Adjuvant arthritis (AA), inducible in susceptible rat strains by subcutaneous injection of heat-killed Mycobacterium tuberculosis H37Ra, serves as an excellent model for human rheumatoid arthritis (RA). Both arthritic rats and RA patients develop T cell responses to the 65-kilodalton (kDa) mycobacterial heat-shock protein (Bhsp65). Bhsp65 contains both arthritogenic and protective/regulatory T cell determinants. Heat-shock proteins (hsps) are highly conserved proteins both in prokaryotes and eukaryotes. The investigators have made an interesting observation that the susceptibility to AA of Fisher rats is very directly modulated by environmental agents: Fisher F344 rats bred and raised in a barrier facility (BB-Fisher) are susceptible to AA, whereas Fisher rats bred and maintained in a conventional (CV) facility (CVFisher) are resistant to AA. Furthermore, BB-Fisher rats, when transferred into a CV facility and kept there for several weeks, acquire resistance to AA. However, this acquisition of AA-resistance by BB-Fisher rats can be circumvented if rats are fed neomycin or acidified water (to prevent or diminish colonization of gut by environmental agents) beginning on the day of their transfer into the CV facility. Strikingly, naive CV-Fisher, and not BB- Fisher rats, spontaneously raised T cell responses to Bhsp65, including Bhsp65 C-terminal determinants (BCTD) [the investigators have previously shown that BCTD are involved in regulation of acute AA in the Lewis rat]. Furthermore, AA-resistance of CV-Fisher rats can be adoptively transferred to naive BB- Fisher rats by unfractionated splenic cells of naive CV-Fisher rats restimulated in vitro with BCTD. These preliminary findings provide a novel perspective on the role of microbes in autoimmunity: protection from an autoimmune disease instead of disease induction (the latter effect has been observed in several other animal models of autoimmunity). The investigators will test the following propositions in this exploratory study: A) Environmental agents are directly involved in conferring resistance against AA to CV-Fisher rats. Experimental reconstitution of BB-Fisher rats with microbial flora derived from CV-Fisher rats (for simplicity, these reconstituted rats are referred to as BBCV-Fisher rats) should render these rats resistant to AA. B) Microbial flora (containing hsp6O homologs of Bhsp65 of M. tuberculosis) induce protection from AA in CV- and BBCV-Fisher rats through an immunological mechanism. This hypothesis will be tested by priming T cells that are cross-reactive with Bhsp65 of M. tuberculosis (molecular mimicry). A subset of these T cells serves to afford protection from AA by mechanism(s) to be defined in this study. Alternatively, microbial flora may induce immune deviation of potentially arthritogenic T cells. C) The """"""""acquired"""""""" AA-resistance of CV- or BBCV-Fisher rats should be adoptively transferable to naive BB-Fisher rats by a defined T cell subset (CD4/CD81). The results of this study should have important implications both for understanding the influence of environmental factors on the pathogenesis of RA in human populations living under different geographical conditions, and in developing new preventive/therapeutic approaches for RA.
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