David M. Rothstein, MD
Pittsburgh Steelers Chair in Transplantation; Professor of Surgery, Medicine, and Immunology
BA, University at Buffalo; MD,The University of Pennsylvania School of Medicine
Regulation of the immune system and tolerance induction
My laboratory studies immunoregulation and tolerance in allograft and autoimmune models. We have used reagents that and promote tolerance by targeting specific molecules. By studying their basic mechanism(s) of action we can identify new immunoregulatory pathways.
I. CD45 and regulatory T cells (Tregs): CD45 is a transmembrane phosphatase that regulates lymphocyte activation. Anti-CD45RB is a potent tolerogenic agent that acts by increasing the number of Tregs. This occurs both by specifically inducing proliferative expansion of Tregs in vivo. New data indicate that this occurs through specific enhancement of interactions between Tregs and antigen presenting cells and we are now examining the biochemical mechanisms involved. If this can be replicated in humans, it provides an approach to specifically promote Treg in vivo.
Based on the potency of combining anti-CD45RB with agents that interfere with CD40/CD154-mediated costimulation in rodents, we are now examining this in non-human primates, with exciting early results. New studies are examining the function of Tregs using new strategies to observe Treg behavior in living tissues using multiphoton microscopy.
II. TIM molecules and regulatory B cells (Bregs): While TIM-1 is expressed transiently by activated CD4+ T cells, we have recently shown that TIM-1 is an inclusive marker for Bregs. This small but potent B cell subset promotes tolerance through mechanisms that include IL-10 expression. Moreover, our data indicate that anti-TIM-1 promotes tolerance by inducing TIM-1+ Bregs. Current studies aim to identify the mechanisms by which TIM-1 signaling induces Bregs elucidate the exact nature of crosstalk between Bregs and T cells required for Breg upregulation an also for Breg suppressive function. In addition, we have identified markers expressed on novel subsets of B cells with inflammatory function. Although these cells hasten allograft rejection, they promote anti-tumor immunity. Approaches to interfere with these cells while promoting Bregs are being developed.
In humans, we have identified both IL-10 and TNFα expressing B cells within the same classic B cell subsets. The ratio of anti- versus pro- inflammatory cytokines is highest in transitional B cells in peripheral blood. These cytokines correlates with increased regulatory activity by this subset in vitro. While stable renal allograft recipients resemble healthy subjects, patients with renal allograft rejection exhibit an decrease in their transitional B cell IL-10:TNFα ratio. Moreover this ratio at time of biopsy is predictive of three-year outcome. Therefore, B cell cytokines may act as a biomarker for and rejection, and may play an important role in immunological reactivity in humans. New prospectively studies are being designed to determine the value of B cell cytokines as biomarkers for allograft outcomes.