New strategies for allogeneic BMT.

Abstract

In humans, the success rate of BMT across major histocompatibility complex (MHC) barriers is lowered by graft-versus-host disease (GvHD), graft rejection and incomplete T-cell recovery. To prevent GvHD, we attempted to minimize the contamination of bone marrow cells (BMCs) with T cells from the peripheral blood when donor BMCs were collected, finally establishing a new 'Perfusion Method' using cynomolgus monkeys. There was significantly less contamination of BMCs with T cells in this method (<6%) than in the conventional 'Aspiration Method' (>20%) consisting of multiple aspirations of BMCs from the iliac crest. Using radio-sensitive and chimerism-resistant MRL/lpr mice, we also established a new method for allogeneic (allo) BMT and organ allografts. In this method, whole BMCs, containing a small number of T cells and mesenchymal stem cells (MSCs), were directly injected into the bone marrow cavity (intrabone marrow [IBM]-BMT). MRL/lpr mice treated with IBM-BMT survived more than 2 years without showing the symptoms of autoimmune diseases. IBM-BMT thus has several advantages: (i) no GvHD develops even if T cells are not depleted from BMCs; (ii) no graft failure occurs even if the dose of radiation as the conditioning regimen for allo BMT is reduced to 5Gy x 2; (iii) hemopoietic recovery is rapid; and (iv) the restoration of T-cell functions is quick and complete even in donor-recipient combinations across MHC barriers. We believe that these strategies for allo BMT and organ allografts herald a new era in transplantation, and that they would be helpful in allogeneic HSCT of autoimmune diseases.