Impaired Anti-viral Immunity Following Syngeneic Bone Marrow Transplant (45.7)

Abstract

Abstract Patients receiving autologous hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT) as therapy for various malignancies or autoimmune diseases have an increased risk for infectious complications post-transplant, especially in the lung. We have used syngeneic BMT in mice and the murine gammaherpesvirus, MHV-68, to study the efficacy of adaptive immune responses post-BMT. Using this model, we have shown that mice 5 weeks post-transplant have fully reconstituted their hematopoeitic lineages in both the lung and periphery. However, the BMT mice have a reduced ability to clear lytic virus from the lung, despite increased expression of interferon gamma, interleukin-2, and TNF-alpha in the lungs of BMT mice. Recruitment of immune cells to the lungs after MHV-68 infection is similar in BMT mice and untransplanted controls, suggesting functional defects. While bone-marrow derived dendritic cells from transplanted mice are able to stimulate allogeneic T cell proliferation in mixed leukocyte reactions (MLRs), CD4+ T cells from BMT mice show reduced proliferative responses in MLRs. These results suggest defects in CD4+ T cell responses post-BMT may contribute to enhanced susceptibility to viral infections. Additionally, levels of TGF beta are significantly increased in the lungs of BMT mice before infection, and numbers of CD4+Foxp3+ regulatory CD4+ T cells are increased in the BMT lung (but not spleen) both before and at day 7 after viral infection. We speculate that TGF beta-induced expansion of Tregs in the lung limits anti-viral host defense post-bone marrow transplantation.