In addition to causing severe peripheral CD4+ T cell depletion, HIV-1 infects the thymus, causing destruction of both the thymic microenvironment and of thymocytes. Thymic injury and age-related involution may contribute to a failure to achieve adequate immune restoration, even with HAART therapy. Therefore, thymus transplantation is being explored as an approach to improving immune restoration. Under the current funded NCDDG Program, we have shown that porcine thymic grafts in immunodeficient mice support normal development of polyclonal, functional and specifically tolerant human T cells. Importantly, human thymocytes developing in porcine thymus appear to be protected from HlV-1-induced depletion. In this proposal, we will further characterize the level of immunocompetence of human T cells developing in porcine thymus grafts, and will elucidate the mechanism by which porcine thymus confers protection against HIV-1. Specifically, we aim to: 1) Determine the duration and mechanisms of protection of human thymopoiesis from HlV-1-induced destruction, and determine the range of viral strains from which protection will be conferred by porcine thymic grafts. We will evaluate the kinetics of T cell depletion and infection caused by R5, X4 and R5X4 HIV-1 isolates, determine the thymic stromal cell types that are infected with HIV in vivo in HU/HU and SW/HU SCID mice, and compare renewal of thymopoiesis in HIV-infected HU/HU and SW/HU thymic implants following anti-retroviral therapy; 2) Analyze the repertoire and immune function of human T cells developing in pig thymus grafts. We will characterize the TCR diversity and immunocompetence and will evaluate immune responses to protein antigens and to HIV-1. We hypothesize that central tolerance to HIV-1 antigens may prevent HIV reactivity among human thymocytes developing in human but not pig thymic grafts that have been previously infected with HIV-1, and that the restoration of HIV-1-specific immune responses could provide a major advantage to porcine thymic xenografting for the treatment of HIV infection. The use of porcine donors has the additional advantage of providing essentially unlimited amounts of specific pathogen-free, genetically defined xenogeneic thymic tissue.

Project Start
2002-08-01
Project End
2003-05-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
6
Fiscal Year
2002
Total Cost
$256,338
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Morris, Heather; DeWolf, Susan; Robins, Harlan et al. (2015) Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients. Sci Transl Med 7:272ra10
Sykes, M (2007) Immune tolerance: mechanisms and application in clinical transplantation. J Intern Med 262:288-310
Hongo, David; Hadidi, Sima; Damrauer, Scott et al. (2007) Porcine thymic grafts protect human thymocytes from HIV-1-induced destruction. J Infect Dis 196:900-10
Shimizu, Akira; Yamada, Kazuhiko (2006) Pathology of renal xenograft rejection in pig to non-human primate transplantation. Clin Transplant 20 Suppl 15:46-52
Wong, Banny S; Yamada, Kazuhiko; Okumi, Masayoshi et al. (2006) Allosensitization does not increase the risk of xenoreactivity to alpha1,3-galactosyltransferase gene-knockout miniature swine in patients on transplantation waiting lists. Transplantation 82:314-9
Nobori, Shuji; Shimizu, Akira; Okumi, Masayoshi et al. (2006) Thymic rejuvenation and the induction of tolerance by adult thymic grafts. Proc Natl Acad Sci U S A 103:19081-6
Rodriguez-Barbosa, Jose-Ignacio; Haller, Gary W; Zhao, Guiling et al. (2005) Host thymectomy and cyclosporine lead to unstable skin graft tolerance after class I mismatched allogeneic neonatal thymic transplantation in mice. Transpl Immunol 15:25-33
Shimizu, Akira; Colvin, Robert B (2005) Pathological features of antibody-mediated rejection. Curr Drug Targets Cardiovasc Haematol Disord 5:199-214
Kamano, Chisako; Vagefi, Parsia A; Kumagai, Naoki et al. (2004) Vascularized thymic lobe transplantation in miniature swine: thymopoiesis and tolerance induction across fully MHC-mismatched barriers. Proc Natl Acad Sci U S A 101:3827-32
Buhler, L; Xu, Y; Li, W et al. (2003) An investigation of the specificity of induced anti-pig antibodies in baboons. Xenotransplantation 10:88-93

Showing the most recent 10 out of 50 publications