Inbred miniature swine provide a unique preclinical model for the study of transplantation immunity and tolerance. We have previously demonstrated that robust tolerance to MHC class l-mismatched renal allografts can be achieved following a short course of calcineurin inhibitors in this model. Since, unlike central tolerance, the induction of tolerance in this system does not involve T cell ablation, and since T cells are long-lived, the central hypothesis of this proposal is that this form of tolerance involves a continuing mechanism for down-regulation of T cell reactivity. During the last project period, our inbreeding program has produced a subline with >94% coefficient of inbreeding, permitting investigation of the mechanism of tolerance by adoptive transfer for the first time in a large animal model. Our data using these animals indicate that tolerance to class I mismatched renal allografts involves regulatory T cells (T-reg) that can be isolated from the long-term tolerated kidney and can also be mobilized in the periphery following DST. We have also observed that tolerance persists for at least 3-months after removal of the graft, and that during this period, immunization by donor class I peptides, but not by rejection of donor skin grafts, abrogates the tolerant state. Finally, we have found that the treatment of tolerant animals with DST and leukapheresis, required for successful adoptive transfer of their tolerance, also leads to loss of the tolerant state. Collectively, these data suggest that tolerance relies on a balance between alloreactivity and regulation, which is maintained via definable cellular interactions between the graft and the recipient's immune system. To test these hypotheses, we will 1) Determine the nature of the cell populations responsible for transfer of tolerance by adoptive transfer; 2) Study the mechanism by which the pathway of antigen presentation determines maintenance vs. loss of tolerance; and 3) Examine the balance between alloreactivity and regulation that determines the fate of a second transplant into a tolerant recipient. It is hoped that an understanding of the mechanisms by which allograft tolerance is induced and maintained in this large-animal model will permit development of appropriate clinical protocols for induction of specific tolerance to organ allografts. ? ?

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 #
2R37AI031046-16
Application #
7148454
Study Section
Special Emphasis Panel (ZRG1-TTT-G (09))
Program Officer
Koh, Crystal Y
Project Start
1991-04-01
Project End
2011-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
16
Fiscal Year
2006
Total Cost
$610,916
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Sachs, David H (2017) Immune Tolerance, Xenografts, and Large-Animal Studies in Transplantation. Ann Am Thorac Soc 14:S220-S225
Tasaki, M; Villani, V; Shimizu, A 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 16:2877-2891
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
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
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
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
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

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