KSEF RDE: Role of Donor Neutrophils in Pulmonary Graft versus Host Disease Pathogenesis after Allogeneic Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation (allo-HCT) often presents the only chance for cure in patients with hematological malignancies. Its benefits are counteracted by the development of Graft versus-host disease (GVHD). It more and more becomes clear, that effector cells of both adaptive and innate immunity contribute. The pro-inflammatory role of recipient neutrophils in the early pathogenesis ofGVHD was recently demonstrated by our group (Nature Medicine 2014: 20,648-654), while the role of donor neutrophils later in the course of disease is poorly understood. Preliminary data from our lab shows that neutrophil depletion during the time of donor cell recovery reduces gastrointestinal GVHD and possibly improves overall outcome. Lethally irradiated B6D2F1 mice received hematopoietic cells from allo C57BL/6 or syngeneic B6D2F1 donors. While significant mortality by week 6 was observed in allo controls (40%), all recipients receiving Ly-6G Ab survived. Interestingly, in addition to decreased pathology in the colon, bronchoalveolar lavage fluid cellularity was decreased as surrogate marker for reduced lung inflammation. Our Kentucky patient population is prone to increased risk for lung toxicity and pulmonary GVHD, as life style habits, such as smoking, and associated impaired lung function renders Kentucky transplant patients especially vulnerable. We aim to better identify the role of neutrophils in pulmonary GVHD. Chemokine receptor CXCR2 is a receptor expressed on neutrophils and critical for neutrophil migration. It has been shown to be involved in non-transplant neutrophil-mediated lung injury. Using different methods of neutrophils depletion (anti-Ly6G neutrophil depleting antibody) or targeting CXCR2 (CXCR2 deficient donors, SB225002 selective non-peptide inhibitor of CXCR2, anti-CXCR2 MAB 2164 antibody (R&DSystems)) we will characterize the role of neutrophil influx into the lung after transplant. This work will be a direct extension of our prior work identifying several signaling pathways involved in T cell and monocyte/macrophage migration to the lung.