CCL1 blockade alleviates human mesenchymal stem cell (hMSC)-induced pulmonary fibrosis in a murine sclerodermatous graft-versus-host disease (Scl-GVHD) model

Background: Human chronic graft-versus-host disease (CGVHD) shares clinical characteristics with a murine sclerodermatous GVHD (Scl-GVHD, B10.D2 → BALB/c) model that is characterized by skin and lung fibrosis. In this study, bone marrow- or adipose tissue-derived human mesenchymal stem cells (hMSCs) were injected into the Scl-GVHD mice to address their therapeutic effect on CGVHD. Methods Lethally irradiated BALB/c mice were transplanted with B10.D2 T cell depleted bone marrow with or without spleen cells to generate Scl GVHD. hMSCs were intravenously treated on days 3, 5 and 7 post-transplantation. And the control antibody or CCL1 blocking antibody was subcutaneously injected into the same schedule as hMSCs. At 14 days after transplantation, the recipient mice sacrificed and their skin and lung analyzed. Results After early injection of hMSCs after transplantation, the clinical and pathological severity of Scl-GVHD in the skin was significantly attenuated, whereas the pathological score was exacerbated in the lungs. hMSCs migrated into the lungs but not into the skin. CD11b monocyte/macrophages and CD4 T cells were markedly decreased in skin tissues, whereas there was an early recruitment of CD11b cells, and subsequently increased infiltration of CD4 T cells, in the lungs. Importantly, hMSCs persistently up-regulated the expression of CCL1 in the lungs but not in the skin. Concurrent treatment of hMSCs with a CCL1-blocking antibody alleviated the severity of the lung histopathology score and fibrosis with preservation of the cutaneous protective effect against CGVHD. Infiltration of CD3 T cells and CD68 macrophages and up-regulation of chemokines were also decreased in lung tissues, along with recruitment of eosinophils and tissue IgE expression. In the skin, chemokine expression was further reduced after CCL1 blockade. Conclusions These data demonstrate that despite a protective effect against Scl-GVHD in the skin, administration of hMSCs exacerbated lung fibrosis associated with eosinophilia and airway inflammation through persistent CCL1 up-regulation. CCL1 blockade offers a potential treatment of pulmonary complications induced after treatment with hMSCs.