The ultimate goal of studies in this project is to determine the capacity of fetal (or neonatal) swine thymic grafts given with or without swine hematopoietic stem cells to reconstitute functional T cells in the presence of HIV infection. We have demonstrated that placement of fetal swine thymus and liver tissue under the kidney capsule of thymectomized, immunocompetent mice that are pre-treated with mAbs against T cells and natural killer cells results in engraftment and growth of the thymic tissue. Remarkably, mature murine CD4+ T cells develop in these pig thymi and migrate to the peripheral lymphoid tissues of the mouse. These cells are functional and are specifically tolerant of the seine donor. Since the thymus is a target of HIV infection in humans, it is likely that destruction of the thymic microenvironment by HIV results in an inability to generate functional T cells to repopulate the peripheral CD4 T cell pool that is destroyed by HIV. Preliminary results suggest that pig thymic tissue is resistant to HIV infection. Because of the excellent breeding characteristics of miniature swine, this species could potentially be an ideal source of functional thymic replacement tissue for HIV-infected humans. We postulate that a xenogeneic porcine thymus might be capable of generating functional human or porcine CD4+ T cells that could continually repopulate the peripheral lymphoid system of AIDS patients. The potential of swine thymic tissue to restore immune function in the presence of HIV infection will be evaluated in the pig yields mouse model, and in a human hematopoietic cell plus pig thymus to SCID mouse transplantation model. The minimal requirements for achievement of functional swine thymic tissue engraftment in immunocompetent animals will be ascertained. Immune function will be evaluated in detail for mouse and human T cells, respectively, that develop in pig thymi. If host T cells developing in a xenogeneic thymus fail to demonstrate adequate immunocompetence, we will explore the possibility that provision of a pig thymus along with pig T cells and antigen-presenting cells could confer improved immunocompetence. A pig to SCID mouse model will be used to measure the ability of swine- specific cytokines to enhance reconstitution of these swine hematopoietic lineages. Results of studies in this project will help to determine the optimal strategy of swine thymic and hematopoietic cell transplantation for use in primate models (Projects 2 and 3).
Showing the most recent 10 out of 50 publications
