IBMECA reduced inflammatory cytokine secretion by antigen-presenting cells and expression of co-stimulatory receptors. At multiple timepoints in vivo, IBMECA-MPs reduced the inflammatory immune response associated with CHS. During sensitization, IBMECA-MPs reduced ear swelling, expression of co-stimulatory markers on the surface of both migratory and lymph node resident dendritic cells, proliferation of effector T cells (e.g., Th1, Tc1) in skin draining lymph nodes, and frequencies of effector T cells in draining lymph nodes. After allergen challenge, IBMECA-MPs reduced frequencies of multiple T-cell subtypes (e.g., Th1, Tregs, etc.) in draining lymph nodes and reduced frequencies of total CD8+ T cells in ear skin. Collectively, these findings support the development and first successful application of a novel strategy for the treatment of T-cell mediated inflammation associated with ACD. Furthermore, ACTIVE 130935777.2 54 072396.1066 PATENT sustained local delivery of IBMECA from MPs could be therapeutically advantageous for treatment of other inflammatory conditions (e.g., transplant rejection, rheumatoid arthritis, etc.), exemplifying the broader impacts of the IBMECA-MP platform. Example 3: Suppression of T-cell mediated inflammation through local delivery of ATP receptor antagonists and adenosine receptor agonists The present Example is directed to application of a novel microparticle-based controlled release systems that encapsulate and release (1) Ado signaling agonists (e.g., Piclidenoson / IB-MECA, Regadenoson) or (2) ATP signaling antagonists (e.g., JNJ-55308942) to suppress T-cell mediated inflammation. These microparticle-based systems allow sustained release of picogram / nanogram quantities of the encapsulated therapeutic agents over a period of days to weeks. Notably, these microparticle-based systems were able to impact T-cell responses in in vitro cell culture models and in vivo contact allergen mouse models. Results Effect of eATP receptor antagonist (JNJ-55308942) and adenosine agonists (IBMECA and Regadenoson) on antigen presenting cells in vitro Contact allergens, such as dinitrofluorobenzene (DNFB), are known to trigger immune responses that drive allergic contact dermatitis. The present disclosure demonstrated that the contact allergen, DNFB, induces eATP secretion from J774A.1 macrophages and DC2.4 dendritic cells in a dose-dependent manner (Figure 16A and 16B), thereby revealing a direct link between allergen exposure and heightened extracellular ATP levels produced by antigen presenting cells. This finding showed ATP signaling from antigen presenting cells, such as macrophages and dendritic cells, is a response associated with contact allergens. The present disclosure investigated the ability of the P2X7R antagonist, JNJ-55308942, and adenosine agonists, IBMECA and Regadenoson, to suppress inflammatory cytokine secretion from J774A.1 macrophages (Figure 17A and 17B) and DC2.4 dendritic cells (Figures 18A and 18B). Surprisingly, as showed in Figure 17A and 17B, JNJ-55308942, IBMECA, and Regadenoson all suppressed TNF^ secretion in macrophages stimulated with LPS in a dose dependent manner (Figure 17A) without impacting cell viability (Figure 17B). Similarly, JNJ- 55380942, IBMECA, and Regadenoson all suppressed secretion of TNF^ from dendritic cells stimulated with LPS in a dose dependent manner (Figure 18A) without impacting cell viability (Figure 18B). Therefore, JNJ-55308942, IBMECA and Regadenoson acts as a suppressor of pro-inflammatory responses in both macrophages and dendritic cells without impacting cell ACTIVE 130935777.2 55 072396.1066 PATENT viability. Moreover, the present disclosure investigated the ability of the P2X7R antagonist, JNJ- 55308942, and adenosine agonists, IBMECA and Regadenoson, to suppress the secretion of inflammatory cytokines, IL-1β and IL-10, from macrophages stimulated with LPS and ATP (LPS+ATP+ J774A.1 cells). Figure 19 demonstrated that JNJ-55308942 reduced secretion of IL-1β from stimulated macrophages in a dose dependent manner, with a lesser effect observed in IBMECA treated LPS+ATP+ J774A.1 cells. Interestingly, cells treated with Regadenoson demonstrated elevated secretion of IL-1β when treated with an intermediate concentration of Regadenoson. Further, JNJ-55308942 also promoted the secretion of the anti-inflammatory cytokine IL-10, where adenosine agonists IBMECA and Regadenoson showed no similar impact on IL-10 secretion (Figure 19). These observations demonstrated P2X7R antagonist JNJ-55308942 and adenosine agonist IBMECA suppressed pro-inflammatory cytokine IL-1β secretion in stimulated macrophage cells, where JNJ-55308942 uniquely promoted the secretion of anti-inflammatory cytokine IL-10. Taken together, ATP signaling from macrophage cells can be modulated by either a P2X7R antagonist or an adenosine agonist. Next, the impact of JNJ-55308942 and Regadenoson on reducing the expression of maturation markers on the surface of LPS stimulated DC2.4 dendritic cells was explored. Figures 20A-20C demonstrated LPS stimulated dendritic cells cultured in the presence of JNJ- 55308942 (Figure 20B) or Regadenoson (Figure 20A and 20C) exhibited significantly reduced expression of maturation markers CD80 and CD86 when compared to dendritic cells stimulated in the absence of JNJ-55308942 (Figure 20B) or Regadenoson (Figure 20C). These results demonstrated that JNJ-55308942 and Regadenoson can reduce the immunostimulatory capacity of dendritic cells. Effect of eATP receptor antagonist (JNJ-55308942) and adenosine agonists (IBMECA and Regadenoson) on T-cell proliferation and differentiation To investigate the effect of eATP P2X7R receptor antagonist JNJ-55308942 on T cell responses to polarizing cytokines, markers for T cell proliferation and differentiation were measured. Figure 21A demonstrates the percentage of Foxp3+CD4+ T cells with low levels of CFSE dye increased when cultured in the presence of JNJ-55308942 in a dose dependent manner, which indicates an increased population of proliferating cells. Contrarily, Figure 21B showed the percentage of Tbet+CD4+ T cells with low levels of CFSE dye were marginally reduced when cultured in the presence of JNJ-55308942. These observations indicate specific subpopulations of CD4+ T cells exhibited increased proliferation as response to JNJ-55308942. Additionally, the effect of JNJ-55308942, IBMECA, and Regadenoson on impacting ACTIVE 130935777.2 56 072396.1066 PATENT Th1 (Tbet+CD4+) cell differentiation and proliferation in the presence of polarizing cytokines IL-2 and IL-12 was evaluated (Figure 22A and 22B). The percentage of Tbet+CD4+ T cells was unchanged when cultured in the presence of JNJ-55308942, IBMECA, or Regadenoson, indicating Th1 cell differentiation was not impacted by these small molecules (Figure 22A). Furthermore, JNJ-5530894 or Regadenoson, did not impact the percentage of Tbet+CFSElow cells, indicating proliferation of this cell population was unaffected (Figure 22B). Surprisingly, cells treated with 10 µM IBMECA exhibited a significant reduction in Tbet+CFSElowcells, demonstrating IBMECA suppresses Th1 cell proliferation (Figure 22B). These findings demonstrate that P2X7R antagonist (JNJ-55308942) and adenosine agonist (IBMECA or Regadenoson) do not suppress Th1 differentiation in IL2 / IL12 stimulated T cells. Effect of microparticle delivery system on regulating CHS inflammation in vivo by delivery of eATP receptor antagonist (JNJ-55308942) or adenosine receptor agonist (Regadenoson) In the present disclosure, microparticles injected into a mouse were evaluated for trafficking to the draining lymph nodes within 96 hours after injection. Microparticles with a small diameter (1.66 ± 0.09 µm) were detected in the lymph node (Figure 23), indicating clearance through the lymphatic system. Surprisingly, no microparticles with a mean diameter of 7.67 ± 0.33 µm were trafficked to the draining lymph node (Figure 23). This finding shows microparticles with a diameter larger than approximately 7.35 µm are not readily cleared from the animal through the lymphatic system. To investigate how microparticles impact dendritic cells after exposure to a contact allergen, microparticles were injected into tissue at the base of an ear one day prior to sensitization with DNFB (see Figure 24A for experimental timeline). An analysis on tissue responses, including measuring ear thickness at the sensitization site, was performed (Figure 24A). To accurately assess how microparticles impact dendritic cells after sensitization with DNFB, a flow cytometry gating procedure was standardized (Figure 24B and 24C). Migratory dendritic cells and lymph node resident (LN) dendritic cells were identified after ear skin sensitization with DNFB by first gating on single cells as determined by the scatter profile observed in the sample (Figure 24B). The single cell population in the sample was further gated on FVDlowand CD83 positive cells (Figure 24C). From this subpopulation of single cells, CD11c+ cell population was gated to quantify LN resident dendritic cells and IAb+ cell population was gated to quantify migratory dendritic cells (Figure 24C). The effect of JNJ-MPs on inflammatory responses within 24 hours after exposure to a contact allergen was then assessed using a CHS model. Figure 25A demonstrated no significant ACTIVE 130935777.2 57 072396.1066 PATENT differences in ear thickness were observed when comparing animals treated with Blank-MPs or JNJ-MPs after 24 hours sensitization with DFNB. Further, JNJ-MPs did not modulate the expression of surface marker proteins in migratory or LN dendritic cells following 24 hours after sensitization with DNFB (Figure 25B). Only cell surface protein CD83 was increased in the population of migratory dendritic cells (Figure 25B). Taken together, JNJ-MPs did not modulate the expression of surface markers on dendritic cells following sensitization after 24 hours. Next, the impact of JNJ-MPs on ear swelling and T cell responses after 5 days of sensitization with DNFB was evaluated (see Figure 26A for experimental timeline). Figure 26B showed no significant difference in ear swelling in animals treated with Blank-MPs and JNJ- MPs during 5 days of sensitization with DNFB. After a 5-day CHS sensitization treatment with DNFB, mice treated with JNJ-MPs exhibited an increase in the percentage of CD4+ T cells and a decrease in the percentage of Tbet+CD4+ T cells relative to control mice receiving Blank- MPs (Figure 26C). However, the percentage of Foxp3+CD4+ cells and the ratio of Treg:Teff cells were unchanged in animals treated with JNJ-MPs relative to control animals receiving Blank-MPs (Figure 26C). Figure 26D showed that T cells in sensitized ear skin of mice treated with JNJ-MPs exhibited a significant reduction in cell proliferation in Foxp3+CD4+, Tbet+CD4+, Foxp3+CD8b+, and Tbet+CD8b+ T cells relative to animals treated with Blank- MPs. These observations showed animals treated with JNJ-MPs suppress inflammatory response of T cells within the tissue of the CHS model. The present disclosure investigated the impact of JNJ-MPs on ear swelling and the expression of genes associated with inflammation in ear skin tissue after a secondary challenge with DNFB. As shown in Figure 27A, mice previously sensitized DNFB were challenged with a secondary exposure to DNFB at 10 days after the initial sensitization. No significant difference in ear thickness was observed in animals treated with Blank-MPs and JNJ-MPs at 1 day and 2 days after challenge with DNFB, although animals treated with JNJ-MPs showed a marginal reduction in ear thickness relative to animals treated with Blank-MPs at 1 day after challenge (Figure 27B). However, this finding was not statistically significant. Expression of genes associated with inflammation was then measured in challenged ear skin from animals treated with JNJ-MPs. Samples from animals that received JNJ-MPs exhibited a significant reduction of Nfkb1 gene expression when compared to challenged ear tissue from control animals receiving Blank-MPs (Figure 27C). Moreover, challenged ear skin samples from animals receiving JNJ-MPs exhibited a marginal reduction in Tnfa and Il1b gene expression relative to the challenged ear tissue from control animals treated with Blank-MPs (Figure 27C). ACTIVE 130935777.2 58 072396.1066 PATENT However, these differences were not statistically significantly different. Overall, these findings implicated JNJ-MPs as a modulator of the inflammatory response within a tissue challenged with a contact allergen. Next, the impact of REG-MPs on inflammatory responses after 24 hours post- sensitization was investigated in a CHS model following the experimental timeline showed in Figure 28A. Animals treated with REG-MPs did not exhibit a significant reduction in ear thickness after 24 hours sensitization with DFNB when compared to control animals treated with Blank-MPs (Figure 28B). The effect of REG-MPs on modulating the response of dendritic cells in the CHS model was then assessed. For migratory dendritic cells, REG-MP did not alter the expression of any of the tested cell surface markers (CD40, CD80, CD86, PDL1, and CD83) relative to control (Figure 28C). Similarly, the expression of CD80, CD86, PDL1, and CD83 cell surface markers in lymph node resident dendritic cells were not altered in animals treated with REG-MPs relative to control animals treated with Blank-MPs. Surprisingly, CD40 expression in lymph node resident dendritic cells was significantly reduced in animals treated with REG-MPs when compared to control animals (Figure 28C) within 24 hours after sensitization with DNFB. Therefore, REG-MPs can suppress inflammatory response in tissues in contact with an allergen. The present disclosure explored the impact of REG-MPs on inflammatory responses in a CHS model during 5 days sensitization with DNFB following the experimental timeline showed in Figure 29A. Animals treated with REG-MPs did not exhibit a significant reduction in ear thickness during 5 days sensitization with DFNB when compared to control animals treated with Blank-MPs (Figure 29B). Figure 29C demonstrated mice treated with REG-MPs exhibited a reduction in the percentage of Tbet+CD4+ and Tbet+CD8b+ T cells present in ear tissue during a 5-day CHS sensitization treatment relative to the levels observed in animals treated with Blank-MPs. However, no significant differences were observed for the percentage of CD4+ cells, Foxp3+CD4+, or the percentage of CD8b+ cells when comparing tissue samples collected from animals treated with Blank-MPs and REG-MPs (Figure 29C). Figure 29D showed samples collected from animals treated with REG-MPs exhibited a significant increase in the ratio of Treg:Th1 cells and a marginal increase of Treg:Th1+Tc1 ratio relative to samples isolated from animals treated with Blank-MPs. These observations showed REG-MPs promoted a reduction in the percentage of Th1 and Tc1 cell populations, which was associated with an increased ratio of Tregs and reduced inflammation in ear skin tissue after sensitization. Discussion The present example showed the modification of ATP / adenosine signaling using ACTIVE 130935777.2 59 072396.1066 PATENT controllable release systems. The controlled release systems encapsulated and released (1) adenosine signaling agonists (e.g., IBMECA and Regadenoson) or (2) ATP signaling antagonists (e.g., JNJ-55308942). The use of these drugs was explored in novel conditions, including a CHS model. 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Immunopharmacol.140, 112729. * * * Although the presently disclosed subject matter and its advantages have been described in detail, it should be understood that various changes, substitutions, and alterations can be made herein without departing from the spirit and scope of the present disclosure. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, and compositions of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the present disclosure of the presently disclosed subject matter, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein can be utilized according to the presently disclosed subject matter. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps. Various patents, patent applications, publications, product descriptions, protocols, and sequence accession numbers are cited throughout this application, this present disclosures of which are incorporated herein by reference in their entireties for all purposes. ACTIVE 130935777.2 63

Claims

072396.1066 PATENT WHAT IS CLAIMED IS:

1. A method of treating an inflammatory disease and / or reducing inflammation in asubject in need thereof, the method comprising administering to the subject an effective amount of a microparticle or a composition thereof, wherein the microparticle is a controlled release microparticle comprising an ATP signaling antagonist, an adenosine receptor agonist, or a combination thereof.

2. The method of claim 1, wherein the adenosine signaling agonist is selected frompiclidenoson (IB-MECA), regadenoson, adenosine, Cl-IB-MECA, dipyridamole, CGS- 21680, or 5'-N-ethylcarboxamidoadenosine.

3. The method of claim 1 or 2, wherein the adenosine signaling agonist is piclidenoson(IB-MECA) or a derivative thereof.

4. The method of any one of claims 1-3, wherein the adenosine signaling agonist isregadenoson or a derivative thereof.

5. The method of any one of claims 1-4, wherein the ATP signaling antagonist is a P2X7receptor antagonist.

6. The method of any one of claims 1-5, wherein the ATP signaling antagonist is selectedfrom JNJ-55308942, A438079, brilliant blue G (BBG), AZ11645373, JNJ-47965567, CE-224,535, oxidized ATP, Pyridoxal Phosphate-6-Azophenyl-2',4'-Disulfonic Acid, or Suramin.

7. The method of any one of claims 1-6, wherein the ATP signaling antagonist is JNJ-55308942 or a derivative thereof.

8. The method of any one of claims 1-7, wherein the ATP signaling antagonist is A438079or a derivative thereof.

9. The method of any one of claims 1-8, wherein the microparticle further comprises atherapeutic agent that modulates immune-related blood cells.

10. The method of any one of claims 1-9, wherein the microparticle is a sustained releasemicroparticle.

11. The method of any one of claims 1-9, wherein the microparticle is a delayed releasemicroparticle.

12. The method of any one of claims 1-9, wherein the microparticle is a long-term releasemicroparticle.

13. The method of any one of claims 1-12, wherein the diameter of the microparticle is upto about 100 µm. ACTIVE 130935777.2 64072396.1066 PATENT14. The method of claim 13, wherein the diameter of the microparticle is larger than about1 µm.

15. The method of any of claims 1-14, wherein the composition comprises apharmaceutically acceptable carrier.

16. The method of claim 1-15, wherein the composition further comprises a secondmicroparticle comprising a therapeutic agent that modulates immune-related blood cells.

17. The method of claim 16, wherein the therapeutic agent that modulates immune-relatedblood cells is IL-2, TGF-β, CCL22, IL-33, rapamycin, or a combination thereof.

18. The method of claim 16 or 17, wherein the second microparticle is a sustained releasemicroparticle, a delayed release microparticle, or a long-term release microparticle.

19. The method of any one of claims 1-18, wherein the composition further comprises athird microparticle comprising a therapeutic agent that modulates immune-related blood cells.

20. The method of claim 19, wherein the therapeutic agent that modulates immune-relatedblood cells is IL-2, TGFβ, CCL22, IL-33, rapamycin, or a combination thereof.

21. The method of claim 19 or 20, wherein the third microparticle is a sustained releasemicroparticle, a delayed release microparticle, or a long-term release microparticle.

22. The method of any one of claims 1-21, wherein the inflammatory disease is aninflammatory disease associated with an autoimmune disease, a central nervous system (CNS) inflammatory disease, a joint inflammation disease, an inflammatory digestive tract disease, inflammatory skin and other inflammatory diseases related to epithelial cells, inflammation associated with cancer, inflammation associated with irritation, or inflammation associated with injury.

23. The method of claim 1-22, wherein the inflammatory disease is selected frominflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Alzheimer's disease, Parkinson, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, Sjogren's syndrome, bronchitis, asthma, or inflammation associated with cancer.

24. The method of claim 22 or 23, wherein the inflammatory disease is dermatitis.

25. The method of any one of claims 22-24, wherein the dermatitis is an allergic contactdermatitis.

26. The method of claim 1-21, wherein the subject has received or is receiving a transplant.

27. The method of claim 26, wherein the subject is at risk of transplant rejection.ACTIVE 130935777.2 65072396.1066 PATENT28. The method of claim 26 or 27, wherein the transplant is a tissue transplant.

29. The method of claim 28, wherein the tissue transplant is a skin transplant or avascularized composite transplant.

30. The method of any one of claims 1-29, wherein the microparticle or composition thereofis administered at an amount from about 0.01 µg to about 100 g per kg of body weight of the subject.

31. The method of any one of claims 26-30, wherein the microparticle or compositionthereof is administered once or more daily, weekly, monthly, or yearly.

32. The method of any one of claims 26-31, wherein the microparticle or compositionthereof is orally, subcutaneously, transdermally, topically, pulmonary inhalation, or parenterally administered.

33. A controlled release microparticle comprising an ATP signaling antagonist, anadenosine receptor agonist, or a combination thereof.

34. The microparticle of claim 33, wherein the adenosine signaling agonist is selected frompiclidenoson (IB-MECA), regadenoson, adenosine, Cl-IB-MECA, dipyridamole, CGS- 21680, or 5'-N-ethylcarboxamidoadenosine.

35. The microparticle of claim 33 or 34, wherein the adenosine signaling agonist ispiclidenoson (IB-MECA) or a derivative thereof.

36. The microparticle of any one of claims 33-35, wherein the adenosine signaling agonistis regadenoson or a derivative thereof.

37. The microparticle of any one of claims 33-36, wherein the ATP signaling antagonist isa P2X7 receptor antagonist.

38. The microparticle of any one of claims 33-37, wherein the ATP signaling antagonist isselected from JNJ-55308942, A438079, brilliant blue G (BBG), AZ11645373, JNJ- 47965567, CE-224,535, oxidized ATP, Pyridoxal Phosphate-6-Azophenyl-2',4'- Disulfonic Acid, or Suramin.

39. The microparticle of any one of claims 33-38, wherein the ATP signaling antagonist isJNJ-55308942 or a derivative thereof.

40. The microparticle of any one of claims 33-39, wherein the ATP signaling antagonist isA438079 or a derivative thereof.

41. The microparticle of any one of claims 33-40, wherein the microparticle furthercomprises a therapeutic agent that modulates immune-related blood cells.

42. The microparticle of any one of claims 33-41, wherein the microparticle is a sustainedrelease microparticle. ACTIVE 130935777.2 66072396.1066 PATENT43. The microparticle of any one of claims 33-41, wherein the microparticle is a delayedrelease microparticle.

44. The microparticle of any one of claims 33-41, wherein the microparticle is a long-termrelease microparticle.

45. The microparticle of any one of claims 33-44, wherein the diameter is up to about 100µm.

46. The microparticle of claim 45, wherein the diameter is larger than about 1 µm.

47. A composition comprising a microparticle of any one of claims 33-46.

48. The composition of claim 47, wherein the composition comprises a pharmaceuticallyacceptable carrier.

49. The composition of claim 47 or 48, wherein the composition further comprises a secondmicroparticle comprising a therapeutic agent that modulates immune-related blood cells.

50. The composition of claim 49, wherein the therapeutic agent that modulates immune-related blood cells is IL-2, TGF-β, CCL22, IL-33, rapamycin, or a combination thereof.

51. The composition of claim 49 or 50, wherein the second microparticle is a sustainedrelease microparticle, a delayed release microparticle, or a long-term release microparticle.

52. The composition of any one of claims 49-51, wherein the composition furthercomprises a third microparticle comprising a therapeutic agent that modulates immune- related blood cells.

53. The composition of claim 52, wherein the therapeutic agent that modulates immune-related blood cells is IL-2, TGFβ, CCL22, IL-33, rapamycin, or a combination thereof.

54. The composition of claim 52 or 53, wherein the third microparticle is a sustained releasemicroparticle, a delayed release microparticle, or a long-term release microparticle.

55. The microparticle of any one of claims 33-46 or the composition of any one of claims47-54 for use in treating an inflammatory disease in a subject in need thereof.

56. The microparticle or the composition for use of claim 55, wherein the subject hasreceived or is receiving a transplant.

57. The microparticle or the composition for use of claim 55 or 56, wherein the subject isat risk of transplant rejection.

58. The microparticle or the composition for use of claim 56 or 57, wherein the transplantis a tissue transplant.

59. The microparticle or the composition for use of claim 58, wherein the tissue transplantACTIVE 130935777.2 67072396.1066 PATENT is a skin transplant or a vascularized composite transplant.

60. The microparticle or the composition for use of any one of claims 55-59, wherein themicroparticle and / or composition is administered at an amount from about 0.01 µg to about 100 g per kg of body weight of the subject.

61. The microparticle or the composition for use of any one of claims 55-60, wherein themicroparticle and / or composition is administered once or more daily, weekly, monthly, or yearly.

62. The microparticle or the composition for use of any one of claims 55-61, wherein themicroparticle and / or composition is orally, transdermally, topically, pulmonary inhalation, or parenterally administered. ACTIVE 130935777.2 68

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