Project Overview Transplantation tolerance Is a dynamic immunological state that accommodates graft acceptance whilst maintaining undiminished immune responses to pathogens. We have recently demonstrated that the induction and preservation of transplantation tolerance can be differentially Impacted by pathogens that elicit distinct innate and adaptive immune signatures. These and other recent observations from our laboratories have led us to hypothesize that the quality of the tolerant state, either at the time of induction or during the maintenance phase, and the type of infection determine the long-term fate of the allograft. This is a new application requesting support for a highly integrated program project focused on understanding the cellular mechanisms in T cells that are necessary for a robust and persistent state of transplantation tolerance (i.e., tolerance that resists reversal by infections and permits long-term preservation of allograft function) (Project 1;Alegre) and understanding the short-term and long-term effects of infections on an already established state of transplantation tolerance (Project 2;Chong). Two Cores support the work of the two projects in the program. The Administrative Core (Core A, Chong) will oversee the administration of the program including the coordination of Progress Reports and co-ordinate meetings with the Internal and External Advisory Boards. The Animal and Microsurgery Core (Core B, Alegre) will be responsible for animal breeding and heart transplantations necessary for the two scientific projects. The Alegre and Chong laboratories have already been functioning as an integrated, cooperative program. Our investigations are revealing the complexity of the tolerant state as well as an unexpectedly divergent impact of infections on tolerance. There are few existing paradigms to guide these studies, thus the formal infrastructure of a Program Project will allow us to more seamlessly share personnel, data, resources, and to generate new hypotheses. Interactions with the internal and external advisory board members will allow new hypotheses and research designs to be vigorously vetted and improved upon. Successful completion of this program project will result in novel mechanistic and diagnostic insights into how transplantation tolerance can persist inspite of recurrent infections and achieve long-term allograft survival superior to current therapies.

Public Health Relevance

Graft acceptance without the need for drugs (a condition of immune tolerance) can be established in mice but remains an unfulfilled goal in human transplantation. This research program focuses on understanding how a state of robust transplantation tolerance that is resistant to reversal by infections is induced, monitored and maintained. Successful completion of this research will provide insights critical to the goal of transplantation tolerance as a transformative means to achieve life-long allograft function in humans.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Kehn, Patricia J
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University of Chicago
Schools of Medicine
United States
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Chong, Anita S (2016) From Pipe Dream to Donor-Specific PC Elimination: Novel Ways to Target Alloantibodies. Transplantation 100:2238-2239
Lei, Yuk Man; Chen, Luqiu; Wang, Ying et al. (2016) The composition of the microbiota modulates allograft rejection. J Clin Invest 126:2736-44
Alegre, Maria-Luisa; Lakkis, Fadi G; Morelli, Adrian E (2016) Antigen Presentation in Transplantation. Trends Immunol 37:831-843
Miller, Michelle L; Chen, Jianjun; Daniels, Melvin D et al. (2016) Adoptive transfer of tracer alloreactive CD4(+) TCR-transgenic T cells alters the endogenous immune response to an allograft. Am J Transplant :
Molinero, Luciana L; Yin, Dengping; Lei, Yuk Man et al. (2016) High-Fat Diet-Induced Obesity Enhances Allograft Rejection. Transplantation 100:1015-21
Yang, Jinghui; Chen, Jianjun; Young, James S et al. (2016) Tracing Donor-MHC Class II Reactive B cells in Mouse Cardiac Transplantation: Delayed CTLA4-Ig Treatment Prevents Memory Alloreactive B-Cell Generation. Transplantation 100:1683-91
Young, J S; Chen, J; Miller, M L et al. (2016) Delayed Cytotoxic T Lymphocyte-Associated Protein 4-Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection. Am J Transplant 16:2312-23
Chen, Jianjun; Wang, Qiang; Yin, Dengping et al. (2015) Cutting Edge: CTLA-4Ig Inhibits Memory B Cell Responses and Promotes Allograft Survival in Sensitized Recipients. J Immunol 195:4069-73
Bartman, Caroline; Chong, Anita S; Alegre, Maria-Luisa (2015) The influence of the microbiota on the immune response to transplantation. Curr Opin Organ Transplant 20:1-7
Geissler, Edward K; Tullius, Stefan G; Chong, Anita S (2015) Establishment of a global virtual laboratory for transplantation: a symposium report. Transplantation 99:381-4

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