Immunomodulatory agent and uses therefor

A technology for inhibitors and joint damage, applied in the field of immunomodulators and their uses, can solve problems such as proving citrulline

Inactive Publication Date: 2015-04-15
THE UNIV OF QUEENSLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite these transgenic mouse studies, it has been difficult to demonstrate citrulline-specific autoreactive T cells in RA patients due to the weak proliferative responses mounted by autoreactive effector memory T cells in vitro

Method used

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  • Immunomodulatory agent and uses therefor
  • Immunomodulatory agent and uses therefor
  • Immunomodulatory agent and uses therefor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0446] T cells proliferate inadequately but produce cytokines in response to citrullinated autoantigen peptides

[0447] Based on the predicted binding capacity to RA-associated DR molecules in molecular models of P4-localized citrulline, or through previous studies in HLA-DR4-IE-transgenic mice, established fibrinogen, vimentin, Synthesis of citrullinated or unmodified peptide antigens from collagen and aggrecan protein sequences (Table 5) (Hida et al., 2004.J.Autoimmun.23:141-150; Hill J et al., 2008.J.Exp.Med 205:967-979; von Delwig et al., 2010. Arthritis Rheum. 62:143-149).

[0448] Table 5. Sequences of the peptides used in the examples

[0449]

[0450] A total of 21 cases of SE were studied + RA patient and 6 SE + healthy controls. All but 4 RA patients were also ACPA +(Table 6). Forty-three percent of RA patients were non-smokers, 38% were past smokers, and 19% were current smokers. One healthy control is a current smoker, and 2 healthy controls have a famil...

Embodiment 2

[0453] IL-6 response changes with disease duration in RA patients

[0454] To better understand individual RA patients and SE + Citrullinated Peptide Response Patterns of Healthy Controls, IL-6 dose response curves for each peptide were plotted for each individual in the study. PBMCs from 4 / 6 healthy controls secreted IL-6 in a dose-dependent manner in response to citrullinated aggrecan, and 3 / 6 secreted IL-6 in response to citrullinated fibrinogen. Using the same thresholds for positive responses as described above, it was found that of the 17 PBMC responses from RA patients, 6 secreted IL-6 in no response to the epitope, 8 responded only to citrullinated aggrecan, and 0 responded Citrullinated fibrinogen, 0 cases responded only to citrullinated type II collagen, and 3 cases responded to multiple citrullinated epitopes. therefore. IL-6 responses to citrullinated aggrecan were highest and most frequently observed in RA patients and healthy controls, suggesting that this was...

Embodiment 3

[0456] effector memory CD4 + T cells secrete cytokines in response to citrullinated peptides

[0457] IL-6 is an important cytokine in RA, which is produced when PMBCs are stimulated by T cells or antigen-presenting cells. To determine the source of cytokines secreted into the supernatants of citrullinated peptide-stimulated PBMCs, RA PBMCs were incubated with citrullinated or native peptides for 5 days prior to intracellular cytokine staining and analysis of cell surface markers , and Brefeldin-A was added for the last 18 hours. When incubated with citrullinated aggrecan or fibrinogen, CD3 + CD4 + T cells produce more intracellular IFN-γ and IL-6 ( Figure 6 A, B). Fluorescence compensated control (FMO) staining demonstrated a gating strategy to determine the threshold for positive staining as described (Herzenberg et al., 2006. Nat Immunol 7(7):681-685) ( Figure 6 C). CD4 - CD28 - In these assays performed on cells (the majority of which represent antigen-presentin...

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Abstract

Disclosed are immunomodulatory agents that are useful for treating or preventing joint damage. More particularly, immunomodulators are disclosed for use in eliciting an antigen-specific tolerogenic response to an aggrecan polypeptide including citrullinated forms thereof to treat or prevent joint damage, including joint damage in subjects with early RA or incipient RA.

Description

[0001] This application claims priority to Australian Provisional Application No. 2012901189, entitled "Immunomodulatory Agents and Uses Therefor", filed 23 March 2012, the entire contents of which are incorporated herein by reference. technical field [0002] The present invention generally relates to immunomodulators useful in the treatment or prevention of joint damage. In particular, the invention relates to the treatment or prevention of joint damage (including joint injuries). Background technique [0003] Inflammatory arthritis is a major clinical manifestation of several autoimmune diseases, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE), Sjogren's syndrome, and Polymyositis. On physical examination, most of these patients have joint deformities, but usually only patients with RA and PsA show bone erosions on imaging studies. [0004] The pathogenesis of chronic inflammatory bone diseases such as RA has not been ...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61K38/39A61P19/02
CPCA61K38/00A61K39/0008A61K31/09A61P19/02A61P29/00A61P43/00A61K9/127A61K39/0005
Inventor R·托马斯
Owner THE UNIV OF QUEENSLAND
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