Colony Stimulating Factor-1 in Graft Vascular Disease

Graft vascular disease (GVD) is the single greatest barrier to the long-term success of solid-organ transplantation. The lesions of GVD characteristically show concentric vascular intimal hyperplasia composed of smooth muscle-like cells (SMLCs) and associated extracellular matrix; this intimal expansion develops diffusely throughout the vasculature of transplanted organs, eventually limiting their arterial conduit function and causing graft ischemia and failure. Experimental allografts placed in Colony Stimulating Factor-1 (CSF- 1, also known as M-CSF)-deficient osteopetrotic (op) mice show greatly reduced accumulation of neointimal SMLCs compared to those placed in control recipients, suggesting that CSF-1, the principal mediator of macrophage differentiation, activation, and survival, has a significant role in GVD. In recent studies, we used op mice, reconstituted by transgenesis to express specific isoforms of CSF-1, as either donors or recipients in carotid arterial allograft transplantation. We found that lack of all CSF-1 in recipients significantly limited neointimal hyperplasia, while recipient expression of cell surface (cs) CSF-1 alone was sufficient for neointimal expansion. Surprisingly, absence of CSF-1 in donor tissue also impaired neointima formation; this reduction was also completely reversed when donor tissue expressed the cs isoform alone. Neointimal SMLCs expressed the CSF-1 receptor (CSF-1R) encoded by the c-fms oncogene, and antibody-mediated blockade of this receptor inhibited SMLC proliferation in vitro. Taken together, these findings suggest that CSF-1, expressed on the surface of both donor and recipient derived cells, can act in a local, autocrine/juxtacrine manner in GVD to stimulate chronic neointimal SMLC proliferation and eventual vascular obstruction. Based on these findings, we hypothesize that an essential function of CSF-1 signaling in GVD pathogenesis resides not only in its ability to stimulate its classical cellular target, the macrophage, but also in its effects on neointimal SMLCs that express the CSF-1R. To test this hypothesis and assess therapeutic opportunities that it suggests, we propose three aims: first, we will identify the essential cell type(s) through which CSF-1 drives GVD; second, we will test the effectiveness of pharmacologic CSF-1R inhibitors for prevention and regression of GVD in mouse transplantation models; and third, we will examine clinical transplant tissues, including grafts with advanced GVD, for evidence of expression and activation of the CSF-1 signaling pathway in human GVD. These studies will advance understanding of how CSF-1 signaling promotes GVD and evaluate its potential as a therapeutic target that can be readily translated into clinical practice to mitigate graft failure.