Tissue macrophage heterogeneity in chronic graft-versus-host disease fibrosis

The National Institute of Allergy and Infectious Diseases awarded Fred Hutchinson Cancer Center $164,376 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate tissue macrophage heterogeneity in chronic graft-versus-host disease fibrosis.

The research examines how heterogeneous populations of tissue macrophages contribute differentially to fibrotic manifestations of chronic graft-versus-host disease, particularly cutaneous sclerosis and pulmonary bronchiolitis obliterans syndrome in allogeneic hematopoietic cell transplantation survivors. The work uses animal modeling of graft-versus-host disease sclerosis and bronchiolitis obliterans syndrome, basic immunology, spatial transcriptomics, and single-cell sequencing to define macrophage subpopulation establishment, developmental ontogeny, cytokine dependencies, and profibrotic relationships with fibroblasts. The research will also examine macrophage-fibroblast interactions in patient tissue specimens to characterize macrophage subset heterogeneity and identify actionable pathways for fibrogenic macrophage-directed therapeutic intervention.

Performance occurs in Seattle, Washington. The award period runs through August 31, 2031. The assistance type is a project grant.

Abstract

Chronic graft-versus-host disease (CGVHD) is the leading cause of morbidity and mortality among long-term survivors of allogeneic hematopoietic cell transplantation (HCT). CGVHD's most debilitating manifestations are fibrotic and include cutaneous sclerosis and pulmonary bronchiolitis obliterans syndrome (BOS). These impart profound and lifelong disability and have inconsistent or only partial responses to drugs that are often effective for other organ systems' CGVHD. Previous foundational work established the centrality of alternatively activated tissue macrophages in mediating fibrotic CGVHD. We have now discovered through spatial transcriptomic-based analyses that CGVHD-associated skin and lung macrophages are phenotypically and likely functionally heterogenous and engage with diverse sets of non-hematopoietic cells in CGVHD target tissue. These heterogeneous features indicate that some of these pathogenic macrophages may evade current macrophage- targeting CGVHD therapeutic approaches. This proposal queries the central hypothesis that heterogeneous tissue macrophage populations exert differential contributions to CGVHD pathogenesis and fibrotic capacity and uses animal modeling, basic immunology, and computational genomics including spatial transcriptomics and single cell sequencing approaches. In aim 1, we will use mouse models of CGVHD sclerosis and BOS to define how tissue macrophage subpopulations mediate fibrosis after HCT. Temporally post-HCT, we will delineate the establishment of CGVHD-mediating tissue macrophage subpopulations, their developmental ontogenies, cytokine dependencies, and, critically, their profibrotic relationships with fibroblasts. These studies may define actionable pathways for fibrogenic macrophage-oriented therapeutic intervention. In aim 2, in CGVHD patient tissue specimens we will discern how such macrophage-fibroblast subset interactions may shift between early VS. Late/established clinical disease and how human fibrogenic tissue macrophages arise from peripheral blood monocytes in CGVHD. These studies may reveal disease stage-specific intervenable targets better tailored to key macrophage-fibroblast perturbations. Collectively, this proposal has the potential to inform more precise therapeutic targeting of pathogenic macrophages and their precursors by defining how tissue macrophage subsets differentially contribute to fibrotic lung and skin CGVHD across the disease courses. Through this career development award, DR. Boiko, an MD/PHD-trained immunologist, computational biologist, and pediatric HCT physician, will obtain enhanced training and scientific development at the fred hutchinson cancer center under the guidance of mentor and gvhd/HCT immunology expert DR. Geoffrey hill and a multidisciplinary advisory team with expertise in in vivo CGVHD modeling, computational genomics, and macrophage-fibroblast interaction analysis. DR. Boiko's training will be enhanced by coursework/skills intensives, conferences, and faculty development programming. By gaining expertise in these areas facilitated by this award, DR. Boiko will be poised to establish an independent research program focused on improving therapies for patients with fibrotic CGVHD.