PMID- 16082332
OWN - NLM
STAT- MEDLINE
DCOM- 20050831
LR  - 20190713
IS  - 0041-1337 (Print)
IS  - 0041-1337 (Linking)
VI  - 80
IP  - 3
DP  - 2005 Aug 15
TI  - Tolerance by selective in vivo expansion of foreign major histocompatibility 
      complex-transduced autologous bone marrow.
PG  - 362-9
AB  - BACKGROUND: Application of gene therapy to induce antigen-specific immune 
      tolerance could be important for transplantation or treatment of autoimmune 
      diseases. Hematopoietic stem cell-based gene therapy has been hampered by 
      relatively weak gene expression in vivo and loss of transduced cells over time. 
      Selective expansion of transduced hematopoietic stem cells has been accomplished 
      by incorporating the dihydrofolate reductase (DHFR) gene into the gene transfer 
      vector. METHODS: To assess whether this strategy could be applied to 
      transplantation, we constructed a retroviral vector plasmid (KA274) containing 
      the cDNA encoding human leukocyte antigen (HLA)-A2.1 and a tyr22 mutant DHFR and 
      generated vesicular stomatitis virus-G-pseudotyped recombinant retrovirus by 
      transfection into 293GPG cells. Bone marrow cells from C57BL/6 mice were infected 
      with KA274 at a multiplicity of infection of 100, and transplanted into lethally 
      irradiated syngeneic mice. RESULTS: After transplantation with transduced bone 
      marrow, the proportion of peripheral blood cells expressing HLA-A2 ranged from 
      3.2% to 38% and increased 2- to 4.9-fold after selection for DHFR-expressing 
      cells using trimetrexate and nitrobenzylmercaptpurine riboside 5' monophosphate. 
      HLA-A2 expression remained above pretreatment levels throughout the study. 
      Cytotoxic spleen cells from reconstituted mice lysed third-party 
      HLA-B7-expressing targets but were unable to lyse HLA-A2-expressing targets. All 
      KA274 reconstituted C57BL/6 mice accepted skin grafts from HLA-A2.1 transgenic 
      mice for more than 245 days but rejected third-party Balb/c skin grafts in 12 
      days. CONCLUSION: Long-term transgene expression and immunologic tolerance to 
      retrovirus-encoded HLA-A2, equivalent to that obtained by donor bone marrow 
      transplantation, was accomplished, and selective expansion of transduced bone 
      marrow cells was induced using DHFR as a selectable marker.
FAU - Zhang, Jia Lin
AU  - Zhang JL
AD  - Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska 
      68198-3285, USA.
FAU - Cai, Jin
AU  - Cai J
FAU - Walls, Shannon
AU  - Walls S
FAU - Jackson, John D
AU  - Jackson JD
FAU - Kuszynski, Charles A
AU  - Kuszynski CA
FAU - Zhao, Yong
AU  - Zhao Y
FAU - Pawliuk, Robert
AU  - Pawliuk R
FAU - Leboulch, Philippe
AU  - Leboulch P
FAU - Fox, Ira J
AU  - Fox IJ
LA  - eng
GR  - DK48794/DK/NIDDK NIH HHS/United States
GR  - P01 HL55435/HL/NHLBI NIH HHS/United States
GR  - R01 AI31641/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Transplantation
JT  - Transplantation
JID - 0132144
RN  - 0 (DNA, Complementary)
RN  - 0 (HLA-A2 Antigen)
SB  - IM
MH  - Animals
MH  - Bone Marrow Cells/*cytology/immunology
MH  - Bone Marrow Transplantation/*methods
MH  - Cell Transplantation
MH  - DNA, Complementary/metabolism
MH  - Flow Cytometry
MH  - Graft Rejection
MH  - Graft Survival
MH  - HLA-A2 Antigen/chemistry
MH  - Hematopoietic Stem Cells/cytology
MH  - *Major Histocompatibility Complex
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Mutation
MH  - Polymerase Chain Reaction
MH  - Retroviridae/genetics/metabolism
MH  - Skin Transplantation
MH  - Time Factors
EDAT- 2005/08/06 09:00
MHDA- 2005/09/01 09:00
CRDT- 2005/08/06 09:00
PHST- 2005/08/06 09:00 [pubmed]
PHST- 2005/09/01 09:00 [medline]
PHST- 2005/08/06 09:00 [entrez]
AID - 00007890-200508150-00012 [pii]
AID - 10.1097/01.tp.0000165791.39723.a1 [doi]
PST - ppublish
SO  - Transplantation. 2005 Aug 15;80(3):362-9. doi: 10.1097/01.tp.0000165791.39723.a1.