PMID- 18813111
OWN - NLM
STAT- MEDLINE
DCOM- 20081117
LR  - 20181113
IS  - 1534-6080 (Electronic)
IS  - 0041-1337 (Print)
IS  - 0041-1337 (Linking)
VI  - 86
IP  - 6
DP  - 2008 Sep 27
TI  - Induction of alloanergy in human donor T cells without loss of pathogen or tumor 
      immunity.
PG  - 854-64
LID - 10.1097/TP.0b013e3181861b6c [doi]
AB  - BACKGROUND: Human leukocyte antigen (HLA)-mismatched allogeneic hematopoietic 
      stem cell transplantation (HSCT) is limited by acute graft-versus-host disease 
      (aGvHD). Nonselective T-cell depletion effectively prevents severe aGvHD but 
      profoundly impairs donor-derived immune reconstitution, increasing infection and 
      disease relapse. The strategy of induction of alloantigen-specific 
      hyporesponsiveness ("alloanergization") in donor bone marrow by allostimulation 
      with costimulatory blockade before haploidentical transplantation has 
      demonstrated early promise in reducing severe aGvHD. However, the differential 
      effect of alloanergization on CD4+ and CD8+ donor T-cell subsets and the degree 
      to which beneficial pathogen- and tumor-immune responses are retained have not 
      been extensively examined. METHODS: We used an in vitro model of alloanergization 
      by allostimulation of human donor T cells with irradiated unrelated recipient 
      peripheral blood mononuclear cells and costimulatory blockade with humanized 
      monoclonal anti-B7.1 and B7.2 antibodies. Residual alloresponses were assessed by 
      proliferation (thymidine uptake, carboxyfluorescein diacetate succinimidyl ester 
      dye dilution) and cytotoxicity assays. Retention of human herpes virus and 
      tumor-associated antigen (TAA)-specific immunity was measured with HLA-class 
      I-restricted pentamers, intracellular cytokine secretion, and CD107a assay using 
      5-color flow cytometry. RESULTS: Alloanergization of HLA-mismatched donor T cells 
      efficiently and selectively abrogated recipient-specific alloproliferation in 
      both CD4+ and CD8+ cells while preserving functional CD4+ and CD8+ immune 
      responses to clinically important human herpes viruses and to the TAA WT1. 
      CONCLUSIONS: Retention of pathogen- and TAA-specific immunity after 
      alloanergization demonstrates that this methodology, which is simple to apply, 
      has potential to improve immune reconstitution while limiting alloreactivity 
      after HLA-mismatched hematopoietic stem cell transplantation, and deserves 
      additional evaluation in further human clinical trials.
FAU - Davies, Jeffrey K
AU  - Davies JK
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, 
      USA. jeff_davies@dfci.harvard.edu
FAU - Yuk, Dongin
AU  - Yuk D
FAU - Nadler, Lee M
AU  - Nadler LM
FAU - Guinan, Eva C
AU  - Guinan EC
LA  - eng
GR  - U19 AI100625/AI/NIAID NIH HHS/United States
GR  - U19 CA100265/CA/NCI NIH HHS/United States
GR  - U19 CA100265-04/CA/NCI NIH HHS/United States
GR  - U19 CA100625/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Transplantation
JT  - Transplantation
JID - 0132144
RN  - 0 (B7-1 Antigen)
RN  - 0 (HLA Antigens)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Isoantigens)
SB  - IM
EIN - Transplantation. 2012 Jun 15;93(11):e44. Dosage error in article text
MH  - B7-1 Antigen/immunology
MH  - Blood Donors
MH  - Clonal Anergy/*immunology
MH  - Graft vs Host Disease/prevention & control
MH  - HLA Antigens/immunology
MH  - *Hematopoietic Stem Cell Transplantation
MH  - Histocompatibility Antigens Class I/immunology
MH  - Humans
MH  - Isoantigens/*immunology
MH  - Leukocytes, Mononuclear/immunology/radiation effects
MH  - Lymphocyte Activation/immunology
MH  - T-Lymphocytes/*immunology
MH  - Tissue Donors
PMC - PMC2669433
MID - NIHMS84733
COIS- Declaration of Conflicts of Interest: The authors have no conflicts of interest 
      to declare.
EDAT- 2008/09/25 09:00
MHDA- 2008/11/18 09:00
PMCR- 2009/09/27
CRDT- 2008/09/25 09:00
PHST- 2008/09/25 09:00 [pubmed]
PHST- 2008/11/18 09:00 [medline]
PHST- 2008/09/25 09:00 [entrez]
PHST- 2009/09/27 00:00 [pmc-release]
AID - 00007890-200809270-00016 [pii]
AID - 10.1097/TP.0b013e3181861b6c [doi]
PST - ppublish
SO  - Transplantation. 2008 Sep 27;86(6):854-64. doi: 10.1097/TP.0b013e3181861b6c.