Mixed Hematopoietic Chimerism Allows Cure of Autoimmune Glomerulonephritis: Its Potential and Risks

Abstract

Patients with severe autoimmune lupus glomerulonephritis that is resistant to immunosuppressive therapy need alternative treatment. Recently, bone marrow transplantation (BMT) has been proposed as a potential therapy for refractory autoimmune disease. BMT involves the administration of hematopoietic stem cells, which are selfrenewing and capable of giving rise to all mature hematopoietic cell types and possibly some non-hematopoietic cell types. The etiologic and pathogenic bases of many autoimmune diseases ultimately reside in the self-renewing hematopoietic stem cell population. Therefore, the effects of BMT as a treatment for and/or preventive measure against these autoimmune diseases have been investigated extensively (Sykes&Nicolic, 2005). Studies in animal models have shown that the transfer of hematopoietic stem cells can reverse the autoimmune state. The induction of fully allogeneic bone marrow (BM) chimerism, however, is fraught with difficulties. Each of the various methods of inducing fully allogeneic BM chimerism through hematopoietic cell transplantation (HCT) requires a different set of conditions, such as host T cell depletion, donor myeloablation, major histocompatibility complex (MHC) fully matched donor BM, or lethal dose of total body irradiation (TBI). Meeting these conditions is usually a burden on the recipient. Moreover, fully allogeneic BM chimerism is always associated with risks of graft versus host disease (GVHD) and immunodeficiency, which make it less practical for clinical application. Accordingly, the induction of mixed allogeneic BM chimerism has been proposed as a treatment for autoimmune disease. Mixed chimerism refers to a state in which allogeneic donor hematopoietic cells coexist with recipient cells in host bone marrow. In this paper, the advantages of inducing mixed BM chimerism are summarized and a process for inducing peripheral/central tolerance is introduced. Several mechanistic pathways which are thought to be involved in reversing the autoimmune state are then described. Based on our original data, we propose one possible mechanism in which newly developed donor T cells, which have been positively selected in the host thymus and restricted host MHC, are able to regulate auto-reactive B cells through T cell receptor (TCR)/MHC interaction. Finally, we discuss the potential risks associated with fully MHC-