TRANSIENT IMMUNOSUPPRESSIVE TREATMENT LEADS TO LONG-TERM RETENTION OFALLOGENEIC MYOBLASTS IN HYBRID MYOFIBERS

Normal and genetically engineered skeletal muscle cells (myoblasts) sh ow promise as drug delivery vehicles and as therapeutic agents for tre ating muscle degeneration in muscular dystrophies. A limitation to the widespread use of myoblast transplantation is the immune response of the host to the transplanted cells. Allogeneic myoblasts are rapidly r ejected unless immunosuppressants are administered. However, continuou s immunosuppression is associated with significant toxic side effects. Here we test whether immunosuppressive treatment, administered only t ransiently after allogeneic myoblast transplantation, allows the long- term survival of the transplanted cells in mice. Two immunosuppressive treatments with different modes of action were used: (a) cyclosporine A (CSA); and (b) monoclonal antibodies to intracellular adhesion mole cule-1 and leukocyte function-associated molecule-1 The use of myoblas ts genetically engineered to express beta-galactosidase allowed quanti tation of the survival of allogeneic myoblasts at different times afte r cessation of the immunosuppressive treatments. Without host immunosu ppression, allogeneic myoblasts were rejected from all host strains te sted, although the relative time course differed as expected for low a nd high responder strains. The allogeneic myoblasts initially fused wi th host myofibers, but these hybrid cells were later destroyed by the massive immunological response of the host. However, transient immunos uppressive treatment prevented the hybrid myofiber destruction and led to their long-term retention. Even four months after the cessation of treatment, the hybrid myofibers persisted and no inflammatory infiltr ate was present in the tissue. Such long-term survival indicates that transient immunosuppression may greatly increase the utility of myobla st transplantation as a therapeutic approach to the treatment of muscl e and nonmuscle disease.