Open AccessImmunomodulation by blockade of the TRANCE co‐stimulatory pathway in murine allogeneic islet transplantation
Author(s) -
Wojtusciszyn Anne,
Andres Axel,
Morel Philippe,
Charvier Solange,
Armanet Mathieu,
Toso Christian,
Choi Yongwon,
Bosco Domenico,
Berney Thierry
Publication year - 2009
Publication title -
transplant international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.998
H-Index - 82
eISSN - 1432-2277
pISSN - 0934-0874
DOI - 10.1111/j.1432-2277.2009.00892.x
Subject(s) - islet , transplantation , medicine , mixed lymphocyte reaction , blockade , spleen , downregulation and upregulation , immunology , endocrinology , t cell , receptor , andrology , immune system , biology , insulin , biochemistry , gene
Summary 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.