CCL8 deficiency in the host abrogates early mortality of acute graft-versus-host disease in mice with dysregulated IL-6 expression.

Although allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for diverse malignant and non-malignant diseases, acute graft-versus-host disease (aGVHD) is strongly linked to mortality due to HSCT. We have previously shown that CC chemokine ligand 8 (CCL8) is closely correlated to aGVHD mortality in both humans and mice. To study the role of CCL8 in aGVHD, CCL8 knockout (CCL8-/-) mice were transplanted with fully allogeneic marrow grafts. These mice showed a significant reduction in mortality (90.0% vs. 23.4% survival for CCL8-/- vs. wildtype recipients at day 28; p<0.0001). As a result, apparent prolonged median survival from 9 days in wildtype mice to 45 days in CCL8-/- mice was observed. Acute GVHD pathology and liver dysfunction in CCL8-/- mice were significantly attenuated compared with those in wildtype mice. In association with the reduced mortality, a surge of plasma interleukin (IL)-6 was observed in CCL8-/- recipients with allogeneic marrow, which was significantly increased compared with wildtype mice that received allografts. Donor T cell expansion and the plasma levels of interferon-γ and TNF-α during aGVHD were similar in both types of mice. Collectively, these findings indicate that CCL8 plays a major role in aGVHD pathogenesis with possible involvement of an IL-6 signaling cascade.