Total lymphoid irradiation and antigen-specific tolerance: future therapy for experimental myasthenia gravis?

Total lymphoid irradiation (TLI) is effective in the immunosuppressive treatment of human and experimental autoimmune disorders, including experimental autoimmune myasthenia gravis (EAMG). Under certain circumstances. TLI may facilitate the induction of specific tolerance to antigens present during or shortly after the TLI treatment. This study was designed to determine whether TLI could induce or enhance tolerance to acetylcholine receptor (AChR), the antigen in myasthenia gravis, or to other antigens. We presented the antigens in various potentially tolerogenic forms to rats that were first pre-treated with TLI, or controls treated with sham irradiation. Injection of deaggregated human gamma globulin (HGG), a classical tolerogen, was most effective; it produced antigen-specific tolerance, which was significantly enhanced by pre-treatment with TLI. Injection of HGG coupled to rat peritoneal cells induced a moderate degree of specific tolerance; in this case, pre-treatment with TLI added only nonspecific suppression. In contrast, AChR, either in solubilized form with no adjuvant, or coupled to syngeneic rat peritoneal cells, failed to induce tolerance, and actually primed the immune system, when given alone or in conjunction with TLI. Subsequent challenge with AChR resulted in an enhanced (secondary) anti-AChR antibody response. These results show that the nature of the antigen itself may predispose to tolerance or to immune stimulation. AChR appears to be highly immunogenic. However, if a tolerogenic fragment or form of AChR can be identified, its use in combination with TLI may result in specific tolerance. If such specific tolerance can be induced during an ongoing autoimmune reaction to AChR, it would be an effective treatment for myasthenia gravis.