Inbred miniature swine provide a unique preclinical model for the study oftransplantation immunity andtolerance. Overthe past 18 years, we have utilized this model to study a robust form oftolerance of MHC class I-mismatched renal allografts that is routinely achieved following a short course of calcineurin inhibitors. Thisproposal represents a G37 renewal ofthe previous long-standing ROl, which received a Merit Award at the timeofthe last competitive renewal. During the past three and one-half years since that renewal, we have madesignificant progress in understanding the role of regulatory T cells (T-reg) in determining the balance betweenalloreactivity and down-regulation of immune reactivity to tolerated renal allografts. Among these studies, hasbeen an evaluation ofthe possible role ofantigen presentation through direct or indirect pathways of activationin the reinforcing oftolerance by donor-type skin allografts in previously tolerant animals from which thetolerizing graft has been removed. We have obtained considerable evidence for dominance of down-regulationby the.direct pathway in this phenomenon. In the next project period, we intend to: 1) Complete our studies onthe nature of cell populations responsible for adoptive transfer oftolerance that are still in progress; 2)Determine whether the thymus is required for breaking and/or reinforcing tolerance after graftectomy inanimals tolerant of class I mismatched renal allografts; and 3) Examine the mechanism by which B cell immunityto class I antigens is controlled in animals tolerant ofa class I-mismatched renal allograft through evaluation ofthe influence of tolerance on antibody fine specificity. The broader goal ofthese studies remains to develop anunderstanding ofthe mechanisms by which allograft tolerance is induced and maintained in this large-animalmodel, in order to permit development of appropriate protocols for induction oftolerance to organ allografts inthe clinic.

Public Health Relevance

Immune tolerance of transplanted organs would allow patients to avoid long-term immunosuppressive drugsand the complications caused by these drugs. We have developed a large animal model in which toleranceof kidney transplants can be induced reproducibly. Our goal here is to understand the mechanism oftolerance in this model in order to eventually extend the studies to human organ transplants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AI031046-21
Application #
7987433
Study Section
Special Emphasis Panel (NSS)
Program Officer
Nabavi, Nasrin N
Project Start
1991-04-01
Project End
2016-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
21
Fiscal Year
2011
Total Cost
$792,421
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Villani, V; Yamada, K; Scalea, J R et al. (2016) Adoptive Transfer of Renal Allograft Tolerance in a Large Animal Model. Am J Transplant 16:317-24
Tasaki, Masayuki; Villani, Vincenzo; Shimizu, Akira et al. (2016) Role of bone marrow maturity, insulin-like growth factor 1 receptor and forkhead box protein N1 in thymic involution and rejuvenation. Am J Transplant :
Scalea, J R; Okumi, M; Villani, V et al. (2014) Abrogation of renal allograft tolerance in MGH miniature swine: the role of intra-graft and peripheral factors in long-term tolerance. Am J Transplant 14:2001-10
Scalea, Joseph R; Villani, Vincenzo; Gillon, Bradford C et al. (2014) Development of antidonor antibody directed toward non-major histocompatibility complex antigens in tolerant animals. Transplantation 98:514-9
Lee, P W; Hanekamp, J S; Villani, V et al. (2014) Evidence for a gene controlling the induction of transplantation tolerance. Am J Transplant 14:952-9
Cetrulo Jr, Curtis L; Torabi, Radbeh; Scalea, Joseph R et al. (2013) Vascularized composite allograft transplant survival in miniature swine: is MHC tolerance sufficient for acceptance of epidermis? Transplantation 96:966-74
Okumi, M; Scalea, J R; Gillon, B C et al. (2013) The induction of tolerance of renal allografts by adoptive transfer in miniature swine. Am J Transplant 13:1193-202
Weiner, Joshua; Scalea, Joseph; Ishikawa, Yoshinori et al. (2012) Tolerogenicity of donor major histocompatibility complex-matched skin grafts in previously tolerant Massachusetts general hospital miniature swine. Transplantation 94:1192-9
Oku, Manei; Okumi, Masayoshi; Shimizu, Akira et al. (2012) Hepatocyte growth factor sustains T regulatory cells and prolongs the survival of kidney allografts in major histocompatibility complex-inbred CLAWN-miniature swine. Transplantation 93:148-55
Yamada, K; Hirakata, A; Tchipashvili, V et al. (2011) Composite islet-kidneys from single baboon donors cure diabetes across fully allogenic barriers. Am J Transplant 11:2603-12

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