Experimental Arthritis
Tolerization with Hsp65 induces protection against adjuvant-induced arthritis by modulating the antigen-directed interferon-γ, interleukin-17, and antibody responses
Shailesh R. Satpute,
Rajesh Rajaiah,
Swamy K. Polumuri,
Kamal D. Moudgil,
Shailesh R. Satpute
University of Maryland School of Medicine, Baltimore
Search for more papers by this authorRajesh Rajaiah
University of Maryland School of Medicine, Baltimore
Search for more papers by this authorSwamy K. Polumuri
University of Maryland School of Medicine, Baltimore
Search for more papers by this authorCorresponding Author
Kamal D. Moudgil
University of Maryland School of Medicine, Baltimore
University of Maryland School of Medicine, HH323C, 660 West Redwood Street, Baltimore, MD 21201Search for more papers by this authorShailesh R. Satpute,
Rajesh Rajaiah,
Swamy K. Polumuri,
Kamal D. Moudgil,
Shailesh R. Satpute
University of Maryland School of Medicine, Baltimore
Search for more papers by this authorRajesh Rajaiah
University of Maryland School of Medicine, Baltimore
Search for more papers by this authorSwamy K. Polumuri
University of Maryland School of Medicine, Baltimore
Search for more papers by this authorCorresponding Author
Kamal D. Moudgil
University of Maryland School of Medicine, Baltimore
University of Maryland School of Medicine, HH323C, 660 West Redwood Street, Baltimore, MD 21201Search for more papers by this authorAbstract
Objective
Pretreatment of Lewis rats with soluble mycobacterial Hsp65 affords protection against subsequent adjuvant-induced arthritis (AIA). This study was aimed at unraveling the mechanisms underlying mycobacterial Hsp65–induced protection against arthritis, using contemporary parameters of immunity.
Methods
Lewis rats were given 3 intraperitoneal injections of mycobacterial Hsp65 in solution prior to the initiation of AIA with heat-killed Mycobacterium tuberculosis. Thereafter, mycobacterial Hsp65–specific T cell proliferative, cytokine, and antibody responses were tested in tolerized rats. The roles of anergy and the indoleamine 2,3 dioxygenase (IDO)–tryptophan pathway in tolerance induction were assessed, and the frequency and suppressive function of CD4+FoxP3+ Treg cells were monitored. Also tested was the effect of mycobacterial Hsp65 tolerization on T cell responses to AIA-related mycobacterial Hsp70, mycobacterial Hsp10, and rat Hsp65.
Results
The AIA-protective effect of mycobacterial Hsp65–induced tolerance was associated with a significantly reduced T cell proliferative response to mycobacterial Hsp65, which was reversed by interleukin-2 (IL-2), indicating anergy induction. The production of interferon-γ (but not IL-4/IL-10) was increased, with concurrent down-regulation of IL-17 expression by mycobacterial Hsp65–primed T cells. Neither the frequency nor the suppressive activity of CD4+FoxP3+ T cells changed following tolerization, but the serum level of anti–mycobacterial Hsp65 antibodies was increased. However, no evidence was observed for a role of IDO or cross-tolerance to mycobacterial Hsp70, mycobacterial Hsp10, or rat Hsp65.
Conclusion
Tolerization with soluble mycobacterial Hsp65 leads to suppression of IL-17, anergy induction, and enhanced production of anti–mycobacterial Hsp65 antibodies, which play a role in protection against AIA. These results are relevant to the development of effective immunotherapeutic approaches for autoimmune arthritis.
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