PMID- 7944661
OWN - NLM
STAT- MEDLINE
DCOM- 19941110
LR  - 20211203
IS  - 0003-4932 (Print)
IS  - 1528-1140 (Electronic)
IS  - 0003-4932 (Linking)
VI  - 220
IP  - 4
DP  - 1994 Oct
TI  - Gene transfer for transplantation. Prolongation of allograft survival with 
      transforming growth factor-beta 1.
PG  - 508-18; discussion 518-9
AB  - OBJECTIVE: The authors tested the ability of plasmid gene transfer to express 
      transforming growth factor-beta 1 (TGF-beta 1), prolong allograft survival, and 
      evaluate promoter effects on gene expression. SUMMARY BACKGROUND DATA: Delivery 
      of immunosuppressants directly to allografts using gene transfer and gene therapy 
      approaches may inhibit immune activation while avoiding the systemic toxicity of 
      conventional immunosuppression. Candidate genes include soluble cytokines, which 
      could be expressed at low levels throughout the graft while inducing a local 
      immunosuppressive effect. Transforming growth factor-beta 1 is a soluble cytokine 
      that has pleiotropic immunosuppressive effects. METHODS: Cardiac grafts from 
      syngeneic (CBA/J, H-2k) or allogenic (C57BL/6, H-2b) donors were placed into 
      CBA/J recipients. Purified plasmid DNA-encoding murine TGF-beta 1 or 
      beta-galactosidase (Lac Z) under the control of RSV, SV40, MMTV, or pancreatic 
      elastase promoters was injected into grafts at surgery. The Lac Z expression was 
      determined by histologic examination and TGF-beta 1 expression by graft survival. 
      Cytotoxic T lymphocyte and flow cytometric analyses were performed to evaluate 
      the immunosuppressive effects of TGF-beta 1 in vitro. RESULTS: Plasmid 
      DNA-encoding TGF-beta 1 prolonged survival from 12.6 +/- 1.1 days to 26.3 +/- 2.5 
      days (p < 0.02, Student's t test). The SV40 promoter was superior to the MMTV 
      promoter in its ability to prolong survival. The effects of the plasmids were 
      specific because Lac Z, antisense TGF-beta 1 inserts, or pancreatic elastase 
      promoter did not prolong allograft survival. Histologic examination demonstrated 
      Lac Z expression at least 14 days post-transplant in myocardial cells. Both RSV 
      and SV40 promoters were effective in this respect, while a control null promoter 
      was not. Toxicity testing showed that gene transfer of TGF-beta 1 did not alter 
      survival or histology of syngeneic grafts. In addition, plasmids and purified 
      TGF-beta 1 protein were not toxic to myoblasts in vitro. Recombinant TGF-beta 1 
      inhibited cytotoxic T lymphocyte generation and altered T cell surface receptor 
      expression and subset expansion in vitro. CONCLUSION: Gene transfer/therapy with 
      plasmid DNA encoding TGF-beta 1 in vivo achieves immunologic effects that prolong 
      allograft survival. Multiple promoters effectively induce plasmid expression, 
      which is achieved in cardiac myocytes for at least 2 weeks without toxicity or 
      adverse systemic effects. Transforming growth factor-beta 1 inhibits immune 
      responses by different mechanisms, revealed by in vitro analysis of T cell 
      cytolytic function, subset distribution, and receptor display.
FAU - Qin, L
AU  - Qin L
AD  - Department of Surgery, Medical University of South Carolina, Charleston.
FAU - Chavin, K D
AU  - Chavin KD
FAU - Ding, Y
AU  - Ding Y
FAU - Woodward, J E
AU  - Woodward JE
FAU - Favaro, J P
AU  - Favaro JP
FAU - Lin, J
AU  - Lin J
FAU - Bromberg, J S
AU  - Bromberg JS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Ann Surg
JT  - Annals of surgery
JID - 0372354
RN  - 0 (Transforming Growth Factor beta)
RN  - EC 3.2.1.23 (beta-Galactosidase)
RN  - EC 3.4.21.36 (Pancreatic Elastase)
SB  - IM
MH  - Animals
MH  - Female
MH  - Flow Cytometry
MH  - Gene Expression
MH  - *Gene Transfer Techniques
MH  - Genetic Vectors
MH  - Graft Rejection/immunology/*prevention & control
MH  - Graft Survival/immunology
MH  - Heart Transplantation/*immunology
MH  - Immunosuppression Therapy/*methods
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Pancreatic Elastase/genetics
MH  - Plasmids
MH  - T-Lymphocytes, Cytotoxic/immunology
MH  - Transforming Growth Factor beta/*genetics
MH  - beta-Galactosidase/genetics
PMC - PMC1234424
EDAT- 1994/10/01 00:00
MHDA- 1994/10/01 00:01
PMCR- 1994/10/01
CRDT- 1994/10/01 00:00
PHST- 1994/10/01 00:00 [pubmed]
PHST- 1994/10/01 00:01 [medline]
PHST- 1994/10/01 00:00 [entrez]
PHST- 1994/10/01 00:00 [pmc-release]
AID - 10.1097/00000658-199410000-00009 [doi]
PST - ppublish
SO  - Ann Surg. 1994 Oct;220(4):508-18; discussion 518-9. doi: 
      10.1097/00000658-199410000-00009.