PORCINE THYMUS SUPPORTS DEVELOPMENT OF FUNCTIONAL HUMANT T CELLS

Abstract

40 Since immune responses toward xenogeneic organs tend to be greater than those to allografts, unacceptably high levels of immunosuppression would likely be required for their success. A state of donor-specific tolerance would obviate the risk of both acute and chronic rejection while eliminating the need for chronic immunosuppressive therapy, thereby permitting normal immunocompetence. We now demonstrate that fetal porcine thymus grafts can reconstitute a polyclonal human T cell repertoire when co-transplanted with fetal human liver under the kidney capsule of SCID mice (SW/HU). Single positive CD4 and CD8 human T cells repopulated the peripheral lymphoid organs of the grafted SCID mice. To determine the functional status of T cells developing in SW/HU SCID thymic grafts, human T cells were stimulated with Concavalin A and phytohematoagglutinin. Human lymphocytes in porcine thymus grafts or mouse spleens showed substantial proliferative responses to lectin stimulation (stimulation indices >50). Con A-stimulated thymocytes from HU/HU and SW/HU grafts showed similar up-regulation of the early activation markers CD25 and CD69 at 24 hours. In order to further asses the function of human T cells that developed in thymic xenografts, we performed allogeneic anti-human mixed lymphocyte reactions (MLR). Human lymphocytes that developed in porcine thymic grafts mounted comparable MLR alloresponses to those elicited from human lymphocytes that developed in HU/HU grafts. No evidence of graft-versus-host disease, autoimmune disease, wasting syndrome or rejection of swine grafts was detected in any SW/HU SCID mice, presumably due to tolerance of human and swine lymphocytes towards mouse, swine and human antigens. Consistent with this possibility, porcine and murine class I+ and class II+ cells with a dendritic morphology were detected by immunohistochemistry, mainly in the corticomedullary junction and the medulla of SW/HU grafts. In summary, this study provides the first evidence that the swine thymus can support normal maturation and export to the periphery of functional polyclonal human lymphocytes in vivo. In addition to inducing xenogeneic transplantation tolerance, the xenogeneic thymus grafting approach could be utilized in the treatment of patients with HIV-associated thymic atrophy, given the HIV resistance of swine tissues.