Inhibition of 15-PGDH Protects Mice from Immune-mediated Bone Marrow Failure

Abstract

AbstractAplastic anemia (AA) is a human immune mediated bone-marrow failure syndrome that is treated by stem cell transplantation for patients who have a matched related donor or immunosuppressive therapy (IST) for those who do not. Responses to IST are variable, with patients still at risk for prolonged neutropenia, transfusion-dependence, immune suppression, and severe opportunistic infections. Therefore, additional therapies to accelerate hematologic recovery in patients receiving front line IST are needed. We have shown that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) with the small molecule SW033291 (PGDHi) increases bone marrow (BM) prostaglandin E2 levels, expands hematopoietic stem cell (HSC) numbers, and accelerates hematologic reconstitution following murine BM transplantation. We now report that in a murine model of immune-mediated BM failure, PGDHi therapy mitigated cytopenias, increased BM HSC and progenitor cells, and significantly extended survival compared to vehicle-treated mice. PGDHi protection was not immune-mediated, as serum IFNγ levels and BM CD8+ T lymphocyte frequencies were not impacted. Moreover, dual administration of PGDHi plus low dose IST enhanced total white blood cell, neutrophil and platelet recovery, achieving responses similar to maximal dose IST at lesser toxicity. Together these data demonstrate that PGDHi can complement IST to accelerate hematologic recovery and reduce morbidity in severe AA.