No abstract

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT). When GVHD is controlled by T-cell-depleted grafts or immunosuppressants, BM transplant recipients often suffer from an increased rate of leukemic relapse and impaired reconstitution of immunity. Using a mouse BMT model, we investigated the effects of hepatocyte growth factor (HGF) gene transfection on the severity of GVHD, the graft-versus-leukemia effect, and the reconstitution of T cells after BMT. After HGF gene transfer, acute GVHD was reduced, while mature donor T-cell responses to host antigens were preserved, resulting in a significant improvement of leukemia-free survival. HGF gene transfer promoted regeneration of bone marrowderived T cells and the responsiveness of these cells to alloantigens. Furthermore, HGF preserved the thymocyte phenotype and thymic stromal architecture in mice with GVHD. This suggested that HGF exerts a potent protective effect on the thymus, which in turn promotes reconstitution of bone marrow-derived T cells after allogeneic BMT. These results indicate that HGF gene transfection can reduce acute GVHD preserving the graftversus-leukemia effect, while promoting thymic-dependent T-cell reconstitution after allogeneic BMT. IntroductionDonor T cells contaminating hematopoietic stem cells (HSCs) contribute both positively and negatively to the outcome of allogeneic bone marrow transplantation (BMT). Donor T cells play a positive role by facilitating engraftment of the allograft and contributing to antitumor immunity, but are also primarily responsible for graft-versus-host disease (GVHD). [1][2][3][4][5][6][7][8] To date, approaches to control acute GVHD have employed methods that attempt to remove or suppress the function of all T cells regardless of their immunologic specificity. Although the administration of immunosuppressants achieves an acceptable rate of engraftment with reasonable control of GVHD, these drugs induce a generalized decrease of immunocompetence with its attendant morbidity and mortality. Immunosuppressants also often have significant acute and chronic adverse effects on organ function. 9,10 Ex vivo T-cell depletion of donor HSCs appears to be more effective at ameliorating or even eliminating GVHD, but this approach is complicated by an unacceptable incidence of graft failure, profound and protracted immunodeficiency, and loss of antitumor immunity. [5][6][7][8] New methods of reducing toxicity while retaining the antitumor potential of BMT, including donor lymphocyte infusion and nonmyeloablative conditioning, have led to a significant decrease in the occurrence of acute GVHD. Unfortunately, along with the decline of acute GVHD, chronic GVHD has begun to emerge as a major complication of BMT. 11 An important cause of impaired reconstitution of immunity after allogeneic BMT is the thymic damage initiated by hostreactive donor T cells, because reconstitution of T-cell immunity depends on the differentiation of donor HSCs in the thymus. 12,13 It is likely tha...

SUMMARYDonor T cells are crucial for target organ injury in graft-versus-host disease (GVHD). We examined the effects of donor T cells on the target organs using a parent-into-F 1 model of acute and chronic GVHD. Donor T cells showed engraftment in the spleen, small intestine and liver of mice with acute GVHD, causing typical GVHD pathology in these organs. Interferon-c and Fas ligand expression were up-regulated, and host lymphocytes were depleted in the target organs of these mice. In contrast, donor T cells did not show engraftment in the small intestine of mice with chronic GVHD, and no GVHD pathology was observed in this organ. However, both donor T-cell engraftment and GVHD pathology were observed in the spleen and liver of chronic GVHD mice, along with the up-regulation of interleukin-4 (IL-4) and IL-10 expression plus the expansion of host lymphocytes such as splenic B cells and hepatic natural killer (NK) 1

Our results indicated that host TLR-4 is crucial for the induction of tissue protective factors and for protection against intestinal cell apoptosis during acute GVHD.

FK506 inhibits both GvHD and GvL activity when given at clinical doses by inhibiting donor T-cell expansion, donor anti-host T-cell reactivity, and Th1 immune responses.