Modeling BK Virus Infection in Renal Transplant Recipients.
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2024-12
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Kidney transplant recipients require a lifelong protocol of immunosuppressive therapy to prevent graft rejection. However, these same medications leave them susceptible to opportunistic infections. One pathogen of particular concern is human polyomavirus 1, also known as BK virus (BKPyV). This virus attacks kidney tubule epithelial cells and is a direct threat to the health of the graft. Current standard of care in BK virus-infected transplant recipients is reduction in immunosuppressant therapy, to allow the patient's immune system to control the virus. This requires a delicate balance; immune suppression must be strong enough to prevent rejection, yet weak enough to allow viral clearance. We seek to model viral and immune dynamics with the ultimate goal of applying optimal control methods to this problem. In this paper, we begin with a previously published model and make simplifying assumptions that reduce the number of parameters from 20 to 14. We calibrate our model using newly available patient data and a detailed sensitivity analysis. Numerical results for multiple patients are given to show that the newer model reflects observed dynamics well.
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Myers, Nicholas, Dana Droz, Bruce W Rogers, Hien Tran, Kevin B Flores, Cliburn Chan, Stuart J Knechtle, Annette M Jackson, et al. (2024). Modeling BK Virus Infection in Renal Transplant Recipients. Viruses, 17(1). p. 50. 10.3390/v17010050 Retrieved from https://hdl.handle.net/10161/32119.
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Scholars@Duke
Chi Wei Cliburn Chan
Computational immunology (stochastic and spatial models and simulations, T cell signaling, immune regulation)
Statistical methodology for immunological laboratory techniques (flow cytometry, CFSE analysis, receptor-ligand binding and signaling kinetics)
Informatics of the immune system (reference and application ontologies, meta-programming, text mining and machine learning)
Annette M Jackson
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.
Eileen Tsai Chambers
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