The following abstracts were included in the May 2018 issue of ASBMT eNews. Read the full issue here.
Relapsed Patients Have Increased Coexpression of PD-1, TIGIT and KLRG-1 on CD8+ T Cells
A new study appearing in Biology of Blood and Marrow Transplantation reports that PD-1, TIGIT and TIM-3 are highly coexpressed on MiHA-specific CD8+ T cells and that relapsed patients’ MiHA-specific CD8+ T cells show increased coexpression of PD-1, TIGIT and KLRG-1 compared to nonrelapsed patients. For the study, researchers used a 13-color flow cytometry panel to evaluate immune checkpoint expression profiles on T cell subsets and cytomegalovirus (CMV)- and/or MiHA-reactive CD8+ T cells of allogeneic stem cell transplantation patients. They discovered that MiHA-reactive CD8+ T cells exhibited an early differentiated CD27++/CD28++ phenotype with low KLRG-1 and CD57 expression. In addition, these T cells displayed increased expression of PD-1, TIM-3 and TIGIT compared with total effector memory T cells and CMV-specific CD8+ T cells in donors and allogeneic transplant patients. High coexpression of PD-1, TIGIT and KLRG-1 on MiHA-reactive CD8+ T cells was associated with relapse after allogeneic transplantation. These findings led researchers to conclude that MiHA-reactive CD8+ T cells of relapsed patients have a distinctive coinhibitory expression signature compared with patients who did not relapse, which may serve as a potential monitoring tool in patients. Read More
Targeting CCL9 in Mice Reverses Chronic GVHD
Researchers have discovered that circulating levels of murine CCL9 and human homolog CCL15 are higher during chronic graft-versus-host disease (GVHD) and that targeting CCL9 in vivo reverses murine chronic GVHD, according to a study published in Blood. Conducting whole serum proteomics analysis, the researchers discovered four upregulated proteins during chronic GVHD that can be targeted by genetic ablation or blocking antibodies, including the RAS and JUN kinase activator, CRKL, and CXCL7, CCL8 and CCL9 chemokines. Donor T cells without CRK/CRKL prevented chronic GVHD, germinal center reactions and macrophage infiltration seen with wild-type T cells. While antibody blockade of CCL8 or CXCL7 was ineffective in treating chronic GVHD, CCL9 blockade reversed chronic GVHD clinical manifestations, histopathological changes and immunopathological hallmarks. Elevated CCL9 expression was found mostly in vascular smooth muscle cells and uniquely present in mice with chronic GVHD. Plasma concentrations of CCL15, which is the human homolog of mouse CCL9, were high in a previously published study of 211 chronic GVHD patients. In another study of 792 patients, CCL15 measured at day +100 could not predict chronic GVHD occurring within the next three months. The researchers concluded that preclinical proteomics screening may be useful for identifying potential new targets for chronic GVHD, especially CCL15 as a diagnosis marker for chronic GVHD. Read More
VA-lip HSP47 Control Cutaneous Chronic GVHD
Vitamin A-coupled liposomes carrying heat shock protein 47 (VA-lip HSP47) control skin fibrosis in chronic graft-versus-host disease (GVHD) by targeting HSP47+ myofibroblasts without inducing immunosuppression, reports a study appearing in Blood. Researchers discovered massive fibrosis with elevated amounts of collagen deposits and accumulation of F4/80+ macrophages, as well myofibroblasts expressing HSP47 and retinol-binding protein 1 in the skin after allogeneic stem cell transplantation. Injections of anti-colony-stimulating factor receptor-blocking antibodies significantly reduced HSP47+ myofibroblasts in the skin. VA-lip HSP47 small interfering RNA (siRNA) delivered HSP47 siRNA to cells expressing vitamin A receptors and knocked down their HSP47 in vitro. VA-lip HSP47 was intravenously injected into fibrotic lesions, which did not affect collagen synthesis in healthy skin. In addition, VA-lip HSP47 knocked down HSP47 expression in myofibroblasts and reduced collagen deposits without inducing systemic immunosuppression. Researchers concluded that these study results highlight a cascade of fibrosis in chronic GVHD and that macrophage production of transforming growth factor β mediates fibroblast differentiation to HSP47+ myofibroblasts that produce collagen. Read More