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
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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