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.
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.
|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 :|
|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|
|Lee, Kang Mi; Stott, Ryan T; Zhao, Gaoping et al. (2014) TGF-Î²-producing regulatory B cells induce regulatory T cells and promote transplantation tolerance. Eur J Immunol 44:1728-36|
|Lee, Kang Mi; Yeh, Heidi; Zhao, Gaoping et al. (2014) B-cell depletion improves islet allograft survival with anti-CD45RB. Cell Transplant 23:51-8|
|Kim, James I; Stott, Ryan T; Soohoo, Julie et al. (2013) Elevated levels of interferon-Ã½Ã½ production by memory T cells do not promote transplant tolerance resistance in aged recipients. PLoS One 8:e82856|
|Yeh, Heidi; Moore, Daniel J; Markmann, James F et al. (2013) Mechanisms of regulatory T cell counter-regulation by innate immunity. Transplant Rev (Orlando) 27:61-4|
|Lee, K M; Kim, J I; Stott, R et al. (2012) Anti-CD45RB/anti-TIM-1-induced tolerance requires regulatory B cells. Am J Transplant 12:2072-8|