Donor apoptotic cell-based therapy for effective inhibition of donor-specific memory T and B cells to promote long-term allograft survival in allosensitized recipients.
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2020-10
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Allosensitization constitutes a major barrier in transplantation. Preexisting donor-reactive memory T and B cells and preformed donor-specific antibodies (DSAs) have all been implicated in accelerated allograft rejection in sensitized recipients. Here, we employ a sensitized murine model of islet transplantation to test strategies that promote long-term immunosuppression-free allograft survival. We demonstrate that donor-specific memory T and B cells can be effectively inhibited by peritransplant infusions of donor apoptotic cells in combination with anti-CD40L and rapamycin, and this treatment leads to significant prolongation of islet allograft survival in allosensitized recipients. We further demonstrate that late graft rejection in recipients treated with this regimen is associated with a breakthrough of B cells and their aggressive graft infiltration. Consequently, additional posttransplant B cell depletion effectively prevents late rejection and promotes permanent acceptance of islet allografts. In contrast, persistent low levels of DSAs do not seem to impair graft outcome in these recipients. We propose that B cells contribute to late rejection as antigen-presenting cells for intragraft memory T cell expansion but not to alloantibody production and that a therapeutic strategy combining donor apoptotic cells, anti-CD40L, and rapamycin effectively inhibits proinflammatory B cells and promotes long-term islet allograft survival in such recipients.
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Dangi, Anil, Shuangjin Yu, Frances T Lee, Melanie Burnette, Stuart Knechtle, Jean Kwun and Xunrong Luo (2020). Donor apoptotic cell-based therapy for effective inhibition of donor-specific memory T and B cells to promote long-term allograft survival in allosensitized recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 20(10). pp. 2728–2739. 10.1111/ajt.15878 Retrieved from https://hdl.handle.net/10161/26156.
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Scholars@Duke
Jean Kwun
Dr. Kwun is currently the Director of Transplant Basic Science Research at the Duke Transplant Center.
Research interests include humoral tolerance to organ transplants in animal model and humans, developing a clinically relevant animal model to study the mechanisms of antibody-mediated rejection (AMR), and establishing a conceptual basis that will translate into therapeutic intervention of AMR.
Xunrong Luo
Dr. Luo earned her B.S. degree from Tsinghua University, and her MD and PhD degrees from Duke University. She then completed an internship and residency in internal medicine at the New York-Presbyterian Weill Cornell Medical Center, followed by a clinical fellowship in Nephrology and a research fellowship in Transplant Nephrology at that institution. She joined the faculty at Northwestern University Feinberg School of Medicine in 2005 in the Division of Nephrology and Hypertension. There, she was the founding director of the Center for Kidney Research and Therapeutics, and the director of the Human Islet Transplant Program of the Comprehensive Transplant Center. Dr. Luo returned to Duke in September 2018 as the Director of Translational Research of Duke Transplant Center. Dr. Luo’s research primarily focuses on the induction and mechanisms of transplantation tolerance. Since 2006, Dr. Luo has been continuously funded as a principal investigator by the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the National Kidney Foundation.
The focus of research of Dr. Luo is to study tolerance mechanisms for tissue/organ transplantation, and to design tolerance therapies for eliminating transplant rejection, therefore increasing longevity and alleviating severe shortage of donor organs for transplantation. Two parallel avenues of research conducted by the Luo Lab are: (1) mechanisms for induction of transplant tolerance (funded by R01 HL139812); (2) mechanisms for maintenance of transplant tolerance (funded by R01 AI114824). The former elucidates differential roles of innate and adaptive immunity in transplant rejection, and devises strategies to inhibit both for tolerance induction. The latter focuses on effects of immune disturbance by inadvertent infections (such as COVID-19) on the stability of established tolerance, and devises strategies to mitigate such disturbances in order to maintain stable transplant tolerance. More recently, the candidate expanded her research portfolio to include immune regulation for xenogeneic transplantation (funded by U01 AI090956). The impetus for this research stems from the recognition of the intense shortage of donor organs appropriate for transplantation. Therefore, alternative sources of transplantable organs such as from xenogeneic sources (specifically porcine sources) would significantly alleviate such organ shortage, allowing wider access to organ transplantation as a curative therapy for all end stage organ diseases. However, immune responses to xenogeneic organs are far more aggressive and unique in nature in comparison to those to allogeneic organs. Therefore, Luo’s funded research focuses on dissecting the immune responses in xenogeneic transplantation, and devising strategies to allow minimization to life-compatible immunosuppression in that setting.
Most significant contributions from the candidate to the advancement of knowledge are listed below that have led to important paradigm shift in the field of transplantation research:
- Establishing a robust non-chimeric approach for transplantation tolerance: The approach pioneered by the candidate takes advantage of the body’s anti-inflammatory ability while clearing billions of self apoptotic cells on a daily basis. As such, when encountering donor cells also rendered apoptotic, the recipient’s immune system employs several parallel regulatory mechanisms to ensure robust tolerance, rather than immunity, to the donor. This approach has now been validated in non-human primate allogeneic transplant models as well as in humanized mouse xenogeneic transplant models. Standard Operating Procedures (SOPs) have been developed with the next goal of conducting a first-in-human clinical trial.
- Establishing the critical role of efferocystic receptors in transplantation: In-depth work from the candidate’s lab is the first to demonstrate the critical role of anti-inflammatory efferocytic receptors in mediating transplantation tolerance. Specifically, her lab demonstrates that one such receptor MerTK is capable of transmitting intracellular signaling to suppress the production of inflammatory cytokines, leading to subsequent expansion of suppressor cell populations. The impact of this work further lies in its implication that their agonism would be a promising target for promoting transplantation tolerance. The impact of this work is further underscored by the selection of our work for the cover of the American Journal of Transplantation of its March 2019 issue.
- Identifying immune signals that disturb the balance of immune regulation by inadvertent viral infections during tolerance maintenance: Specific cytokines and cell populations have been identified that mediate viral-precipitated transplant rejection in otherwise stably tolerized transplant recipients. The candidate’s research further examines strategies that would preserve established tolerance in settings of inadvertent viral infections. The significance of this research is sharply accentuated in light of the recent COVID-19 pandemic that reminded us that transplant recipients, even tolerized, live in an environment in which many microbial pathogens can activate various arms of the immune system to break established tolerance. Therefore, understanding mechanisms of such immune disturbances will be critical for designing therapeutic interventions to preserve tolerance in such settings.
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