ICOSL+ plasmacytoid dendritic cells as inducer of graft-versus-host disease, responsive to a dual ICOS/CD28 antagonist

Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). CD146 and CCR5 are proteins that mark activated T helper 17 (Th17) cells. The Th17 cell phenotype is promoted by the interaction of the receptor ICOS on T cells with ICOS ligand (ICOSL) on dendritic cells (DCs). We performed multiparametric flow cytometry in a cohort of 156 HCT recipients and conducted experiments with aGVHD murine models to understand the role of ICOSL+ DCs. We observed an increased frequency of ICOSL+ plasmacytoid DCs, correlating with CD146+CCR5+ T cell frequencies, in the 64 HCT recipients with gastrointestinal aGVHD. In murine models, donor bone marrow cells from ICOSL-deficient mice compared to those from wild-type mice reduced aGVHD-related mortality. Reduced aGVHD resulted from lower intestinal infiltration of pDCs and pathogenic Th17 cells. We transplanted activated human ICOSL+ pDCs along with human peripheral blood mononuclear cells into immunocompromised mice and observed infiltration of intestinal CD146+CCR5+ T cells. We found that prophylactic administration of a dual human ICOS/CD28 antagonist (ALPN-101) prevented aGVHD in this model better than did the clinically approved belatacept (CTLA-4-Fc), which binds CD80 (B7-1) and CD86 (B7-2) and interferes with the CD28 T cell costimulatory pathway. When started at onset of aGVHD signs, ALPN-101 treatment alleviated symptoms of ongoing aGVHD and improved survival while preserving antitumoral cytotoxicity. Our data identified ICOSL+-pDCs as an aGVHD biomarker and suggest that coinhibition of the ICOSL/ICOS and B7/CD28 axes with one biologic drug may represent a therapeutic opportunity to prevent or treat aGVHD

Hepatitis C Virus Clearance and Diffusing Capacity for Carbon Monoxide in Women With and Without Human Immunodeficiency Virus

Hepatitis C virus (HCV) infection is associated with extrahepatic effects, including reduced diffusing capacity of the lungs. It is unknown whether clearance of HCV infection is associated with improved diffusing capacity. In this sample of women with and without human immunodeficiency virus, there was no association between HCV clearance and diffusing capacity

Reducing Racial Bias Among Health Care Providers: Lessons from Social-Cognitive Psychology

The paper sets forth a set of evidence-based recommendations for interventions to combat unintentional bias among health care providers, drawing upon theory and research in social cognitive psychology. Our primary aim is to provide a framework that outlines strategies and skills, which can be taught to medical trainees and practicing physicians, to prevent unconscious racial attitudes and stereotypes from negatively influencing the course and outcomes of clinical encounters. These strategies and skills are designed to: l) enhance internal motivation to reduce bias, while avoiding external pressure; 2) increase understanding about the psychological basis of bias; 3) enhance providers’ confidence in their ability to successfully interact with socially dissimilar patients; 4) enhance emotional regulation skills; and 5) improve the ability to build partnerships with patients. We emphasize the need for programs to provide a nonthreatening environment in which to practice new skills and the need to avoid making providers ashamed of having racial, ethnic, or cultural stereotypes. These recommendations are also intended to provide a springboard for research on interventions to reduce unintentional racial bias in health care