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Accelerating the induction of Fas-mediated T cell apoptosis: A strategy for transplant tolerance?

Lookup NU author(s): Professor Simi Ali, Professor John Kirby

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Abstract

Acute allograft rejection is primarily a consequence of clonal expansion of donor-specific T cells with specificity for donor antigen. Immunosuppression current involves the administration of toxic drugs that limit lymphoproliferation, but this treatment is not antigen-specific and allows opportunistic infection. An ideal strategy would be production of donor-specific T cell tolerance in the presence of an otherwise intact and functional T cell repertoire. Methods to enhance normal apoptotic clearance of activated T cells might contribute to development of this state. This study focuses on manipulation in vitro of Fas-mediated T cell apoptosis and compares two methods to enhance the extent and kinetics for clearance of activated T cells. First, the CD4 coreceptor was cross-linked in the presence and absence of Fas-stimulation. It was found that CD4 cross-linking potently induced apoptosis, even in the absence of Fas stimulation. Resting and activated T cells were susceptible to this treatment, precluding the development of antigen-specific tolerance after T cell activation. In a second system, T cells were treated with two staurosporine analogues, Bisindolylmaleimide (Bis) III and VIII and apoptosis was induced by stimulation of Fas. Resting T cells remained resistant to Fas-mediated apoptosis, but treatment of mitogen or alloantigen-activated cells with either Bis III or VIII caused a synergistic increase in apoptosis. These agents also reduced the period of resistance to Fas-mediated apoptosis after T cell activation, possibly by reducing expression of c-FLIP, allowing early activation of caspase 8 in alloreactive T cells. Development of this strategy might provide a route to the induction specific tolerance after organ transplantation.


Publication metadata

Author(s): Kirby JA; Ali S; Carroll HP

Publication type: Article

Publication status: Published

Journal: Clinical and Experimental Immunology

Year: 2001

Volume: 126

Issue: 3

Pages: 589-597

ISSN (print): 0009-9104

ISSN (electronic): 1365-2249

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1046/j.1365-2249.2001.01706.x

DOI: 10.1046/j.1365-2249.2001.01706.x

PubMed id: 11737081


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