CD4(-KILODALTON HEAT-SHOCK-PROTEIN PROTECT AGAINST PRISTANE-INDUCED ARTHRITIS() TH2 CELLS SPECIFIC FOR MYCOBACTERIAL 65)

Previous studies showed that mice with pristane-induced arthritis (PIA ) and those protected from the disease by preimmunization with mycobac terial 65-kDa heat shock protein (hsp65), possess raised immune respon ses to hsp65. Thus, a paradox exists whereby T cells from both arthrit ic and hsp65-protected animals proliferate vigorously in response to t he same Ag. Here we demonstrate that T cells from mice with PIA and hs p65-protected mice produce different cytokines in vitro in response to hsp65. The use of a sensitive CelELISA to measure Ag-driven lymphokin e production revealed that spleen cells from hsp65-protected mice, but not those from pristane-injected or normal mice, produced the Th2-ass ociated cytokines IL-4, IL-5, and IL-10 in response to stimulation wit h hsp65. By contrast, the Th1-associated cytokines IL-2 and IFN-gamma were produced by spleen cells from mice of all groups in response to h sp65. Furthermore, there was a dramatic increase in the IgG1 to IgG2a ratio of anti-hsp65 Abs from arthritic to protected mice. Thus, it app ears that a Th2 response is protective against PIA. To examine this th eory, a regimen of IL-12 administration which polarizes the hsp65-spec ific (Th2) immune response toward Th1 was identified. This regime abol ished hsp65-mediated protection against PIA. Other experiments reveale d that the specificity of the response to hsp65 was important, as othe r bacterial proteins known not to protect against PIA induced similar Th2-associated cytokines in vitro. It is considered that the protectio n afforded by hsp65 preimmunization is mediated by Th2-associated cyto kines produced by hsp65-specific CD4(+) T cells.