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Targeting the innate immune system to induce long-term tolerance and to resolve macrophage accumulation in atherosclerosis

a technology of atherosclerosis and innate immune system, which is applied in the direction of immunosuppressive agents, drug compositions, microcapsules, etc., can solve the problems of no alternative regimen seriously challenged the almost universal use of immunosuppressive agents, and all immunosuppressive agents have serious adverse effects, so as to prolong the survival of allografts and reduce the stimulatory capacity of dendritic cells

Inactive Publication Date: 2019-09-26
MT SINAI SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present patent is about a method for using a composition containing nanoparticles to slow down the progression of atherosclerosis and improve the survival of allografts in patients. The nanoparticles in the composition target specific cells and reduce their numbers in the patient's circulation. This approach has the potential to reduce the risk of rejection and improve the overall outcomes of transplantation procedures.

Problems solved by technology

However, all immunosuppressive agents have serious adverse effects, such as infections, and considerable metabolic toxicity4.
Despite efforts to use currently available immunosuppressive agents in less toxic ways, no alternative regimen has seriously challenged these drugs' almost universal use.
However, the induction of transplantation tolerance achieved in murine models cannot be fully explained by mechanisms that target only the adaptive immunity, such as deletion of activated T cells5-7.
However, the innate immune system is a potential in vivo therapeutic target that has not been successfully explored in organ transplantation.
However, use of this drug is associated with severe side effects 19,20, including increased infection susceptibility.
Experimental antibodies targeting the innate immune system have been shown to induce long-term tolerance, with severe side effects.

Method used

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  • Targeting the innate immune system to induce long-term tolerance and to resolve macrophage accumulation in atherosclerosis
  • Targeting the innate immune system to induce long-term tolerance and to resolve macrophage accumulation in atherosclerosis
  • Targeting the innate immune system to induce long-term tolerance and to resolve macrophage accumulation in atherosclerosis

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example 1

[0190]Development of mTOR-HDL Nanoparticles

[0191]mTOR-HDL nanoparticles (see FIG. 1A) were synthesized by hydrating a lipid film, containing rapamycin and phospholipids, with APOA1 in PBS. Subsequently, and after vigorous homogenization, the sample was sonicated to generate mTOR-HDL nanoparticles with 62±11% rapamycin encapsulation efficiency and a mean hydrodynamic diameter of 12.7±4.4 nm, as determined by high performance liquid chromatography and dynamic light scattering, respectively. The size of the nanoparticles can vary, but will typically be from about 10 nm to about 250 nm.

[0192]As revealed by transmission electron microscopy (FIG. 4), the mTOR-HDL had the discoidal structure that is typical of HDL-based nanoparticles16. The biodistribution and cellular specificity of 1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindotricarbocyanine Iodide (DiR)-labeled mTOR-HDLs were evaluated in C57Bl / 6 wild type mice using ex vivo near infrared fluorescence (NIRF) imaging and flow cytometry. mTO...

example 2

Targeted CD40-TRAF6 Inhibition Resolves Macrophage Accumulation in Atherosclerosis

[0285]In atherosclerosis, macrophage accumulation is directly linked to destabilization and rupture of plaque, causing acute atherothrombotic events. Circulating monocytes enter the plaque and differentiate into macrophages, where they are activated by CD4+ T lymphocytes through CD40-CD40 ligand signaling. Here we show that interruption of this signaling pathway in monocytes / macrophages exerts rapid anti-inflammatory effects in an ApoE− / − mouse model of atherosclerosis. For this purpose we developed an infusible reconstituted high-density lipoprotein nanoparticle carrying a small molecule inhibitor of the interaction of CD40 and tumor necrosis factor receptor-associated factor 6. We show monocyte / macrophage specific targeting of our nanoimmunotherapy, which impairs their migratory capacity. Rapid reduction of plaque inflammation by this therapy represents a novel strategy in the treatment of atheroscle...

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Abstract

Methods and compositions for inducing long-term tolerance by hybrid nanoparticles are provided. Compositions and formulations comprising hybrid nanoparticles with inherent affinity for innate immune cells are provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This present application claims priority to U.S. Provisional Patent Application Ser. No. 62 / 329,676 filed Apr. 29, 2016, which is incorporated herein by reference in its entirety.GOVERNMENT SUPPORT[0002]This invention was made with government support under grants R01 HL118440, R01 HL125703, R01 CA155432, R01 EB009638, K25 EB016673, and P30 CA008748 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]Methods and compositions for inducing long-term tolerance by hybrid nanoparticles are provided. Compositions and formulations comprising hybrid nanoparticles with inherent affinity for innate immune cells are provided.BACKGROUND[0004]Indefinite allograft survival remains an elusive goal in organ transplantation. Transplantation requires suppression of the immune system to prevent organ rejection. Patients undergoing organ transplantation usually receive an immunosuppressi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/51A61K38/13A61K31/436A61K9/00A61P37/06
CPCA61K9/5169A61P37/06A61K9/0019A61K31/436A61K38/13A61K9/1275A61K9/5123A61K45/06A61K51/1224
Inventor MULDER, WILLEMOCHANDO, JORDIFAYAD, ZAHIBRAZA, MOUNIADUIVENVOORDEN, RAPHAELFAY, FRANCOIS
Owner MT SINAI SCHOOL OF MEDICINE