Transforming growth factor-beta/interleukin-2-induced regulatory CD4+ T cells prolong cardiac allograft survival in rats.
BACKGROUND
Treatment of naive CD4+ T cells in vitro with transforming growth factor-beta (TGF-beta) or TGF-beta/interleukin-2 (IL-2), combined with stimulation in a mixed lymphoid culture (MLC), has been shown to generate CD4+ CD25+ regulatory T cells. However, little is known about the effect of these regulatory T cells on cardiac allograft survival in vivo.


METHODS
CD4+ CD25+ T cells were generated from Lewis (LEW) rat spleen through a primary MLC with TGF-beta (10 ng/ml) or TGF-beta/IL-2 (10 U/ml). The effect of adoptive transfer of the CD4+ CD25+ T cells (5.0 x 10(7)) was evaluated using an animal model of ACI rat cardiac allograft survival in LEW recipients.


RESULTS
The MLC with TGF-beta or TGF-beta/IL-2 generated CD4+ CD25+ regulatory T cells, which suppressed the cytotoxic activity of LEW spleen T cells against irradiated ACI spleen cells in vitro. Adoptive transfer of the CD4+ CD25+ regulatory T cells intravenously to naive syngeneic recipients significantly prolonged the ACI cardiac allograft survival (N = 6, 13.5 +/- 3.4 days) compared with the control group (N = 6, 5.0 +/- 0.6 days).


CONCLUSIONS
Intravenous administration of CD4+ CD25+ regulatory T cells, successfully generated by TGF-beta/IL-2 treatment, had a significant effect on cardiac allograft survival in this rat model. Adoptive transfer of regulatory T cells may represent a novel approach for preventing allograft rejection.
Watanabe
Meguru
M
Department of Cardiothoracic Surgery, University of Southern California, Children's Hospital Los Angeles, Los Angeles, California 90027, USA. mbarr@surgery.usc.edu
Mencel
Robert L
RL
Cramer
Donald V
DV
Starnes
Vaughn A
VA
Barr
Mark L
ML
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D007262:Infusions, Intravenous; D007376:Interleukin-2 / Q000276:immunology*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D015375:Receptors, Interleukin-2 / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016212:Transforming Growth Factor beta; D014184:Transplantation, Homologous
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta