Role of CXC chemokines at the innate-adaptive interface of alloimmune lung injury

Duke University, Durham NC

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Chronic rejection is the main obstacle to long-term survival post pulmonary transplantation, affecting over 50% of lung transplant recipients at 5 years and characterized by airway obstruction and obliterative bronchiolitis (OB). OB is also increasingly recognized as a complication of bone marrow transplantation (BMT). Our understanding of OB pathogenesis is very limited, partly due to the lack of an adequate animal model. Our laboratory has developed and pursued the hypothesis that activation of innate immunity promotes the development of alloimmune lung injury after human lung transplant. In support of this hypothesis, our group has demonstrated that mice develop lymphocytic bronchiolitis (LB) and OB after low-dose BMT followed by inhaled lipopolysaccharide (iLPS), the prototypic activator of innate immunity. Recent data suggest that CXC chemokines, interacting with the CXC receptor 3 (CXCR3), play an important role in recruiting T-cells to sites of innate immune activation. CXCR3 and its ligands have been found to be upregulated in patients with OB. Our own preliminary results suggest that CXCR3 ligands are elevated in the lung fluid of BMT recipient mice that develop LB and OB after iLPS. Consequently, we hypothesize that CXCR3-ligand interactions regulate the development of post-transplant LB and OB. This hypothesis will be tested through two complementary and independent aims: 1) Determine the effect of CXCR3 deficiency in circulating donor cells on pulmonary lymphocyte recruitment and OB in BMT mice challenged with iLPS using CXCR3-deficient and sufficient donor mice and 2) Determine the effect of exaggerated local CXCR3-ligand production on pulmonary lymphocyte recruitment and OB in BMT mice challenged with iLPS using recipient mice that express normal or high levels of CXCL10 in the lung. Biologic, immunologic, histopathologic, and physiologic parameters of the resulting murine phenotypes will be analyzed. Relevance: Enhanced understanding of the interplay between immunological and environmental processes in the development of chronic rejection is likely to lead to development of novel therapeutic targets. Our results may support blocking the CXCR3-chemokine immune signaling in human lung transplant patients as a novel means to prevent post-transplant rejection and improve long-term patient outcomes and survival. [unreadable] [unreadable] [unreadable]