Tissue Macrophage Fibrogenesis in Chronic Graft-Versus-Host Disease Following Hematopoietic Cell Transplantation
Many pediatric blood cancers are cured by hematopoietic cell transplantation (HCT), whereby a donor’s blood- and immune-cell forming stem cells are transferred to a recipient. Unfortunately, the resultant donor-derived immune system sometimes erroneously attacks recipient tissue, called graft-versus-host disease (GVHD). The chronic GVHD (cGVHD) form can last for years post-HCT, affecting numerous organ systems. The most life-limiting cGVHD manifestations are fibrotic, including sclerosis of the skin and bronchiolitis obliterans syndrome (BOS) of the lung. One major donor-derived immune cell, the macrophage, is implicated in causing these cGVHD forms by stimulating local tissue fibroblasts, cells which normally maintain tissue structure and in fibrosis produce excessive, disorganized collagen and related molecules with a net effect of progressive organ scarring and failure. Although recent cGVHD therapies target key macrophage-stimulating molecules, these fibrotic cGVHD forms do not consistently respond. This phenomenon, alongside our group’s data showing that skin contains multiple cGVHD-associated macrophage subsets with potentially different sustaining factors, hints that this conundrum may be related to such variety in cGVHD macrophages, the molecules required to sustain them throughout the cGVHD disease course, or how this range of macrophages interacts with fibroblasts to promote fibrosis. This work addresses these possibilities in mouse models and patient specimens.
Project Goals
In the mouse models, we will assess skin and lung cGVHD-associated macrophage populations, their heterogeneity, their dependencies (or lack thereof) on the major cGVHD drug targets IL-17 and CSF-1, developmental origins from blood cell precursors, and the fibroblast types with which they interact in cGVHD tissue. These approaches will utilize technologies that measure individual cells’ gene expression and their spatial relationships to other cells within cGVHD tissue and separately that measure the genetic factors controlling cell development into cGVHD-causing tissue macrophages. Our mouse model approach can turn off key genes’ expression at desired timepoints with a drug-induced switch to facilitate studying how macrophage subsets and cGVHD dependencies may differentially drive the disease across the post-HCT timeline. In cGVHD lung tissue samples from patients with early vs. late BOS, we will use spatial cell gene expression to determine how these macrophage population subsets and the fibroblasts with which they interact may vary over the disease course. Finally, for both lung and skin, we will define in patients how cGVHD tissue macrophages develop from blood cells. Overall, these studies may facilitate better, more precise drug targeting of cGVHD-causing macrophages and their fibroblast interactions to reduce patients’ complications from fibrotic cGVHD.
