Transplantation of T-cell receptor α/β-depleted allogeneic bone marrow in nonhuman primates. Exp Hematol 2021 Jan;93:44-51
Date
11/12/2020Pubmed ID
33176119Pubmed Central ID
PMC7855119DOI
10.1016/j.exphem.2020.09.198Scopus ID
2-s2.0-85095986934 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
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.
Author List
D'Souza SS, Bennett S, Kumar A, Kelnhofer LE, Weinfurter J, Suknuntha K, Coonen J, Mejia A, Simmons H, Golos T, Hematti P, Capitini CM, Reynolds MR, Slukvin IIAuthor
Peiman Hematti MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBone Marrow Cells
Female
Graft vs Host Disease
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Immunosuppressive Agents
Macaca fascicularis
Male
Receptors, Antigen, T-Cell
Sirolimus
Transplantation Conditioning
Transplantation, Homologous
Whole-Body Irradiation
