Transplant Immunology and Cytokine Immunobiology
South Dakota State University (1997) - B.S. - Biology; B.S. – Psychology University of Nebraska Medical School; Eppley Institute for Research in Cancer and Allied Diseases (2005) - Ph.D. - Microbiology and Pathology University of Pittsburgh School of Medicine; Thomas E. Starzl Transplantation Institute (2005-2009) - Postdoctoral Training - Transplant Immunology
Tenure-track Assistant Professor of Surgery and Immunology
University of Pittsburgh School of Medicine; Thomas E. Starzl Transplantation Institute
Tissue damage releases alarmins which are self-derived immunomodulatory molecules that recruit and activate the immune system. Numerous processes involved in the transplantation of allogeneic materials result in the destruction of donor and recipient cells and may trigger alarmin release. Our research is revealing that alarmins, such as the stromal cell-derived cytokine IL-33, are potent orchestrators of both pro-inflammatory and regulatory immune responses. I am currently the PI on two NIH-funded projects. In the first one, we are elucidating if the regulatory T cell-expanding properties of IL-33, which we show is released from recipient tissue damaged during pre-transplant conditioning, can be harnessed to support transplant tolerance or prevent the development of graft-vs. host disease (GVHD) after allogenic hematopoietic stem cell transplantation (AlloHCT). In the second project, we are testing the hypothesis that IL-33 is critical to initiate tissue repair mechanisms of both the adaptive and innate immune system. In these studies, we are particularly interested in defining the role IL-33 plays in development of chronic allograft vasculapathy (CAV) after heart transplantation.
What made you decide to work in transplantation?:
My Ph.D. thesis research focused on improving anti-tumor immune responses in mouse cancer models. These studies also made me appreciate the power of regulatory T and myeloid cells, which would rapidly stifle what started out as robust anti-tumor responses. As I finished my degree in 2005 and looked for places to complete post-doctoral training, my impression was that there was a lot of leadership and vision from the Transplant Community in early attempts to harness these regulatory populations. As such, I chose to work with Dr. Angus Thomson at the University of Pittsburgh. For the next four years, I help him characterize potential regulatory myeloid cell populations and aided his attempts to harness their therapeutic capacity for clinical tolerance induction. My training with Dr. Thomson gave me an excellent foundation in Transplant Immunology and Cytokine Immunobiology. It also led to my integration into the group of dedicated clinicians, clinician scientists, and basic researchers that are collaboratively bringing down the tragic barriers, such as CAV and GVHD, which stand in the way of successful long term transplant outcomes. Also, it must be mentioned that the support of the AST in the form of crucial early funding to myself and my trainees was critical to initiating my independent research program. In addition, AST-sponsored meeting such as the ATC, WTC, and CEoT, have been an ideal platform for me to present our research and interact with the individuals that have shaped my career and my research program.
What do you find to be the most valuable aspect of your work?:
My laboratory makes basic findings in Cytokine Immunobiology and then we work collaboratively with others in the Transplant Community to translate these discoveries into clinical applications that we hope will improve outcomes for transplant recipients. Given the emergence of biologics in medicine, many of which target cytokines, I expect my group is well positioned to make significant contributions in this space. As an example, our rodent studies of the IL-33 pathway in heart transplantation elucidated that rejection increased expression of a soluble version of the IL-33 receptor, which is also an IL-33 antagonist. With researchers at the University of Pittsburgh, Vanderbilt University, and Children's Mercy Hospital in Kansas City, we established that serum levels of the IL-33 receptor is a precise indicator of rejection in pediatric heart and small bowel recipients (Mathews et al. AJT. 2016). Importantly, serum levels of this IL-33 antagonist decreased with successful heart rejection treatment. This study nicely complements work completed by others in AlloHCT recipients and also demonstrated that serum IL-33 receptor levels correlate with GVHD severity and predict recipient response to anti-rejection therapy (Ponce et al. Blood. 2015; Vader Lugt et al. NEJM. 2013). In total, these studies support the potential of routine measures of serum IL-33 receptor to act as a biomarker of pathogenic alloimmune responses and of recipient responses to anti-rejection therapy.