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Studies of Molecular Targeting Agents and Cytokines on T Cells: Implications in Murine Acute Graft-versus-Host Disease
AdvisorMurphy, William J.
Biochemistry and Molecular Biology
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Allogeneic bone marrow transplantation (BMT) offers great promise for the treatment of a variety of diseases ranging from leukemia and aplastic anemia to other diseases of hematopoietic origin. Allogeneic BMT is especially advantageous in cancer patients because it can offer graft-versus-tumor (GVT) effects. The occurrence of graft-versus-host disease (GVHD) and tumor relapse represents the two major obstacles impeding the efficacy of allogeneic BMT in cancer. In this dissertation, we evaluated the effects of CDDO-Me, a new derivative of CDDO, on murine acute GVHD protection and GVT effects. We found that CDDO-Me had an ability to inhibit allogeneic T cell responses and induce cell death of alloreactive T cells in vitro. Administration of CDDO-Me to mice following allogeneic BMT resulted in significant and increased protection from acute lethal GVHD compared to CDDO. This protection correlated with decreased TNF-alpha production, reduced donor T cell proliferation and reduced adhesion molecule (alpha4beta7 integrin) expression on the donor T cells. CDDO-Me was also superior to CDDO in inhibiting leukemia growth in vitro. When CDDO-Me was administered following an allogeneic BMT to leukemia-bearing mice, significant increases in survival were observed. This demonstrates that CDDO-Me can markedly alleviate acute lethal GVHD while retaining GVT responses in advanced tumor-bearing mice. These results suggest that CDDO-Me may be of significant value for removal of the minimal residual tumor disease that can exist after BMT. Recently, a subset of CD4+ T helper cells noted for their production of IL-17 has been characterized as Th17 cells. Th17 cells are implicated in the control of some extracellular pathogens and play an important role in some autoimmune diseases. More donor Th17 cells and higher serum IL-17 levels have been found to be present in allogeneic BMT patients and mouse models. Th17 cells or IL-17 may be involved in the development of acute GVHD although the results from murine models are not consistent. Regulatory T cells (Treg cells) play an important role in immune homeostasis and the prevention of autoimmune disorders. Adoptive transfer of Treg cells into BMT recipients has been found to alleviate acute GVHD. Proinflammatory cytokines, such as TNF-alpha and IFN-gamma, play important roles in the pathogenesis of acute GVHD. Are these proinflammatory cytokines involved in the pathogenesis of acute GVHD by affecting the development of Th17 and Treg cells in the BMT setting? This question remains unknown. In this dissertation, we examined the influence of TNF-alpha and IFN-gamma on Th17 and Treg cell development in vitro. We found that the development of Th17 and Treg cells was specifically impaired in purified TNF-alpha-deficient CD4+ T cells in vitro, whereas the development of Th1 cells was not impaired as determined by IFN-gamma production. Unexpectedly, the development of Th17 and Treg cells was not impaired by the deficiency of TNF-alpha when CD4+ T cells were co-cultured with non-T spleen cells, suggesting that some factor(s) from non-T spleen cells can compensate for the deficiency of TNF-alpha so that the development of Th17 and Treg cells is not impaired. In addition, we found that more IL-17-producing CD4+ and CD8+ T cells, especially IL-17-producing CD8+ T cells, can be induced from IFN-gamma-deficient T cells compared to wild type T cells. The dramatic induction of IL-17-producing CD8+ T cells from IFN-gamma-deficient mice is consistent with the phenomenon that CD8+ T cells is a major source of IFN-gamma and thus IFN-gamma may act as an autocrine suppressor of IL-17 by these cells. Thus, CD8+ T cells have a built-in means to down-regulate IL-17.