The Prospects for BMT — from Mouse to Human

Abstract

Using animal models for autoimmune diseases, we have found that bone marrow transplantation (BMT) can be used to treat not only systemic autoimmune diseases but also organ-specific autoimmune diseases. We have also found that transplantation of hemopoietic stem cell (HSC)enriched populations from autoimmune-prone mice to normal mice induces autoimmune diseases in the recipients. These findings have recently been confirmed in humans; BMT can be used to treat autoimmune diseases, whereas autoimmune diseases have been transferred from donors to recipients by BMT. Based on these findings, we have proposed a new concept of stem cell disorders to include aplastic anemia, leukemia and autoimmune diseases. To elucidate the differences between normal and abnormal HSCs, we have established a method for purifying HSCs and have found qualitative differences between them both in vivo and in vitro. Although normal HSCs do not readily proliferate in major histocompatibility complex (MHC)-incompatible microenvironments, abnormal HSCs show a marked proliferative response. Abnormal HSCs are thus more resilient than normal HSCs. Based on these findings, we have attempted to recruit donor-derived stromal cells by grafting non-irradiated bones subcutaneously in the case of BMT across MHC barriers. The bone grafts have, in fact, led to successful long-term reconstitution even in chimeric resistant combinations such as [Normal → MRL/Ipr] and [DBA/2 → C57BL/6] chimeric mice. T cell functions are completely restored by bone grafts; this is due to the migration of stromal cells into the thymus, where they are engaged in positive selection as thymic nurse cells. Stromal cells thus play a crucial role in successful BMT across MHC barriers. Intractable diseases are defined as diseases of unknown etiopathogenesis, and for which therapeutic strategies remain to be established. Of the 36 diseases recognized as intractable by the Ministry of Health and Welfare of Japan, we show that approximately half will become curable by BMT.