The Kidney Foundation of Canada

Dr. Sacha de Serres 

Dr. Sacha de Serres

Université Laval, Quebec

The role of dendritic cells and follicular helper T cell in antibody-mediated rejection of the kidney graft


2017-2019: $100,000 | Biomedical Research Grant | Category: Transplantation

Biography

Dr. Sacha De Serres is a new investigator at Laval University. He obtained his M.D. at Université de Montréal and trained in Internal Medicine and Nephrology at Laval University. He then completed a KRESCENT Post-Doctoral Fellowship in Transplantation Immunology at the Brigham and Women’s Hospital at Harvard University in Boston. Dr. De Serres’s research focuses on the innate immunity in transplantation.

The aim of his project is to study the interaction between two specific type of cells, the dendritic cells and the follicular helper T cells, during kidney rejection. More precisely, Dr De Serres’ aim is to decipher how these cells instruct the B cells to produce antibodies against the graft. Dr. De Serres’ hope is that this knowledge will help to individualize immunosuppressive therapy and thus reduce the side effects of the anti-rejection drugs. It should also help to develop better treatments for chronic rejection, which will ultimately increase the life expectancy of the transplanted kidneys. These tools might prove beneficial not only to kidney transplant recipients, but eventually to the recipients of other organs.

Lay Summary

In the last twenty years, considerable progress has been achieved in kidney transplantation. However, the life expectancy of transplanted kidneys has not increased as much as expected. In Canada, the percentage of kidneys from deceased donors that are still functional 5 years after transplant is only slightly above 80%. In other words, young patients transplanted today may need 2, 3 or even more grafts during their lifetime. Adequate graft survival would be that once a patient receives a kidney, he or she will die with this graft functioning. Given that each year in dialysis costs over 50,000$ dollars more than a year with a functioning transplant, there is a clear economic incentive to improve graft survival.

Premature graft loss is most often due to late rejection, which is caused by anti-HLA antibodies. Although many agents have been tested to treat antibody-mediated rejection, so far none of them has been very successful. Once the patient develops these antibodies, he or she is somewhat ‘vaccinated’ against the graft. To improve outcomes, we need to block the immune system at a checkpoint before antibody generation.

The purpose of the proposed research is to better understand how innate immune cells called dendritic cells can instruct specialized T cells called follicular helper cells to interact with B cells that produce anti-HLA antibodies. We previously described that dendritic cells can invade the graft slowly in patients following transplantation, and that they are in close contact with activated T cells. More recently, we confirmed that patients with class II anti-HLA antibodies have a predominance of follicular T cells in their blood and in their kidney biopsy, that was not observed with class I anti-HLAs. We now want to better characterize this dendritic cells – T cell interaction in humans in vitro and in vivo. In particular, we want to determine whether specific inhibition of cytokines involved in the dendritic cells – follicular T cells crosstalk can prevent donor-specific antibody formation by human B cells.
The hope is to find an immunological target(s) (single or in combination) that will block the pathway to antibody formation before the process reaches the B cells checkpoint. Some cytokine candidates, such as anti-IL21, are already in development for other diseases. Moreover, this work will clarify whether inhibition of follicular helper cell generation seems an interesting target for class II anti-HLA only, or also for class I anti-HLAs.