Nikolic B, Stanley KS, Sykes M; International Conference on AIDS.
Int Conf AIDS.
1998; 12: 788-9 (abstract no. 41232).
Massachusetts General Hospital, Boston, USA.
OBJECTIVES: In addition to causing severe peripheral CD4+ T cell dysfunction and depletion, HIV infects the thymus, causing destruction of thymic epithelium and thymocytes. Thymic injury due to HIV infection, combined with the normal post-pubertal thymic involution existing in many HIV-infected patients, could result in a failure to generate new CD4+ T cells to replace those that are destroyed in the periphery, even with adequate retroviral suppression. In this study, we have investigated whether swine thymus can support maturation of human T cells and protect them from intrathymic HIV infection. METHODS: We co-transplanted porcine fetal thymus and human fetal liver (SW/HU) under the kidney capsule of SCID mice. Control animals received human fetal thymus with human fetal liver (HU/HU) or porcine fetal thymus with porcine fetal liver (SW/SW). We followed the appearance of human T cells in the peripheral blood and analyzed their phenotypes by FACS, responses to lectin stimulation, and polyclonality by RT-PCR. Alloreactivity, xenoreactivity and tolerance toward porcine donor antigens were assessed by mixed lymphocyte reactions. Chimeric animals were challenged with direct injection of a primary HIV-1 isolate into the thymus grafts, and the level of HIV infection was measured by semi-quantitative PCR and in situ hybridization. RESULTS: Reconstitution of polyclonal, functional human CD4+ and CD8+ T cells was observed in the peripheral lymphoid organs of SCID mice receiving porcine fetal thymus grafts combined with human fetal liver tissue. These T cells were specifically tolerant to MHC antigens of the porcine thymus donor, while being responsive to non-donor porcine xenoantigens and to human alloantigens. After HIV challenge, the HU/HU grafts (n = 8) were grossly T cell depleted and infected with HIV. The SW/SW grafts (n = 7) appeared resistant to HIV infection, and did not show gross evidence of T cell depletion. The SW/HU grafts (n = 7) showed at least a 10-fold reduction in number of infected cells compared to HU/HU grafts, and did not show obvious thymocyte depletion. CONCLUSION: Our study shows that xenogeneic thymic transplantation may permit the achievement of tolerance with restoration of immunocompetence in humans using porcine tissues, which appear to be resistant to HIV. Thus, xenogeneic thymic transplantation has the potential to provide an important adjunct to the therapy of HIV-infected patients.
- Acquired Immunodeficiency Syndrome
- Antigens, CD4
- Antigens, CD8
- Antiretroviral Therapy, Highly Active
- CD4-Positive T-Lymphocytes
- Fetal Tissue Transplantation
- HIV Infections
- HIV Seropositivity
- Immune Tolerance
- Liver Transplantation
- Lymphocyte Culture Test, Mixed
- Mice, SCID
- Sus scrofa
- Thymus Gland
- Transplantation, Heterologous
- drug therapy
From Meeting Abstracts