PMID- 27401140
OWN - NLM
STAT- MEDLINE
DCOM- 20170606
LR  - 20181113
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 24
IP  - 9
DP  - 2016 Sep
TI  - Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While 
      Conserving Immunity to Viruses and Leukemia.
PG  - 1655-64
LID - 10.1038/mt.2016.147 [doi]
AB  - 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.
FAU - Whitehill, Greg D
AU  - Whitehill GD
AD  - Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, 
      and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
FAU - Amarnath, Shoba
AU  - Amarnath S
AD  - Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
FAU - Muranski, Pawel
AU  - Muranski P
AD  - Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, 
      and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
FAU - Keyvanfar, Keyvan
AU  - Keyvanfar K
AD  - Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, 
      and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
FAU - Battiwalla, Minoo
AU  - Battiwalla M
AD  - Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, 
      and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
FAU - Barrett, Austin J
AU  - Barrett AJ
AD  - Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, 
      and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
FAU - Chinnassamy, Dhanalakshmi
AU  - Chinnassamy D
AD  - Stem Cell Allotransplantation Section, Hematology Branch, National Heart, Lung, 
      and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
AD  - Laboratory of Transplantation Immunotherapy, Hematology Branch, National Heart, 
      Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 
      USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20160706
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Antigens, Neoplasm)
RN  - K72T3FS567 (Adenosine)
SB  - IM
MH  - Adenosine/*pharmacology
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antigens, Neoplasm
MH  - Cell Survival/drug effects
MH  - Graft vs Host Disease/etiology/*prevention & control
MH  - Haplotypes
MH  - Humans
MH  - *Immunity
MH  - Leukemia/complications/*immunology/therapy
MH  - *Lymphocyte Depletion
MH  - Lymphocyte Subsets/drug effects/immunology/metabolism
MH  - Middle Aged
MH  - T-Cell Antigen Receptor Specificity/immunology
MH  - T-Lymphocytes/*drug effects/*immunology/metabolism
MH  - Tissue Donors
MH  - Viruses/*immunology
MH  - Young Adult
PMC - PMC5113112
EDAT- 2016/07/13 06:00
MHDA- 2017/06/07 06:00
PMCR- 2017/09/01
CRDT- 2016/07/13 06:00
PHST- 2016/04/19 00:00 [received]
PHST- 2016/07/06 00:00 [accepted]
PHST- 2016/07/13 06:00 [entrez]
PHST- 2016/07/13 06:00 [pubmed]
PHST- 2017/06/07 06:00 [medline]
PHST- 2017/09/01 00:00 [pmc-release]
AID - S1525-0016(16)45341-4 [pii]
AID - 10.1038/mt.2016.147 [doi]
PST - ppublish
SO  - Mol Ther. 2016 Sep;24(9):1655-64. doi: 10.1038/mt.2016.147. Epub 2016 Jul 6.