Abstract: T Cells Against the Pathogenic and Protective Epitopes of Heat-shock Protein 65 Are Crossreactive and Display Functional Similarity: Novel Aspect of Regulation of Autoimmune Arthritis

T Cells Against the Pathogenic and Protective Epitopes of Heat-shock Protein 65 Are Crossreactive and Display Functional Similarity: Novel Aspect of Regulation of Autoimmune Arthritis

MALARVIZHI DURAI, HONG RO KIM, KAMALESH BALA, and KAMAL D. MOUDGIL

ABSTRACT.

Objective. In autoimmune situations, the outcome of immune response against a disease-related antigen is typically viewed in terms of the balance between the pathogenic versus the protective subsets of antigen-reactive T cells. Using the rat adjuvant arthritis (AA) model of human rheumatoid arthritis (RA), we examined the antigen specificity and the functional attributes of the T cell repertoire directed against defined pathogenic versus protective epitopes of heat-shock protein 65 (hsp65), and determined the immunologic basis of the AA-protective effect of subsets of T cells primed by the pathogenic determinant.

Methods. Lewis (RT.1¹) rats were pretreated subcutaneously with the pathogenic epitope 177–191 of mycobacterial hsp65 (B177) in adjuvant (incomplete Freund's adjuvant/complete Freund's adjuvant/CpG) and then immunized with heat-killed M. tuberculosis H37Ra for disease induction. The antigen specificity/crossreactivity of the T cells primed by B177 or the AA-protective determinant 465–479 of the homologous rat hsp65 (R465) was tested by using proliferation assay, cytokine ELISA, tolerance induction, and adoptive transfer.

Results. Pretreatment of Lewis rats with the arthritogenic determinant B177 using an immunogenic rather than a tolerogenic regimen affords protection against AA instead of initiation or aggravation of AA. This protective effect of B177 is mediated in part by activation of T cells that are crossreactive with R465.

Conclusion. Downmodulation of AA by a pathogenic foreign epitope involving T cells crossreactive with a distant, protective self-determinant represents a novel aspect of immune regulation, and suggests further exploration of the use of pathogenic epitopes for the treatment of autoimmune arthritis. (First Release Oct 15 2007; J Rheumatol 2007;34:2134–43)

Key Indexing Terms:

ANIMAL MODELS
ARTHRITIS
AUTOIMMUNITY
HEAT-SHOCK PROTEINS
IMMUNE REGULATION

From the Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Supported by grants from the National Institutes of Health (Bethesda, MD) (AI-47790 and AI-059623), Arthritis Foundation (Atlanta, GA), the Maryland Chapter of the Arthritis Foundation, and the Maryland Arthritis Research Center (MARRC; Baltimore, MD).

M. Durai, PhD, Postdoctoral Fellow; H.R. Kim, PhD, Postdoctoral Fellow; K. Bala, MBBS, Graduate Student; K.D. Moudgil, MD, PhD, Associate Professor, Department of Microbiology and Immunology, University of Maryland School of Medicine.

Drs. Kim and Bala contributed equally to this work.

Address reprint requests to Dr. K.D. Moudgil, Department of Microbiology and Immunology, University of Maryland School of Medicine, Howard Hall 323C, 660 W. Redwood St., Baltimore, MD 21201. E-mail: kmoud001@umaryland.edu

Accepted for publication July 4, 2007.