Use of tam receptor inhibitors as immunoenhancers and tam activators as immunosuppressors

a technology of tam receptor and inhibitor, which is applied in the field of immunoenhancement or immunosuppression, can solve the problems of compromising the ability to eradicate primary infections, unable to kill pathogens used in traditional vaccines, and immunocompromised people are very vulnerable to opportunistic infections, etc., to suppress the immune response, increase or enhance the activity of tam receptor, and suppress the immune response

Inactive Publication Date: 2010-10-21
SALK INST FOR BIOLOGICAL STUDIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, they lack the immunogenecity of the whole, killed pathogens used in traditional vaccines.
Patients with severe sepsis often also exhibit immunosuppression, which compromises their ability to eradicate the primary infection and predisposes them to secondary opportunistic and / or nosocomial infections.
Immunodeficiency can be either congenital or acquired, and an immunocompromised person is very vulnerable to opportunistic infections.
In addition, organ rejection following transplantation often is initiated by immune inflammation.

Method used

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  • Use of tam receptor inhibitors as immunoenhancers and tam activators as immunosuppressors
  • Use of tam receptor inhibitors as immunoenhancers and tam activators as immunosuppressors
  • Use of tam receptor inhibitors as immunoenhancers and tam activators as immunosuppressors

Examples

Experimental program
Comparison scheme
Effect test

example 1

Materials and Methods

[0316]This Example describes materials and methods that were used in performing Examples 2-9. Although particular methods are described, one of skill in the art will understand that other, similar methods also can be used.

Mice

[0317]C57BL / 6J mice were purchased from The Jackson laboratory, and STAT1 knock-out mice and genetically matched controls were purchased from Taconic. The mutations in the Tyro3− / −, Axl− / − Mer− / − and Ifnar1 mice have been described previously Lu et al., (1999) Nature 398, 723-728; Muller et al. (1994) Science 264, 1918-1921).

Antibodies

[0318]Axl (M-20), IκBβ (C-20), TRAF6, TRAF3, IFNAR1, and IFNAR2 antibodies were obtained from Santa Cruz Biotechnology; phospho-STAT1 Tyr 701, -STAT2 Tyr690, STAT3 Tyr705, STAT1, STAT2, STAT3, IκBα, phospho-P38 Thr180 / Tyr 182, β-actin, and ERK 1 / 2 antibodies were obtained from Cell Signaling Technology; phospho-ERK1 / 2 Thr183 / Tyr185, β-tubulin and ubiquitin antibodies were purchased from Sigma; and p38α and IFN...

example 2

Dendritic Cell Hyper-Activation and Expansion in TAM Triple Knock-Outs

[0329]This Example demonstrates dendritic cell hyper-activation and expansion in TAM triple knock-outs. The immune system phenotypes of TAM TKOs indicated that their autoimmune syndromes might be due to abnormalities in APC physiology (Lu & Lemke (2001) Science 293:306-311). Therefore, the status of the DC subset of professional APCs was assessed in TAM TKO spleens. The percentage of splenic CD11c+ cells was markedly elevated in TAM TKOs relative to wild-type (WT), as was the absolute number of CD11c+ cells (FIGS. 1A, 1B). Splenic DCs were also hyperactivated in the triple mutants. CD11c+ DCs in TAM TKOs expressed higher levels of MHC class I and class II (FIG. 1C), and BAFF / BlyS (FIG. 1D), which is elevated in patients with autoimmune diseases such as SLE (Collins et al., (2006) Arthritis Res Ther 8:R6).

[0330]TAM TKO CD11c+ DCs express super-elevated levels of MHC class II and B7.2 in response to intraperitoneal ...

example 3

TAM Receptor Activation Inhibits TLR-Induced Cytokine Production in DCs

[0331]This Example demonstrates that TAM receptor agonists inhibit TLR-driven cytokine production in WT DCs. Given the results described in Example 2, it was determined whether treatment with TAM receptor agonists might inhibit TLR-driven cytokine production in WT DCs. Analyses were performed in both splenic CD11c+ DCs, and in DCs differentiated from mouse bone marrow (BM) in the presence of FLT-3 ligand (Gilliet et al., (2002) J Exp Med 195:953-958).

[0332]In both DC populations, the major TAM receptors expressed were Axl and Mer (FIG. 1G), with no detectable Tyro 3. The TAM receptors are activated by the binding of two closely-related, soluble ligands—Gas6 and Protein (ProS; Prasad et al., (2006) Mol Cell Neurosci 33: 96-108; Stitt et al., (1995) Cell 80: 661-670). Overnight (15 hours) co-incubation of recombinant Gas6 with CpG substantially inhibited TLR9-induced production of Type I IFNs, IL6, and TNFα in wild...

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Abstract

This disclosure concerns compositions and methods for immunoenhancement and / or immunosuppression. In certain embodiments, the disclosure concerns methods of using a TAM receptor inhibitor for immunoenhancement, for example as a vaccine adjuvant, for the treatment of sepsis, or for treating an immunocompromised subject. Also disclosed are methods of screening for immunoenhancing agents. In other embodiments, the disclosure concerns methods of using a TAM receptor agonist for immunosuppression, for example as a treatment for an autoimmune disorder, for the treatment of an allergy, or for treating graft-versus-host disease in a subject. Also disclosed are methods of screening for immunosuppressive agents.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 60 / 986,984, filed on Nov. 9, 2007, U.S. Provisional Application No. 61 / 013,598, filed on Dec. 13, 2007, and 61 / 083,462 filed on Jul. 24, 2008 each of which is incorporated herein by reference in its entirety.FIELD OF THE DISCLOSURE[0002]This disclosure concerns compositions and methods for immunoenhancement or immunosuppression. In certain embodiments, the disclosure concerns methods of using a Tyro 3, Axl, and Mer (TAM) receptor inhibitor for immunoenhancement, for example as a vaccine adjuvant, or for the treatment of sepsis or other disorder where immunoenhancement is desired. In other embodiments, the disclosure concerns methods of using a TAM receptor agonist for immunosuppression, for example for the treatment of autoimmune diseases, post-transplant immunosuppression, or for the treatment of other disorders where immunosuppression is desired.BACKGROUND[0003]Ther...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K39/00G01N33/574A61P35/00A61P31/00A61P37/00
CPCA61K31/519A61K39/3955A61K31/4196A61P1/04A61P17/06A61P19/02A61P21/02A61P25/00A61P27/02A61P29/00A61P31/00A61P31/04A61P31/12A61P33/00A61P35/00A61P37/00A61P37/04A61P37/06A61P37/08A61P43/00A61P7/06A61P3/10Y02A50/30
Inventor ROTHLIN, CARLA V.LEMKE, GREG E.
Owner SALK INST FOR BIOLOGICAL STUDIES
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