Hepatocyte growth factor preserves graft-versus-leukemia effect and T-cell reconstitution after marrow transplantation

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...

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

“…In GVHD, after bone marrow transplantation, HGF inhibited apoptosis and donor T-cell function, thus ameliorating acute GVHD. 41 If we extrapolate these results to HBV infection, the HGF-reduction in T-cell function in the GVHD model may have ramifications in explaining the documented hyporesponsiveness of the immune system during HBV infection. In our studies, we also showed reduced killing of hepatocyte targets by peptidespecific T-cells in the presence of EGF/HGF but did not attribute the effect to target resistance or a reduction in T-cell effector function.…”

In Vivo Administration of the Recombinant IL-7/Hepatocyte Growth Factor β Hybrid Cytokine Efficiently Restores Thymopoiesis and Naive T Cell Generation in Lethally Irradiated Mice after Syngeneic Bone Marrow Transplantation

“…Similar explanations could be offered for the ability of rIL-7/ HGFb to induce increased numbers of TECs, which also lack IL7Ra. Again, rIL-7/HGFb may directly induce the survival, proliferation, and/or the differentiation of TECs or their progenitors (21). The possibility that TECs are stimulated indirectly by the activation of thymocytes is less likely given the inability of anti-IL-7Ra Ab to inhibit the effects of rIL-7/HGFb.…”

“…In contrast, exogenous HGF has been shown to enhance hematopoietic stem cell engraftment after BMT and to promote thymopoiesis, at least in part by protecting against GVHD and diminishing injury to thymic epithelial cells (TECs) (21). Consequently, we have determined whether rIL-7/HGFb also enhances thymopoiesis and T cell regeneration after syngeneic BMT.…”

Recent Advances in the Treatment of Graft-Versus-Host Disease

“…Three growth factors, IL-11, keratinocyte growth factor, and hepatocyte growth factor, have recently been shown to prevent GI tract damage and subsequent inflammatory responses induced by endotoxins in the GI tract lumen in murine models. [57][58][59][60][61][62] Therapy using these growth factors preserved donor T cell responses to host antigens and significantly improved leukemia-free survival and may, therefore, form the basis of novel approaches to separate the GVL effect from GVHD. [60][61][62] However, the results of a phase I/II double-blind, controlled clinical trial of recombinant IL-11 in the prevention of acute GVHD were not satisfactory.…”

“…[57][58][59][60][61][62] Therapy using these growth factors preserved donor T cell responses to host antigens and significantly improved leukemia-free survival and may, therefore, form the basis of novel approaches to separate the GVL effect from GVHD. [60][61][62] However, the results of a phase I/II double-blind, controlled clinical trial of recombinant IL-11 in the prevention of acute GVHD were not satisfactory. Patients who received IL-11 exhibited severe fluid retention and early mortality making it impossible to determine whether IL-11 reduced the rate of acute GVHD.…”