Early expression of plasma CCL8 closely correlates with survival rate of acute graft-vs.-host disease in mice

Abstract

Objective: To elucidate the significance of early expression of CC-chemokine ligand motif 8 (CCL8) in mice with graft-vs.-host disease (GVHD), we investigated its induction mechanisms and correlation with overall survival rate in GVHD mice. Plasma CCL8 increases on day 5 of allogeneic transplantation, when signs of GVHD are barely detectable. Increase of allogeneic splenocytes in grafts exacerbates GVHD and leads to upregulation of plasma CCL8 on day 5. Overall survival is the gold standard in determining the severity of acute GVHD in mice, but the absence of clinical and/or pathological manifestations in the early phase make it difficult to estimate vital outcomes at this stage of allogeneic marrow transplantation.

Materials and methods: After lethal irradiation, BALB/c mice received bone marrow transplantation from C57BL/6 mice. Survival rate was monitored and clinical and pathological scores of GVHD were examined. Coculture of BALB/c-derived dendritic cells and C57BL/6-derived splenocytes was performed. CCL8 was measured by immunoassay.

Results: The plasma CCL8 level at day 5 of transplantation was closely correlated with survival rate and clinical/pathological scores on day 14. In vitro study revealed that the BALB/c-derived dendritic cells expressed CCL8 upon stimulation of C57BL/6 CD4(+) T cells by cell interactions through major histocompatibility complex class II molecules.

Conclusions: These investigations indicate that early and preclinical expression of CCL8 in plasma predicts overall survival of GVHD mice. Together with an involvement of allo-recognition in CCL8 expression, it suggests that CCL8 plays an important role in GVHD pathology.