The role of recipient-derived B cells regulating ischemia reperfusion injury and its link to alloimmune responses after lung transplantation

About This Grant

Abstract As of today, lung transplantation continues to be the only treatment option for patients suffering from end-stage respiratory failure. Ischemia reperfusion injury (IRI)-mediated primary graft dysfunction (PGD) is a very common complication of lung transplantation affecting more than 50% of recipients. PGD is the main risk factor for short- term mortality and any degree of PGD is associated with chronic lung allograft dysfunction (CLAD) which remains the main barrier for long term survival. Therefore, it is of critical importance to better understand and characterize the mechanisms responsible for the development of IRI for clinical translation into improved outcomes. Currently, induction and maintenance therapies after lung transplantation are centered around the reduction of the robust T cell immune response against the allograft, including T cell help to B cell activation. However, it is known that T-cell independent signals can activate B cells to develop strong immune responses which are not targeted in contemporary treatment regimens. We have recently reported on the role of lung-infiltrating B cells in the pathogenesis of IRI. We found that the synergistic activation of the BCR/TLR4 receptors on these B cells is necessary for the production of the monocyte chemokine CCL7 in a TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. Also, we have generated new data suggesting that IRI produces a specific IRI-derived lung effector B cell subpopulation that upregulates activation and costimulatory markers (CXCR5+ CD25+ CD30+ CD80+ CD86+) which are essential for the development of B cell immune responses that could be important for donor specific antibody (DSA) production and development of AMR and CLAD after lung transplantation. The overarching goals of this application are to identify the key pathways associated with B cell recruitment after IRI; the mechanisms of early activation of recipient-derived B cells in the lung and which role these early events have on the development of subsequent deleterious immune responses by B cells. In this proposal, we will use state-of-the-art techniques including, murine lung transplantation, intravital microscopy, single cell RNA sequencing, proteomics and transcriptomic techniques to elucidate how lung macrophages direct B cells recruitment and colocalization to the lung after transplantation (SA1), if T-cell independent signals are capable of activate recipient-derived B cells early after reperfusion (SA2.1), If intravascular BCR activation on graft-infiltrating recipient B cells is necessary for their extravasation (SA 2.2) and to examine mechanisms that drive the development of deleterious B cell-mediated immune responses after lung transplantation (SA3). As B cells can be depleted with currently available agents, this project has the potential to change current paradigms of induction and maintenance immunosuppression after lung transplantation by identifying immunological targets for B cell-centered therapies which are not currently used in contemporary treatment regimens, therefore, improving the survival of lung transplant recipients.