Chronic rejection is the most important clinical problem in human lung transplantation. The underlying causes of this process (which is manifest as obliterative bronchiolitis (OB) in lung transplants) are not completely understood, but host anti-donor cellular immunity has been shown to be a key factor. The CD40 costimulatory pathway is critical for optimal cellular immune responses, and evidence suggests that CD40 activity plays a major role in chronic rejection. However, the mechanism(s) by which CD40 facilitates chronic rejection are not known. CD40 signaling can induce the production of TGFbeta, a pro-fibrotic cytokine whose role in chronic rejection and organ fibrosis is well-established, in human B cells. We postulate that CD40-mediated induction of TGFbeta1 by alveolar macrophages (AM), which are important sources of this cytokine in pulmonary fibrosis, represents a mechanistic link between CD40 activity and chronic rejection. We therefore propose to study 1) indices of CD40 activity in tissues from lung transplant patients with OB and from patients with acute rejection (who are at increased risk of developing OB) and 2) the ability of CD40 signaling to induce TGFbeta1 in AM from lung transplant patients. The Principal Investigator has an extensive background in basic immunology and clinical lung transplantation. The research project outlined here will train her to integrate these elements of her background and to approach clinical problems such as chronic rejection with the combined tools of basic science and clinical research. This award will provide her with the training, resources and protected time she needs to establish a successful career as an independent investigator in lung transplant immunology.
