Transplantation of T-cell receptor α/β-depleted allogeneic bone marrow in nonhuman primates
Autor: | Andres Mejia, Peiman Hematti, Saritha S. D'Souza, Akhilesh Kumar, Matthew R. Reynolds, Sarah Bennett, Christian M. Capitini, Jason T. Weinfurter, Kran Suknuntha, Laurel E. Kelnhofer, Heather A. Simmons, Thaddeus G. Golos, Jennifer Coonen, Igor I. Slukvin |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Male Cancer Research Transplantation Conditioning Cyclophosphamide medicine.medical_treatment Receptors Antigen T-Cell Graft vs Host Disease chemical and pharmacologic phenomena Bone Marrow Cells Hematopoietic stem cell transplantation Article 03 medical and health sciences 0302 clinical medicine Immune system Genetics medicine Animals Transplantation Homologous Molecular Biology Sirolimus business.industry Hematopoietic Stem Cell Transplantation Cell Biology Hematology Total body irradiation Hematopoietic Stem Cells Tacrolimus Transplantation Macaca fascicularis 030104 developmental biology medicine.anatomical_structure surgical procedures operative 030220 oncology & carcinogenesis Immunology Female Bone marrow business Immunosuppressive Agents Whole-Body Irradiation medicine.drug |
Zdroj: | Exp Hematol |
ISSN: | 1873-2399 |
Popis: | Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curative treatment for hematologic cancers and chronic infections such as human immunodeficiency virus (HIV). Its success in these settings is attributed to the ability of engrafting immune cells to eliminate cancer cells or deplete the HIV reservoir (graft-versus-host effect [GvHE]). However, alloHSCT is commonly associated with graft-versus-host diseases (GvHDs) causing significant morbidity and mortality, thereby requiring development of novel allogeneic HSCT protocols and therapies promoting GvHE without GvHD using physiologically relevant preclinical models. Here we evaluated the outcomes of major histocompatibility complex-matched T-cell receptor α/β-depleted alloHSCT in Mauritian cynomolgus macaques (MCMs). Following T-cell receptor α/β depletion, bone marrow cells were transplanted into major histocompatibility complex-identical MCMs conditioned with total body irradiation. GvHD prophylaxis included sirolimus alone in two animals or tacrolimus with cyclophosphamide in another two animals. Posttransplant chimerism was determined by sequencing diagnostic single-nucleotide polymorphisms to quantify the amounts of donor and recipient cells present in blood. Animals treated posttransplant with sirolimus developed nearly complete chimerism with acute GvHD. In the cyclophosphamide and tacrolimus treatment group, animals developed mixed chimerism without GvHD, with long-term engraftment observed in one animal. None of the animals developed cytomegalovirus infection. These studies indicate the feasibility of alloHSCT engraftment without GvHD in an MHC-identical MCM model following complete myeloablative conditioning and anti-GvHD prophylaxis with posttransplant cyclophosphamide and tacrolimus. Further exploration of this model will provide a platform for elucidating the mechanisms of GvHD and GvHE and for testing novel alloHSCT modalities for HIV infection. |
Databáze: | OpenAIRE |
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