Innate Immune Activation Potentiates Alloimmune Lung Disease Independent of Chemokine (C-X-C Motif) Receptor 3

BACKGROUND: Pulmonary graft-versus-host disease (GVHD) after hematopoietic cell transplant (HCT) and allograft rejection after lung transplant are parallel immunologic processes that lead to significant morbidity and mortality. Our murine model of pulmonary GVHD after inhaled lipopolysaccharide (LPS) suggests that innate immune activation potentiates pulmonary transplant-related alloimmunity. We hypothesized that the chemokine (C-X-C motif) receptor 3 (CXCR3) receptor is necessary for the development of LPS-induced pulmonary GVHD.METHODS: Recipient mice underwent allogeneic or syngeneic HCT, followed by inhaled LPS. CXCR3 inhibition was performed by using CXCR3-knockout donors or by systemic anti-CXCR3 antibody blockade. Pulmonary histopathology, cellular sub-populations, cytokine proteins, and transcripts were analyzed.RESULTS: Compared with the lungs of LPS-unexposed and syngeneic controls, lungs of LPS-exposed allogeneic HCT mice demonstrated prominent lymphocytic pen-vascular and peri-bronchiolar infiltrates. This pathology was associated with increased CD4(+) and CD8(+) T cells as well as an increase in CXCR3 expression on T cells, a 2-fold upregulation of CXCR3 transcript, and a 4-fold increase in its ligand CXCL10/Interferon gamma-induced protein 10 kDa (IP-10). CXCR3 inhibition using gene-knockout strategy or antibody blockade did not change the severity of pulmonary pathology, with a mean pathology score of 6.5 for sufficient vs 6.5 for knockout (p = 1.00) and a mean score of 6.8 for antibody blockade vs 7.4 for control (p = 0.46). CXCR3 inhibition did not prevent CD3 infiltration or prevent production of interleukin-12p40 or significantly change other Th1, Th2., or Th17 cytokines in the lung.CONCLUSIONS: In the setting of allogeneic HCT, innate immune activation by LPS potentiates pulmonary GVHD through CXCR3-independent mechanisms. Clinical strategies focused on inhibition of CXCR3 may prove insufficient to ameliorate transplant-related lung disease. J Heart Lung Transplant 2011;30:717-25 (C) 2011 International Society for Heart and Lung Transplantation. All rights reserved.