James Gardner and Nicole Conkling Awarded 2017 ASTS Research Grants
Dr. Gardner, who just completed his Chief Residency in General Surgery at UCSF and is a rising fellow in the Division of Transplant Surgery, was the only transplant fellow in the country to receive the prestigious ASTS-Astellas Fellowship. The award will fund Dr. Gardner's research, which he pursued throughout his residency with the support of Department of Surgery funding, during his clinical fellowship years.
Dr. Gardner's work, conducted in mentored collaboration with the Mark Anderson Lab at the UCSF Diabetes Center, is focused on the mechanisms regulating self-tolerance in the adaptive immune system, and translating these findings into relevant therapeutics for inducing and maintaining donor-specific tolerance. Dr. Gardner and Dr. Anderson originally discovered a novel population of cells distributed throughout the body’s secondary lymphoid organs, which are capable of inducing robust self-tolerance and preventing autoimmunity (Gardner et al. Science 2008, Immunity 2013). Their work on this population is also supported by an NIH/NIHAI R01 - (Developing eTACs as a Novel Method of Tolerance in Type 1 Diabetes) and an American Diabetes Association Young Investigator Award.
Dr. Conkling, a Resident Research Fellow in Plastic Surgery, was awarded the ASTS Resident Scientist Scholarship to fund her project to study chimeric antigen receptor T-regulatory cell therapy for rejection in a mouse model of composite tissue transplantation in the Transplantation Immunology Lab ("Tang Lab") led by Qizhi Tang, Ph.D. A composite tissue allograft (CTA) such as a hand or face is made up skin, muscle, tendon, nerves, bone and blood vessels that may be transplanted to a victim of trauma, burn, or other disfiguring tissue loss to restore both form and function.
Immunosuppressive medication is currently the only option for preventing rejection of CTAs. However, because the surgery is life-enhancing as opposed to life-saving (such as the transplantation of a kidney or liver for end-stage renal or liver disease respectively), committing a patient to a lifetime of immunosuppressive therapy becomes harder to ethically justify. The holy grail in this area is to discover alternate less toxic ways to induce immunological tolerance to CTAs by lowering or even eliminating immunosuppressive medication requirements.
Dr. Conkling's project, funded by the ASTS, is emblematic of this research, with a long-term goal of developing targeted cell-based anti-rejection therapies in the setting of composite transplants. She is also funded by a Ruth L. Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship (F32 NIH/NIAID), which speaks to the exceptional mentorship and innovation in the Tang lab.
2017 ASTS–Astellas Fellowship in Transplantation
James M. Gardner, M.D., Ph.D.
Abdominal Transplant Fellow (PGY-6)
Division of Transplant Surgery
Donor-Specific Tolerance Induction by Extrathymic Aire-Expressing Cells
Synopsis: The purpose of our research is to understand the fundamental mechanisms regulating self-tolerance in the adaptive immune system, and to translate these findings into relevant therapeutics for inducing and maintaining donor-specific tolerance. In mentored collaboration with the Mark Anderson lab at the UCSF Diabetes Center, our lab studies a gene called the Autoimmune Regulator, or Aire, which was found to be a key regulator of central tolerance, and is required by educator cells in the thymus to expose the developing T-cell pool to a diverse array of one’s own antigenic diversity. In 2008 we discovered of a novel population of Aire-expressing cells outside the thymus—distributed throughout the body’s secondary lymphoid organs—which we named extrathymic Aire-expressing cells (eTACs), and which we demonstrated could be modified to induce robust self-tolerance and prevent autoimmunity (Gardner et al. Science 2008, Immunity 2013).
Our current research has three aims. First, to better understand the basic biology and immunology of eTACs. To this end, we have defined and are currently publishing work describing the family of antigen-presenting cells to which eTACs belong, and the mechanisms by which they induce tolerance. This basic biology and immunology is essential to any further therapeutic efforts. Second, to define the developmental biology of this cell population, and specifically how eTACs can be differentiated in vitro for diagnostic and therapeutic purposes. This work will greatly facilitate the ability to both study these cells and to develop translational cellular therapies. Third, to pioneer a therapeutic role for eTACs in inducing and maintaining donor-specific tolerance in a murine allogeneic transplant model. Together this research program aims to define a novel branch of adaptive immunity, and to apply these findings directly to transplant tolerance.
2017 ASTS Resident Scientist Scholarship
Chimeric Antigen Reception T-regulatory Cells for Targeted Rejection Therapy in Murine Hindlimb Composite Tissue Transplant
Synopsis: Vascularized composite tissue allotransplantation (VCTA) still faces many challenges regarding the unique immunologic demands of composite grafts and their propensity toward rejection. Acute rejection is extremely common in clinical VCTA, and chronic rejection remains poorly described. Interest has emerged in cellular therapies as an alternative to immunosuppressive drugs to treat rejection. T-regulatory cells (T-regs), which induce a more tolerogenic state, are known to be instrumental in long-term graft survival, attenuating the long-term sequelae of chronic rejection. Engineered chimeric antigen receptor (CAR) T-regs activated by donor antigens may allow for efficient, targeted therapy for VCTA rejection.
This study employs a murine hindlimb transplant model with two specific aims. First, transplanted mice will be observed clinically and serially biopsied to study the kinetics and cellular aspects of VCTA rejection, examining the architecture of the tissues and populations of graft cellular infiltrates. Second, recipients with rejection will be treated with CAR T-regs as salvage therapy. We hypothesize that CAR T-reg infusion will halt or reverse the rejection process. This project seeks to elucidate what is known about rejection in VCTA, as well as apply a targeted cellular intervention for salvage of rejected grafts. CAR T-cells have shown clinical promise in other fields, and they could feasibly be translated to the treatment of rejection in human VCTA. CAR T-regs represent a powerful tool for treating composite allografts threatened by rejection, as well as progress toward achieving the goal of tolerance without the life-long use of immunosuppressive drugs.