Development of immunosuppressive myeloid cells to induce tolerance in solid organ and hematopoietic cell transplant recipients
| Autor: | Thomas Hsin-Hsu Wu, Judith A. Shizuru, Robert Lowsky, Jeffrey Waters, Edgar G. Engleman, Robert S. Negrin, Pingping Zheng, Jeanette Baker, John D. Scandling, Rahul D. Pawar, Stephan Busque, Kent P. Jensen, Asha Shori, John S. Tamaresis, Samuel Strober, Holden T. Maecker, Suparna Dutt, Everett Meyer, David Hongo, Xuhuai Ji, Anirudh Saraswathula, Philip W. Lavori |
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| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
Clinical Trials as Topic Transplantation Conditioning Immunobiology and Immunotherapy business.industry medicine.medical_treatment Hematopoietic Stem Cell Transplantation Immunosuppression Hematology Hematopoietic stem cell transplantation Organ transplantation Transplant Recipients Immune tolerance Transplantation Mice Cytokine Immunology medicine Myeloid-derived Suppressor Cell Immune Tolerance Animals Humans Cytokine secretion Myeloid Cells business |
| Zdroj: | Blood Adv |
| ISSN: | 2473-9537 |
| Popis: | Replacement of failed organs followed by safe withdrawal of immunosuppressive drugs has long been the goal of organ transplantation. We studied changes in the balance of T cells and myeloid cells in the blood of HLA-matched and -mismatched patients given living donor kidney transplants followed by total lymphoid irradiation, anti-thymocyte globulin conditioning, and donor hematopoietic cell transplant to induce mixed chimerism and immune tolerance. The clinical trials were based on a conditioning regimen used to establish mixed chimerism and tolerance in mice. In preclinical murine studies, there was a profound depletion of T cells and an increase in immunosuppressive polymorphonuclear (pmn) myeloid-derived suppressor cells (MDSCs) in the spleen and blood following transplant. Selective depletion of pmn MDSCs in mice abrogated mixed chimerism and tolerance. In our clinical trials, patients given an analogous tolerance conditioning regimen developed similar changes, including profound depletion of T cells and a marked increase in MDSCs in blood posttransplant. Posttransplant pmn MDSCs transiently increased expression of lectin-type oxidized LDL receptor-1, a marker of immunosuppression, and production of the T-cell inhibitor arginase-1. These posttransplant pmn MDSCs suppressed the activation, proliferation, and inflammatory cytokine secretion of autologous T-cell receptor microbead-stimulated pretransplant T cells when cocultured in vitro. In conclusion, we elucidated changes in receptors and function of immunosuppressive myeloid cells in patients enrolled in the tolerance protocol that were nearly identical to those of MDSCs required for tolerance in mice. These trials were registered at www.clinicaltrials.gov as #NCT00319657 and #NCT01165762. |
| Databáze: | OpenAIRE |
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