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Scientific article
English

Immunomodulation by blockade of the TRANCE co-stimulatory pathway in murine allogeneic islet transplantation

Published inTransplant international, vol. 22, no. 9, p. 931-939
Publication date2009
Abstract

We explore herein the effect of TNF-related activation-induced cytokine (TRANCE) co-stimulatory pathway blockade on islet survival after allograft transplantation. Expression of TRANCE on murine C57Bl/6 (B6) CD4+ T cells after allogeneic activation was analyzed by fluorescence-activated cell sorter (FACS). The effect of a TRANCE receptor fusion protein (TR-Fc) and anti-CD154 antibody (MR1) on B6 spleen cell proliferation after allogeneic activation was assessed by mixed lymphocyte reaction (MLR). Three groups of B6 mice were transplanted with allogeneic islets (DBA2): Control; short-term TR-Fc-treatment (days 0-4); and prolonged TR-Fc-treatment (days -1 to 13). Donor-specific transfusion (DST) was performed at the time of islet transplantation in one independent experiment. Transplantectomy samples were analyzed by immunohistochemistry. TRANCE expression was upregulated in stimulated CD4+ T cells in vitro. In MLR experiments, TR-Fc and MR1 both reduced spleen cell proliferation, but less than the combination of both molecules. Short-course TR-Fc treatment did not prolong islet graft survival when compared with controls (10.6 +/- 1.9 vs. 10.7 +/- 1.5 days) in contrast to prolonged treatment (20.7 +/- 3.2 days; P < 0.05). After DST, primary non function (PNF) was observed in half of control mice, but never in TR-Fc-treated mice. Immunofluorescence staining for Mac-1 showed a clear decrease in macrophage recruitment in the treated groups. TRANCE-targeting may be an effective strategy for the prolongation of allogeneic islet graft survival, thanks to its inhibitory effects on co-stimulatory signals and macrophage recruitment.

Keywords
  • Animals
  • CD4-Positive T-Lymphocytes/immunology
  • CD40 Ligand/biosynthesis
  • Cell Separation
  • Flow Cytometry
  • Graft Survival
  • Islets of Langerhans Transplantation/*methods
  • Macrophages/metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Models, Biological
  • RANK Ligand/*antagonists & inhibitors/*metabolism
  • Spleen/cytology
  • Transplantation, Homologous
Citation (ISO format)
WOJTUSCISZYN, Anne et al. Immunomodulation by blockade of the TRANCE co-stimulatory pathway in murine allogeneic islet transplantation. In: Transplant international, 2009, vol. 22, n° 9, p. 931–939. doi: 10.1111/j.1432-2277.2009.00892.x
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ISSN of the journal0934-0874
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