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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
3P01AI039755-04S1
Application #
6344637
Study Section
Project Start
2000-08-15
Project End
2001-07-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
4
Fiscal Year
2000
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
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
Sykes, M (2007) Immune tolerance: mechanisms and application in clinical transplantation. J Intern Med 262:288-310
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