title: Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia.
abstract: Selective depletion (SD) of alloreactive T cells from allogeneic hematopoeitic stem cell transplants to prevent graft-versus-host disease (GVHD) without compromising immune reconstitution and antitumor responses remains a challenge. Here, we demonstrate a novel SD strategy whereby alloreacting T cells are efficiently deleted ex vivo with adenosine. SD was achieved in human leukocyte antigen (HLA) mismatched cocultures by multiple exposures to 2 mmol/l adenosine over 7 days. Adenosine depleted greater than to 90% of alloproliferating T cells in mismatched, haploidentical, and matched sibling pairs while conserving response to third-party antigens. Alloreactive CD4 and CD8 T cells were targeted for depletion while NK and B cells were preserved. Our novel approach also preserved nonalloreactive naive, central, and effector memory T-cell subsets, Tregs, and notably preserved T-cell responses against DNA viruses that contribute to transplant related mortality after allogeneic hematopoeitic stem cell transplants. Additionally, T cells recognizing leukemia-associated antigens were efficiently generated in vitro from the cell product post-SD. This study is the first to demonstrate that adenosine depletion of alloactivated T cells maintains a complete immune cell profile and recall viral responses. Expansion of tumor antigen-specific subsets postdepletion opens the possibility of generating T-cell products capable of graft-versus-tumor responses without causing GVHD.
authors.affiliation: Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Greg D
authors.initials: GD
authors.lastname: Whitehill
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Shoba
authors.initials: S
authors.lastname: Amarnath
authors.affiliation: Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.affiliation: Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Keyvan
authors.initials: K
authors.lastname: Keyvanfar
authors.affiliation: Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Minoo
authors.initials: M
authors.lastname: Battiwalla
authors.affiliation: Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Barrett
authors.affiliation: Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.|Laboratory of Transplantation Immunotherapy, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Dhanalakshmi
authors.initials: D
authors.lastname: Chinnassamy
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm; D002470:Cell Survival / Q000187:drug effects; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control*; D006239:Haplotypes; D006801:Humans; D007109:Immunity; D007938:Leukemia / Q000150:complications / Q000276:immunology* / Q000628:therapy; D008212:Lymphocyte Depletion; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D014019:Tissue Donors; D014780:Viruses / Q000276:immunology*; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D000241:Adenosine