Chimeric human leukocyte antigen and epitope-bearing molecules having immunosuppressant activity

Abstract

The present invention relates to chimeric molecules that comprise human major histocompatibility complex elements, linked to epitopes of interest, that have been joined together to form dimers or higher multimers. Such chimeric molecules may be used to treat or prevent diseases associated with autoimmunity, particularly diabetes. It is based, at least in part, on the discovery that a chimeric molecule comprising an IILA-DR element linked to an epitope of GAD65, an antigen associated with autoimmune diabetes, stimulated the secretion of the inhibitory cytokine IL-10 from CD4 T cells of Type I diabetic patients.

Description

1. INTRODUCTION[0001] The present invention relates to chimeric molecules that comprise human major histocompatibility complex elements, linked to epitopes of interest, that have been joined together to form dimers or higher multimers. Such chimeric molecules may be used to treat or prevent diseases associated with autoimmunity, particularly diabetes. It is based, at least in part, on the discovery that a chimeric molecule comprising an HLA-DR element linked to an epitope of GAD65, an antigen associated with autoimmune diabetes, stimulated the secretion of the inhibitory cytokine IL-10 from CD4 T cells of Type 1 diabetic patients.2. BACKGROUND OF THE INVENTION2.1 Diabetes as an Autoimmune Disease[0002] Type 1 diabetes, also known as "insulin dependent diabetes mellitus" ("IDDM") is usually diagnosed before the age of 30 (hence its former name, "juvenile diabetes") and occurs in 1 out of 800 people in the United States (see www. niaid.nih.gov / publications / autoimmune.htm#dia-betes). I...

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Problems solved by technology

The resulting depletion of insulin results in an inability to absorb, store and utilize carbohydrates such as glucose, and therefore produces symptoms of weakness, weight loss, excessive hunger and thirst--"starvation amidst plenty" (see my.webmd.com / content / dmk / dmk_article.sub.--40027).

These reagens have a variety of side effects that call into question the ethics of applying them to asymptomatic humans.

However, some studies have shown a lack of protection by peptide-based therapy (Petersen et al., 1997, Autoimmunity 25:129-138; Funda et al., 1998, APMIS 106:1009-1016), mostly because of the short lifespans of the peptides in blood, which ranges from 22 seconds to 10 minutes (Ishioka et al., 1994, J. Immunol. 152:4310-4319).

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