PMID- 16720899
OWN - NLM
STAT- MEDLINE
DCOM- 20060711
LR  - 20210102
IS  - 0257-277X (Print)
IS  - 0257-277X (Linking)
VI  - 34
IP  - 1
DP  - 2006
TI  - Redirection of T cells by delivering a transgenic mouse-derived MDM2 tumor 
      antigen-specific TCR and its humanized derivative is governed by the CD8 
      coreceptor and affects natural human TCR expression.
PG  - 67-87
AB  - Retroviral transfer of T cell antigen receptor (TCR) genes selected by 
      circumventing tolerance to broad tumor- and leukemia-associated antigens in human 
      leukocyte antigen (HLA)-A*0201 (A2.1) transgenic (Tg) mice allows the therapeutic 
      reprogramming of human T lymphocytes. Using a human CD8 x A2.1/Kb mouse derived 
      TCR specific for natural peptide-A2.1 (pA2.1) complexes comprising residues 81-88 
      of the human homolog of the murine double-minute 2 oncoprotein, MDM2(81-88), we 
      found that the heterodimeric CD8 alpha beta coreceptor, but not normally 
      expressed homodimeric CD8 alpha alpha, is required for tetramer binding and 
      functional redirection of TCR- transduced human T cells. CD8+T cells that 
      received a humanized derivative of the MDM2 TCR bound pA2.1 tetramers only in the 
      presence of an anti-human-CD8 anti-body and required more peptide than wild-type 
      (WT) MDM2 TCR+T cells to mount equivalent cytotoxicity. They were, however, 
      sufficiently effective in recognizing malignant targets including fresh leukemia 
      cells. Most efficient expression of transduced TCR in human T lymphocytes was 
      governed by mouse as compared to human constant (C) alphabeta domains, as 
      demonstrated with partially humanized and murinized TCR of primary mouse and 
      human origin, respectively. We further observed a reciprocal relationship between 
      the level of Tg WT mouse relative to natural human TCR expression, resulting in T 
      cells with decreased normal human cell surface TCR. In contrast, natural human 
      TCR display remained unaffected after delivery of the humanized MDM2 TCR. These 
      results provide important insights into the molecular basis of TCR gene therapy 
      of malignant disease.
FAU - Voss, Ralf-Holger
AU  - Voss RH
AD  - Department of Hematology and Oncology, Johannes Gutenberg-University, Mainz, 
      Germany.
FAU - Kuball, Jurgen
AU  - Kuball J
FAU - Engel, Renate
AU  - Engel R
FAU - Guillaume, Philippe
AU  - Guillaume P
FAU - Romero, Pedro
AU  - Romero P
FAU - Huber, Christoph
AU  - Huber C
FAU - Theobald, Matthias
AU  - Theobald M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Immunol Res
JT  - Immunologic research
JID - 8611087
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA-A2 Antigen)
RN  - 0 (Receptors, Antigen, T-Cell, alpha-beta)
RN  - EC 2.3.2.27 (MDM2 protein, human)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
SB  - IM
MH  - Animals
MH  - CD4-Positive T-Lymphocytes/*immunology
MH  - CD8-Positive T-Lymphocytes/*immunology
MH  - Cell Line, Tumor
MH  - Epitopes, T-Lymphocyte/*immunology
MH  - Flow Cytometry
MH  - HLA-A2 Antigen/immunology
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - Proto-Oncogene Proteins c-mdm2/genetics/*immunology
MH  - Receptors, Antigen, T-Cell, alpha-beta/*immunology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Self Tolerance/immunology
EDAT- 2006/05/25 09:00
MHDA- 2006/07/13 09:00
CRDT- 2006/05/25 09:00
PHST- 1999/11/30 00:00 [received]
PHST- 1999/11/30 00:00 [revised]
PHST- 1999/11/30 00:00 [accepted]
PHST- 2006/05/25 09:00 [pubmed]
PHST- 2006/07/13 09:00 [medline]
PHST- 2006/05/25 09:00 [entrez]
AID - IR:34:1:67 [pii]
AID - 10.1385/IR:34:1:67 [doi]
PST - ppublish
SO  - Immunol Res. 2006;34(1):67-87. doi: 10.1385/IR:34:1:67.