GVHD continues to limit the effectiveness of both related and unrelated allogeneic hematopoietic stem cell transplantation (HSCT). Yet the mechanism of initiation of GVHD remains unclear. The hypothesis driving this proposal is that a CC chemokine is a major regulator of the initiation of tissue damage in GVHD. Chemokines are a family of related proteins that regulate leukocyte migration. Recently the applicants and other groups cloned and characterized a novel subfamily of CC chemokines they termed Exodus-1, 2 and 3 for their extraordinary T-cell chemotactic ability. These three chemokines share a similar sequence around their amino terminal that no other chemokines have, asp-cys--cys-leu (DCCL). Exodus-2 and 3 are both ligands for the CC chemokine CCR7. These CCR7 chemokines are distantly related to other chemokines (twenty-eight percent homology with MIP-1a) but share among themselves several biological activities, including 1) preferential stimulation of T-lymphocyte and NK cell chemotaxis and 2) inhibition of hematopoiesis and regulation of hematopoietic progenitor migration. Recent data indicate that Exodus-2and 3 mediate T-cell adhesion to the endothelium, stimulating T-cells to stop rolling and adhere to the endothelial region expressing chemokines. Exodus-2 has been also reported as 6Cline, SLC, and TCA4. Exodus-3 has also been described as MIP-3b and ELC. They observed that Exodus-2 but not 3 is highly expressed in several target organs in human and murine GVHD. Therefore, it is hypothesized that Exodus-2 is an important mediator of T-cell tissue infiltration during initiation and/or progression of GVHD organ toxicity. This study will test this hypothesis in four aims focusing on Exodus-2 because its expression pattern is most compatible with a role in GVHD.
Aim 1 - the timing and location of Exodus-2 expression during the initiation in models of murine GVHD will be analyzed.
Aim 2 - the effect of anti-sera or competitive inhibitor neutralization of Exodus-2 in murine GVHD will be analyzed.
Aim 3 - the effect of homozygous deletion of Exodus-2 in a knock-out mouse on GVHD pathology will be investigated.
Aim 4 - the role of Exodus-2 expression in specific GVHD target organs will be studied using transgenic mice that over-express Exodus-2 selectively in liver or skin or gut. At the end of this proposal, the mechanisms by which Exodus-2 initiates GVHD should be better understood, and the possibility whether or not it might lead to effective therapeutic agents would be better defined.
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