Revisiting tolerance induced by autoantigen in incomplete Freund's adjuvant

Injection of autoantigens in IFA has been one of the most effective ways of preventing experimental, T cell-mediated, autoimmune disease in mice. The mechanism that underlies this protection has, however, remained controversi al, with clonal deletion, induction of suppressor cells or of type 2 immuni ty being implicated at one time or another. Using high resolution enzyme-li nked immunospot (ELISPOT) analysis, we have revisited this paradigm. As mod els of autoimmunity against sequestered and readily accessible autoantigens , we studied experimental allergic encephalomyelitis, induced by myelin oli godendrocyte glycoprotein, proteolipid protein, myelin basic protein, and r enal tubular Ag-induced interstitial nephritis, We showed that the injectio n of each of these Ags in FFA was immunogenic and CD4 memory cells producin g IL-2, IL-4, and IL-5, but essentially no IFN-gamma, IgG1, but not IgG2a, autoantibodies were produced. The engaged T cells were not classic Th2 cell s in that IL-4 and IL-5 were produced by different cells. The IFA-induced v iolation of self tolerance, including the deposition of specific autoantibo dies in the respective target organs, occurred in the absence of detectable pathology. Exhaustion of the pool of naive precursor cells was shown to be one mechanism of the IFA-induced tolerance. In addition, while the IFA-pri med T cells acted as suppressor cells, in that they adoptively transferred disease protection, they did not interfere with the emergence of a type 1 T cell response in the adoptive host. Both active and passive tolerance mech anisms, therefore, contribute to autoantigen:IFA-induced protection from au toimmune disease.