The major impediments to the success of organ transplantation remain the failure of current immunosuppressive drugs to prevent rejection and the morbidities associated with the side effects of those drugs. Strategies for achieving tolerance would avoid both these problems. Most tolerance inducing protocols target the T cell compartment, especially regulatory T cells (Tregs) that can specifically suppress alloreactive immunity. However, recent studies suggest that there is an analogous subset of B cells in mice and humans. The combination of anti-CD45RB and anti-TIM1 results in almost 100% long term islet allograft survival, and this effect is dependent on the presence of recipient B cells. TIM1+ cells from tolerant mice are able to transfer tolerance to untreated animals in a donor specific manner. Tolerance transfer requires the presence of native Tregs in the second recipient. We hypothesize that combined antibody therapy induces a regulatory B cell population (Bregs) that interacts with Tregs to promote tolerance. This proposal seeks to elucidate the interaction of Bregs with Tregs and the molecules that are important in governing tolerance in this model.

Public Health Relevance

Transplant tolerance and avoidance of lifelong immunosuppression remains an elusive goal for patients. In this project, we propose to study a novel mechanism of inducing tolerance through the development of regulatory B cells, which significantly improves of the success of tolerance induction protocols in mice. Understanding the role of B cells in tolerance will have a major impact on the current immunosuppressive regimens used in transplant patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK094965-01A1
Application #
8443187
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$158,750
Indirect Cost
$11,350
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Bruinsma, Bote G; Avruch, James H; Sridharan, Gautham V et al. (2017) Peritransplant Energy Changes and Their Correlation to Outcome After Human Liver Transplantation. Transplantation 101:1637-1644
Schuetz, C; Lee, K M; Scott, R et al. (2017) Regulatory B Cell-Dependent Islet Transplant Tolerance Is Also Natural Killer Cell Dependent. Am J Transplant 17:1656-1662
Karimian, Negin; Yeh, Heidi (2017) Opportunities for Therapeutic Intervention During Machine Perfusion. Curr Transplant Rep 4:141-148
Navarro-Alvarez, N; Shah, J A; Zhu, A et al. (2016) The Effects of Exogenous Administration of Human Coagulation Factors Following Pig-to-Baboon Liver Xenotransplantation. Am J Transplant 16:1715-1725
Bruinsma, Bote G; Sridharan, Gautham V; Weeder, Pepijn D et al. (2016) Metabolic profiling during ex vivo machine perfusion of the human liver. Sci Rep 6:22415
Bruinsma, Bote G; Berendsen, Tim A; Izamis, Maria-Louisa et al. (2015) Supercooling preservation and transplantation of the rat liver. Nat Protoc 10:484-94
Bruinsma, Bote G; Avruch, James H; Weeder, Pepijn D et al. (2015) Functional human liver preservation and recovery by means of subnormothermic machine perfusion. J Vis Exp :
Bruinsma, Bote G; Wu, Wilson; Ozer, Sinan et al. (2015) Warm ischemic injury is reflected in the release of injury markers during cold preservation of the human liver. PLoS One 10:e0123421
Lei, J; Kim, J I; Shi, S et al. (2015) Pilot Study Evaluating Regulatory T Cell-Promoting Immunosuppression and Nonimmunogenic Donor Antigen Delivery in a Nonhuman Primate Islet Allotransplantation Model. Am J Transplant 15:2739-49
Adler, J T; Dong, N; Markmann, J F et al. (2015) Role of Patient Factors and Practice Patterns in Determining Access to Liver Waitlist. Am J Transplant 15:1836-42

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