Tolerization with Hsp65 induces protection against adjuvant-induced arthritis by modulating the antigen-directed interferon-gamma, interleukin-17, and antibody responses.
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-gamma (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.


CONCLUSIONS
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.
Satpute
Shailesh R
SR
University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Rajaiah
Rajesh
R
Polumuri
Swamy K
SK
Moudgil
Kamal D
KD
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000517:prevention & control*; D001323:Autoantibodies / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism; D018835:Chaperonin 10 / Q000276:immunology / Q000494:pharmacology; D018834:Chaperonin 60; D018833:Chaperonins / Q000276:immunology / Q000494:pharmacology*; D003429:Cross Reactions / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D012995:Solubility; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D001323:Autoantibodies; D001426:Bacterial Proteins; D015704:CD4 Antigens; D018835:Chaperonin 10; D018834:Chaperonin 60; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D018840:HSP70 Heat-Shock Proteins; D020381:Interleukin-17; D007376:Interleukin-2; C074119:heat-shock protein 65, Mycobacterium; D007371:Interferon-gamma; D018833:Chaperonins