Hematopoietic engraftment and graft failure after bone marrow transplantation

This article reviews the complex process of establishing functional long-term hematopoiesis required for successful clinical bone marrow transplantation. The failure to establish sustained hematopoiesis, either primary or secondary graft failure, is defined and multiple etiologic factors involved are discussed.

Data from published studies of experimental and clinical BMT, as well as in vitro stem cell biology, were used to elucidate the elements required for establishing functional hematopoiesis. These include pleuripotential hematopoietic stem cells; homing of stem cell to the hematopoietic micro-environment; hematopoietic stroma and secreted cytokines acting synergistically to promote expansion and hematopoietic differentiation of the stem cells; and, in the setting of allogeneic transplantation, immunological tolerance between the host and the graft, without which graft rejection or graft-vs.-host disease may occur.

The factors influencing the establishment of functional hematopoiesis and the risks for graft failure vary with the type of transplant performed. In an autologous transplant, damage to the stem cells or to the stromal microenvironment can contribute to prolonged time to engraftment or primary graft failure. In contrast, the hematopoietic stem cells are normal in both syngeneic and allogeneic transplantation. However, in the latter, because of immunological disparity between the host and recipient, there can be either primary or secondary graft failure due to a host-vs.-graft phenomenon, graft rejection. Classic graft rejection is an immunologic phenomenon mediated by residual host immunocompetent cells, either T cells or NK cells, depending on the allogeneic disparity between host and donor. T cell depletion and increased HLA disparity are risk factors for rejection. Numerous strategies have attempted to decrease the risk of rejection; most have focused primarily on increased immunosuppression of the host either with additional radiation, chemotherapy or in vivo anti-T cell serotherapy. Recent attempts have explored preventing rejection by manipulating donor cell composition of the infused graft.