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*
Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN 55455;
SAIC-Frederick and the Laboratory of Leukocyte Biology, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702;
Schering-Plough Research Institute, Kenilworth, NJ 07033; and
§
Telethon Institute of gene therapy-H. San Raffaele, Milan, Italy
Induction and maintenance of Ag-specific tolerance are pivotal for immune homeostasis, prevention of autoimmune disorders, and the goal of transplantation. Recent studies suggest that certain cytokines, notably IL-10 and TGF-ß, may play a role in down-regulating immune functions. To further examine the role of cytokines in Ag-specific hyporesponsiveness, murine CD4+ T cells were exposed ex vivo to alloantigen-bearing stimulators in the presence of exogenous IL-10 and/or TGF-ß. Primary but not secondary alloantigen proliferative responses were inhibited by IL-10 alone. However, the combined addition of IL-10 + TGF-ß markedly induced alloantigen hyporesponsiveness in both primary and secondary MLR cultures. Alloantigen-specific hyporesponsiveness was observed also under conditions in which nominal Ag responses were intact. In adoptive transfer experiments, IL-10 + TGF-ß-treated CD4+ T cells, but not T cells treated with either cytokine alone, were markedly impaired in inducing graft-vs-host disease alloresponses to MHC class II disparate recipients. These data provide the first formal evidence that IL-10 and TGF-ß have at least an additive effect in inducing alloantigen-specific tolerance, and that in vitro cytokines can be exploited to suppress CD4+ T cell-mediated Ag-specific responses in vivo.
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B. J. Chen, X. Cui, C. Liu, and N. J. Chao Prevention of graft-versus-host disease while preserving graft-versus-leukemia effect after selective depletion of host-reactive T cells by photodynamic cell purging process Blood, May 1, 2002; 99(9): 3083 - 3088. [Abstract] [Full Text] [PDF]
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F. Cottrez and H. Groux Regulation of TGF-{{beta}} Response During T Cell Activation Is Modulated by IL-10 J. Immunol., July 15, 2001; 167(2): 773 - 778. [Abstract] [Full Text] [PDF]
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P. A. Taylor, R. J. Noelle, and B. R. Blazar CD4+CD25+ Immune Regulatory Cells Are Required for Induction of Tolerance to Alloantigen via Costimulatory Blockade J. Exp. Med., June 4, 2001; 193(11): 1311 - 1318. [Abstract] [Full Text] [PDF]
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M. K. Levings, R. Sangregorio, F. Galbiati, S. Squadrone, R. de Waal Malefyt, and M.-G. Roncarolo IFN-{{alpha}} and IL-10 Induce the Differentiation of Human Type 1 T Regulatory Cells J. Immunol., May 1, 2001; 166(9): 5530 - 5539. [Abstract] [Full Text] [PDF]
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G. Rossi, J. Sarkar, and D. Scandella Long-term induction of immune tolerance after blockade of CD40-CD40L interaction in a mouse model of hemophilia A Blood, May 1, 2001; 97(9): 2750 - 2757. [Abstract] [Full Text] [PDF]
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K. Weinberg, B. R. Blazar, J. E. Wagner, E. Agura, B. J. Hill, M. Smogorzewska, R. A. Koup, M. R. Betts, R. H. Collins, and D. C. Douek Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation Blood, March 1, 2001; 97(5): 1458 - 1466. [Abstract] [Full Text] [PDF]
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V. A. Boussiotis, Z.-M. Chen, J. C. Zeller, W. J. Murphy, A. Berezovskaya, S. Narula, M. G. Roncarolo, and B. R. Blazar Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-{beta}-treated alloreactive T cells that do not induce graft-versus-host disease Blood, January 15, 2001; 97(2): 565 - 571. [Abstract] [Full Text] [PDF]
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K.-H. Sonoda, D. E. Faunce, M. Taniguchi, M. Exley, S. Balk, and J. Stein-Streilein NK T Cell-Derived IL-10 Is Essential for the Differentiation of Antigen-Specific T Regulatory Cells in Systemic Tolerance J. Immunol., January 1, 2001; 166(1): 42 - 50. [Abstract] [Full Text] [PDF]
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