REGULATION OF THE EFFECTOR STAGES OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS VIA NEUROANTIGEN-SPECIFIC TOLERANCE INDUCTION - III - A ROLEFOR ENERGY DELETION/

Our previous work has shown that specific peripheral immune tolerance induced by the intravenous administration of ECDI-fixed, antigen-coupl ed syngeneic splenocytes is an extremely efficient method for preventi on and treatment of chronic relapsing experimental autoimmune encephal omyelitis (R-EAE) in susceptible SJL/J mice. The current study examine d the mechanisms by which unresponsiveness is induced in primed enceph alitogenic T cells. The results indicate that the inhibition of MBP-sp ecific T cells by the i.v. injection of MBP-coupled splenocytes is not due to the induction of antigen-specific regulatory T cells, but rath er to the induction of anergy/deletion of the effector cells. This con clusion is supported by the findings that spleen or lymph node cells i solated from MBP-tolerant mice fail to inhibit the adoptive transfer o f R-EAE in cotransfer assays, and that tolerance is not inhibited by p rior thymectomy or prior treatment with cyclophosphamide or anti-CD8 m onoclonal antibody. In contrast, we demonstrate that splenocytes from MBP-tolerized, asymptomatic mice have a significantly reduced ability to serially transfer R-EAE to naive secondary recipients following ant igen re-activation in vitro, in the first several weeks following tole rization, but that the ability to serially transfer R-EAE returns to s ham tolerant control levels within 1-2 months. We also demonstrate a s ignificantly reduced precursor frequency of MBP-specific, IL-2-produci ng T cells in the MBP-tolerant within three days of treatment. Collect ively, the data most closely support. a model wherein inhibition of MB P-specific encephalitogenic CD4(+) effector T cells by i.v. injected M BP-coupled splenocytes is due to the direct induction of anergy/deleti on from which they can recover over time.