Research Group

  • Prof. David Rothstein, Principal Investigator
  • Prof. Sundharam Hariharan, Co-Principal Investigator
  • Dr Aravind Cherukuri, Research Associate
  • Ms. Lauren Sciullo, Technician
  • Prof. Douglas Landsittel, Collaborator

Location

  • University of Pittsburgh, Pittsburgh, USA

Title

  • The role of regulatory and inflammatory B lymphocytes in kidney transplant rejection

B cells are leukocytes that protect the host by secreting antibodies. There is an emerging understanding that B cells can also inhibit immune response in transplantation and autoimmunity. Thus, a subset of B cells with regulatory properties (Bregs) was initially identified in mice based on expression of an inhibitory cytokine, IL-10. However, in humans, Bregs characterized by IL-10 led to discrepant results with regards to their identity and role in immune disease. We recently showed that human B cell subsets purported to contain Bregs, express both anti- and pro-inflammatory cytokines (IL-10 and TNF-α), and the IL-10:TNF-α ratio in immature transitional B cells (TrB) correlates with Breg activity better than IL-10 alone. Importantly kidney transplant recipients with rejection demonstrated an altered balance of these cytokines with a significantly decreased TrB IL-10:TNF-α. At time of a biopsy for transplant dysfunction/ rejection, this ratio predicted clinical outcome over the next three years. We hypothesize that TrB IL-10:TNF-α may be a biomarker for immune activity - and may be able to not only predict prognosis after rejection, but could also be an early predictor of adverse clinical events. We now propose a longitudinal study to prospectively analyze the predictive role of the B cell/subset-IL-10/TNF-α ratio for outcomes like rejection, antibodies against the transplant, and decline in transplant function. The availability of a Biorepository containing serial samples from kidney transplant recipients that can be indexed to transplant biopsies as well as renal function measurements, provides a unique opportunity to determine whether in individual patients the B cell cytokine profile is predictive of rejection and graft outcome, and if so, how early prior to development of clinical events this occurs. These studies will further our understanding of immune regulation by B cells and if successful will provide a warning that allows us to modify immunosuppression therapy before adverse clinical events occur. This would have a significant impact on improving outcomes in organ transplantation.

Progress Report