PMID- 19707185
OWN - NLM
STAT- MEDLINE
DCOM- 20100113
LR  - 20211020
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 17
IP  - 11
DP  - 2009 Nov
TI  - Transgene expression levels determine the immunogenicity of transduced 
      hematopoietic grafts in partially myeloablated mice.
PG  - 1904-9
LID - 10.1038/mt.2009.198 [doi]
AB  - We investigated whether transgene expression levels influence the immunogenicity 
      of transduced hematopoietic grafts upon transplantation into partially 
      myeloablated mice. To this aim, bone marrow cells (BMCs) transduced with 
      retroviral vectors driving green fluorescent protein (GFP) expression either at 
      high (high-EGFP) or low levels (low-EGFP) were transplanted into congenic 
      recipients conditioned with sublethal doses of total body irradiation (TBI) or 
      busulfan. Virtually all recipients showed evidence of donor engraftment 4 weeks 
      after transplantation. However, as opposed to recipients receiving low-EGFP 
      transduced grafts, the risk of rejecting the EGFP(+) cells by 30 days after 
      transplantation was significantly higher in mice conditioned with busulfan and 
      receiving high-EGFP transduced grafts. Anti-EGFP cellular immune responses were 
      demonstrated in high-EGFP-treated mice conditioned with busulfan by 
      interferon-gamma (IFN-gamma), enzyme-linked immunospot assay (ELISPOT), and 
      cytotoxic T lymphocyte (CTL) assays, in contrast to that observed in mice 
      transplanted with low-EGFP BMC. These results show for the first time that 
      transgene expression levels can be critical for the immunogenicity of 
      gene-modified hematopoietic grafts, especially in immunocompetent or in partially 
      immunosuppressed recipients. These results have profound implications in vector 
      choice and in the design of gene therapy (GT) protocols.
FAU - Eixarch, Herena
AU  - Eixarch H
AD  - Banc de Sang i Teixits, Institut de Recerca Hospital Universitari Vall d'Hebron, 
      Universitat Autonoma de Barcelona, Barcelona, Spain.
FAU - Gomez, Alba
AU  - Gomez A
FAU - Kadar, Elisabeth
AU  - Kadar E
FAU - George, Monica
AU  - George M
FAU - Martinez, Nuria
AU  - Martinez N
FAU - Espejo, Carmen
AU  - Espejo C
FAU - Petriz, Jordi
AU  - Petriz J
FAU - Gimeno, Ramon
AU  - Gimeno R
FAU - Barquinero, Jordi
AU  - Barquinero J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090825
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Immunosuppressive Agents)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 82115-62-6 (Interferon-gamma)
RN  - G1LN9045DK (Busulfan)
SB  - IM
MH  - Animals
MH  - Bone Marrow Transplantation/adverse effects/methods
MH  - Busulfan/pharmacology
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Flow Cytometry
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors
MH  - Green Fluorescent Proteins/*genetics/*immunology
MH  - Hematopoietic Stem Cell Transplantation/*adverse effects/*methods
MH  - Immunity, Cellular/drug effects/*immunology
MH  - Immunosuppressive Agents/pharmacology
MH  - Interferon-gamma/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Retroviridae/genetics
MH  - Transduction, Genetic
MH  - Transplantation Conditioning
MH  - Whole-Body Irradiation
PMC - PMC2835042
EDAT- 2009/08/27 09:00
MHDA- 2010/01/14 06:00
PMCR- 2010/11/01
CRDT- 2009/08/27 09:00
PHST- 2009/08/27 09:00 [entrez]
PHST- 2009/08/27 09:00 [pubmed]
PHST- 2010/01/14 06:00 [medline]
PHST- 2010/11/01 00:00 [pmc-release]
AID - S1525-0016(16)30802-4 [pii]
AID - 10.1038/mt.2009.198 [doi]
PST - ppublish
SO  - Mol Ther. 2009 Nov;17(11):1904-9. doi: 10.1038/mt.2009.198. Epub 2009 Aug 25.