Solid organ transplantation is a common and effective treatment of end-stage organ failure.
Although immunosuppressive treatment has been successful in preventing acute graft rejection,
the long-term survival of solid organ transplants is affected by a condition termed graft vascular
disease (GVD), through which the vasculature within the graft becomes occluded. GVD is
composed of deposition of extracellular matrix, smooth muscle-like cells (SMLCs) and immune
cells that accumulate to form obstructive neointimal lesions. Currently there is no treatment to
either prevent or reverse neointimal accumulation; once GVD leads to graft failure, the ultimate
solution is to retransplant. Furthermore, animal models previously used to study GVD have
produced GVD that differs from what is observed in clinical samples, which reflects on the need
to better understand the limitations of the models.
Some of the open questions in the field include 1) what are the origins (donor vs recipient) and
cell types that contribute to neointimal lesions, and 2) what are the early events that drive the
proliferation and migration of cells that eventually become neointimal SMLCs in GVD.
Investigators have attempted to answer these questions using murine vascular transplant
models of GVD with Major Histocompatibility Complex (MHC) mismatches but recent work
suggests that these models differ importantly from clinical GVD — in these mouse models,
neointimal cells may arise from the recipient, whereas in clinical heart transplantation, GVD
neointimal cells are mostly graft derived.
A recently described vascular transplant model of GVD based on H-Y antigen-driven
incompatibility may provide a remedy to this problem. In this model, milder tissue incompatibility
(H-Y antigens provide minor histocompatibility mismatch) allows survival of donor medial cells,
similar to observations in clinical GVD pathogenesis. While this observation is promising for the
relevance of the new model, it is still not clear whether medial smooth muscle cells from the
donor tissue are participating in vascular occlusion, as has been shown in other models of
vascular injury. This proposal will address some of these basic pathogenetic questions in this
model, specifically looking at donor vs recipient origin of neointimal lesions, the extent to which
differentiated mature smooth muscle cells from the graft vasculature contribute to neointimal
SMLCs, and the requirement for the previously identified colony stimulating factor 1 (CSF1)/
colony stimulating factor 1 receptor (CSF1R) signaling pathway in this model of GVD.