Mechanisms of autoreactivity in SLE

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Autologous BMTX is already being studied or used anecdotally in the treatment of SLE and other autoimmune diseases. The rationale is that massive immunosuppression should ablate the autoimmune process that underlies the immunopathology of the disease. The patient then has his immune system and other blood elements 'rescued' with autologous stem cells that carry no risk of graft-versus-host disease or introducing foreign viruses. The stem cells are relatively easy to harvest from the peripheral blood after mobilization with high dose cytoxan and G-CSF. Although these self precursors would carry the same genetic factors that led to the original autoimmune disease, this approach should still be effective treatment because the disease normally takes decades to develop from birth in a genetically predisposed individual, and it often does not occur at all, as evidenced by the discordance of identical twins. Surprisingly, despite the growing experience in human disease, little animal data exist for this approach. Thus, in the current application, we will model this treatment in SLE mice, and we will test two novel approaches to enhance its effectiveness: use of drug-resistance genes, and prophylactic treatment after bone marrow reconstitution. We will also begin to explore an alternative approach of nonmyeloablative allogeneic reconstitution. We propose five specific aims: 1. What is the influence of donor and recipient age on the pace of disease in the transplanted mouse? 2. Can we avoid the recurrence of disease in recipient mice by known preventative therapies? 3. What is the role of preexisting antibodies in the recrudescence of disease after transplantation? 4. Can we use MDR-1 genes to increase the efficacy of syngeneic transplantation? 5. Can non-myeloablative allogeneic BMTx with a therapeutic GVH permit a safe alternative? These studies will provide insight into the mechanisms involved in these modes of therapy and potential failures, and will develop new ways to modify the approaches to prevent recurrent disease. Such insights should be readily translatable to human autoimmune diseases.