Molecular Signatures of Antibody-Mediated Rejection and Graft Outcome After Kidney Transplantation. Q&A with Dr. Dela Golshayan, M.D., Ph.D.

Laura Tabellini Pierre on August 31, 2020

When Newsweek Magazine rates you the 9th best Hospital in the World, you know you are doing something remarkable! 

Located in Lausanne, Switzerland, Lausanne University Hospital (CHUV) sits on Lake Geneva and is surrounded by snowcapped and picturesque Swiss mountain peaks. Each year, the Hospital serves over 45,000 patients and helps around 3,000 babies come into the world. Therefore, it’s no surprise that one of our grant winners for the nCounter® Human Organ Transplant Panel is Dela Golshayan, M.D., Ph. D., Associate Professor in Nephrology and Transplantation Medicine at CHUV. Dr. Golshayan received her M.D/Ph.D at the University of Lausanne and holds another doctorate in Transplantation Immunology from the Imperial College London. Her project is entitled “Molecular signatures of antibody-mediated rejection and graft outcome after kidney transplantation.”

NS: Your specialty in medical school was nephrology. What fascinates you about the field of transplant immunology?

DG: Immunology is a broad and fascinating topic. Many diseases in nephrology are immune-mediated. An understanding of transplantation immunology is a prerequisite for developing successful therapeutics that lead to improved graft outcome. 

NS: Can you tell us more about your research at Lausanne University Hospital?

DG: My research focuses on immune-mediated diseases, specifically in the fields of nephrology and transplantation. In past years, my laboratory’s main research topic has been immune regulation and mechanisms that lead to transplantation tolerance.

Our overall research aim is to better understand the pathogenesis of acute graft rejection and chronic allograft dysfunction and the role of immune cell subsets in these processes. Therefore, we have developed experimental transplantation models, with an interest in studying the biology of regulatory T cells and their role in the induction of tolerance. 

Following from our basic experimental findings, and as a physician-scientist involved in the routine care of transplant recipients at our Transplantation Center, I had the unique opportunity to develop, in parallel, translational research aiming at defining immune determinants that are associated with acute T cell- and antibody-mediated rejection, as well as graft outcome after kidney transplantation; this translational study will complement our existing model data. 

NS: How many patients come through the transplant center every year, and what is the average number of people in Europe in need of a kidney transplant?

DG: The kidney transplantation program at Lausanne University Hospital was established in the mid 1970’s. We currently perform an average of 55 kidney transplantations per year, about half of which are done with organs from living donors. We follow these patients over the long term. Our Hospital is also responsible for regional heart and lung transplantation programs and liver transplant recipients’ follow-up.

NS: What is the average survival time after a successful kidney transplant?

DG: According to data from the Swiss Transplant Cohort Study, 10 years after kidney transplantation, patient survival is currently at around 81% and graft survival at around 86%.

NS: What are the main obstacles to understanding and preventing antibody-mediated rejection (AMR)?

GD: We need better definitions and a more precise characterization of rejection episodes, from a clinical and immunological perspective ─ an evaluation of B cell responses and the pathogenicity of anti-HLA antibodies and a histological perspective ─ characterization of immune infiltrates in graft biopsies.

NS: Some recipients are already HLA-sensitized and, therefore at higher risk of developing AMR. Is there a pre-transplant screening to predict the likelihood of AMR?

DG: The recipient’s immunological status is an important variable at the time of organ allocation and predicts the risk of acute rejection after transplantation. The amount and specificity of anti-HLA antibodies are carefully monitored before transplantation and on the day of surgery through crossmatch tests. Unfortunately, there is no routine test that can rapidly assess the immune repertoire and measure T and B cell activation and function at the time of transplantation and during follow-up. Such tests would help better predict the recipient’s immunization status and the risk of cellular and/or antibody-mediated rejection.

NS: It seems that immunosuppression is the only strategy currently. What do you think an “individualized immunosuppressive therapy” entails?

DG: Tailored immunosuppression would limit the risks related to under-or over-immunosuppression, i.e., it would improve patient and graft outcome by limiting not only rejection episodes and immunization but also infections and oncological complications.

NS: Immune suppression therapy-free tolerance is usually a concept associated with stem cell and bone marrow transplants, but not with solid organ transplants. Do you think there will be a day when a life without immunosuppressive drugs is also possible for solid organ transplant recipients?

DG: Transplantation tolerance has already been achieved in a small group of patients that could benefit from combined bone marrow and kidney transplantation. The underlying mechanisms are the induction of hematopoietic mixed chimerism and central, thymus-mediated, immune tolerance. Research is also ongoing to modify the peripheral immune repertoire pharmacologically or via cell therapy (in particular, using customized regulatory T cells) to promote tolerance in solid organ transplantation.

NS: When did you hear for the first time about the NanoString® nCounter platform, and what made you decide to apply for the grant?

DG: This type of technology is successfully applied in oncology to evaluate the prognosis and response to therapy. The same type of information is needed in transplantation to personalize treatment and improve graft outcome.

NS: How do you think the results obtained with the NanoString grant will fast forward your research and have a clinical impact?

DG: It is crucial to develop tools that identify recipients at risk of rejection to optimize and individualize immunosuppressive therapy. Molecular profiling of peripheral immune cells and/or graft tissues will help us better characterize transplant recipients’ immune repertoire by identifying an early signature for acute rejection and graft outcome. 

NS: One goal of this Q&A series with our grant winners is to celebrate their work. Can you tell us something interesting about your lab and the people you work with, maybe a fun lab story?

DG: The lab has always benefitted from dedicated people and collaborators. As a clinician, I learned a lot from basic scientists and still do. For example, we have a mutual “helpline” to calculate series dilutions that are useful at the end of a long day at the bench! 

Check out the nCounter Human Organ Transplant Panel and comprehensively profile 770 genes across 37 pathways to identify biomarkers for rejection, uncover mechanisms of tissue damage, and study toxicities brought on by immunosuppressive drugs. 

For Research Use Only. Not for use in Diagnostic Procedures.

Post by Laura Tabellini Pierre