Work

288: A small molecular weight antagonist of CXCR3 reduces the severity of experimental idiopathic pneumonia syndrome and improves survival following allogeneic stem cell transplantation

Year: 2007

Type: article

Abstract: BACKGROUND: Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication after allogeneic stem cell transplantation (allo-SCT) The pathophysiology of IPS involves the secretion of inflammatory cytokines including IFNγ and TNFα along with the recruitment of donor T cells to the lung. CXCR3 is a chemokine receptor that is expressed on activated Th1/Tc1 T cell subsets and the expression of its ligands CXCL9 (Mig) and CXCL10 (IP-10) can be induced in a variety of cell types by IFNγ alone or in combination with TNFα. OBJECTIVES: We examined the effects of a small molecular weight antagonist of CXCR3, AMG487, on donor T cell recruitment to the lung and overall survival in an established murine SCT model. METHODS: Lethally irradiated bm1 mice received SCT from either syngeneic (bm1) or allogeneic, MHC class I disparate (B6) donors. AMG487 was continuously delivered for 14 or 28 days by an infusion pump that was implanted subcutaneously two days before SCT. Drug exposure levels were determined in the sera of mice at day 7 and 14 after implantation. RESULTS: In pilot experiments, we found that pulmonary mRNA expression of both CXCR3 and its ligand IP-10 were significantly up-regulated after allo-SCT. Increases were seen as early as week one, persisted through week six, and were associated with elevated BAL fluid protein levels (IP-10 / Mig) and enhanced cell surface expression (CXCR3) on lymphocytes infiltrating the lungs of allo-SCT recipients. Subsequently, we found that compared to vehicle treated controls, lung pathology at day 46 was significantly reduced in allo-SCT recipients treated with drug for 14 days (7.2 ± 0.6 vs. 3.0 ± 0.4). This reduction was associated with significantly decreased BAL cellularity (1.1 ± 0.1 vs. 0.6 ± 0.1 ×106) and CD8+ T cell infiltration, and correlated with serum drug levels. AMG487 also significantly reduced the severity of GVHD in both the large and small bowel. Infusion of AMG487 for 28 days resulted in similar differences between groups, and was associated with improved survival when SCT parameters were modified to enhance mortality from GVHD, (67% vs. 17%). CONCLUSIONS: Administration of AMG487 for as little as 2 weeks around the time of allo-SCT has profound effects on T cell recruitment to the lung and GI tract of transplanted mice. Experiments are ongoing to determine whether the reduction in target tissue injury and improved survival are accompanied by preservation of graft-versus-leukemia responses after SCT.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2006.12.293