Pulmonary dysfunction remains a frequent and potentially fatal complication following allogeneic hematopoietic stem cell transplantation (SCT). Almost half of the pneumonias that occur in this setting are non-infectious in origin and are referred to as idiopathic pneumonia syndrome (IPS). We have developed mouse models of IPS in order to examine the pathophysiologic mechanisms responsible for this process. Significant progress has been made in identifying roles for donor derived T cells and accessory cells (monocytes/macrophages/neutrophils) in the development of IPS These findings are significant because they support a paradigm shift away from identifying IPS solely as a clinical syndrome and toward understanding IPS as a process in which the lung is a target of two distinct, but inter-related pathways of immune mediated injury. However, the mechanisms by which leukocytes traffic to the lung during IPS have not been explored. Initial studies demonstrate that chemokine ligands and receptors that are responsible for leukocyte migration to inflamed tissue are associated with IPS, but a mechanistic relationship between chemokines and recruitment of cells to the lung during IPS remains to be determined. Extensive preliminary data support a central hypothesis that links enhanced chemokine expression and leukocyte infiltration to the lung with systemic inflammation that occurs after allogeneic SCT and proposes that the sequential influx of cells is causally rather than temporally related; modification of the local chemokine milieu by infiltrating leukocytes will directly contribute to the recruitment of subsequent effector populations. Preliminary data will confirm that donor lymphocyte effectors are recruited to the lung first and are followed by donor accessory cell subsets. This sequential influx of cells follows, and then correlates with, increased expression of corresponding chemokine ligands and receptors respectively. This proposal will use established mouse SCT models to test this hypothesis.
The specific aims of this proposal will investigate the following chemokine receptor:ligand pairs and their contribution to the recruitment of lymphocytes, macrophages and neutrophils to the lung during the development of IPS: SA1: CCR5 / RANTES (CCL5) and MIP-1alpha (CCL3) --> Th1 lymphocytes --> days 7-21 SA2: CXCR3 / IP-10 (CXCL10) and Mig (CXCL9) SA3: CCR2: / MCP-1 (CCL2) --> monocytes/macrophages --> days 14-28 SA4:CXCR2 / KC and MIP-2 (CXCL1) --> neutrophils --> days 21 to 42
