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Transplantation. 2000 Mar 27;69(6):1176-85.

Pancreatic islet xenograft tolerance after short-term costimulation blockade is associated with increased CD4+ T cell apoptosis but not immune deviation.

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1
National Pancreas Transplant Unit, University of Sydney at Westmead Hospital, NSW, Australia.

Abstract

BACKGROUND:

Our purpose was to determine if short-term inhibition of the CD40/CD40L and CD28/B7 costimulatory pathways was capable of inducing specific unresponsiveness to pancreatic islet xenografts and to ascertain the mechanism of tolerance induction.

METHODS:

Diabetic B6AF1 mice were transplanted with Wistar or DA rat islets and were treated short term with CTLA4-Fc and anti-CD40L mAb (MR1).

RESULTS:

Coadministration of CTLA4-Fc with MR1, resulted in indefinite rat islet xenograft survival in mice. Tolerance was species but not strain specific as long-term surviving recipients rejected third party BALB/c islet allografts but accepted a second rat islet xenograft from the same or different donor strain. Tolerance induction was associated with a large leukocyte infiltrate that did not exhibit features of immune deviation as intragraft T cell-specific cytokine gene expression was globally reduced. In particular, interleukin-4 gene expression was markedly suppressed. There was a complete inhibition of anti-donor IgG, IgG1, and IgM antibody in the serum of CTLA4-Fc/MR1- treated animals. Tolerance induction was associated with increased CD4+ T cell apoptosis as there was an increased proportion of annexin-V staining and Fas expressing CD4+ T cells and a decrease in CD4+ T cell Bcl-2 expression in the grafts and draining lymph nodes of CTLA4-Fc/MR1-treated recipients.

CONCLUSION:

Combined costimulatory blockade was capable of producing tolerance to pancreatic islet xenografts. The induction of this tolerant state was associated with increased T cell apoptosis, whereas the maintenance phase of tolerance was associated with the accumulation of a large number of inactive lymphocytes within the graft.

PMID:
10762224
[Indexed for MEDLINE]
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