Inhibition of 15-PGDH Protects Mice from Immune-Mediated Bone Marrow Failure
| Autor: | Kelsey F. Christo, Sanford D. Markowitz, Alvin P. Jogasuria, Amar Desai, Folashade Otegbeye, Joseph M. Ready, Stanton L. Gerson, Julianne N.P. Smith, Monika I. Antczak |
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| Rok vydání: | 2020 |
| Předmět: |
Article
Mice 03 medical and health sciences 0302 clinical medicine White blood cell Animals Humans Medicine Progenitor cell Aplastic anemia Bone Marrow Transplantation Transplantation business.industry Hematopoietic Stem Cell Transplantation Bone marrow failure Anemia Aplastic Hematopoietic stem cell Hematology medicine.disease 3. Good health medicine.anatomical_structure 030220 oncology & carcinogenesis Immunology Hydroxyprostaglandin Dehydrogenases Bone marrow Stem cell business 030215 immunology |
| Zdroj: | Biol Blood Marrow Transplant |
| ISSN: | 1083-8791 |
| Popis: | Aplastic 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 and by 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 are needed to accelerate hematologic recovery in patients receiving front-line IST. 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 cell numbers, and significantly extended survival compared with vehicle-treated mice. PGDHi protection was not immune-mediated, as serum IFN-γ 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 those seen with maximal-dose IST with lower toxicity. Taken together, these data demonstrate that PGDHi can complement IST to accelerate hematologic recovery and reduce morbidity in severe AA. |
| Databáze: | OpenAIRE |
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