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Title: Use of the methylxanthine derivative A802715 in transplantation immunology: II. In vivo experiments
Authors: Lin, Y ×
Segers, Constant
Mikhalsky, D
Tjandra-Maga, Tikma Budya
Schönharting, M
Waer, Mark #
Issue Date: 27-Jun-1997
Series Title: Transplantation vol:63 issue:12 pages:1734-8
Abstract: BACKGROUND: We have previously demonstrated in vitro that the methylxanthine derivative A802715 suppresses the cyclosporine (CsA)-resistant "signal two"-dependent pathway of T cell activation and hence acts synergistically with CsA. Here, this synergism was further investigated in vivo in rats. METHODS: Primary cardiac allografts were placed in the neck, and secondary grafts were transplanted intra-abdominally. A802715 was given orally for 30 days or by continuous intravenous infusion via a mini-osmotic pump for 2 weeks. CsA was given orally for up to 30 days. T cell responses were examined in vitro using mixed lymphocyte reaction, concanavalin A whole blood, and cell-mediated lympholysis assays. RESULTS: In a major histocompatibility complex incompatible WKAH-->PVG combination, neither oral CsA (7.5 mg/kg/day) nor oral A802715 (100 mg/kg/day) was able to prolong graft survival. However, a combination of both drugs, given at the same dose, sustained graft survival during treatment. A similar synergism was not obtained with pentoxifylline, another methylxanthine derivative. The synergism between A802715 and CsA could be further increased by using a continuous intravenous infusion of A802715, since (1) lower doses of A802715 (20 mg/kg/day) and CsA (5 mg/kg/day) could be used, and (2) six of seven grafts survived permanently. In a major histocompatibility complex compatible Wag/Rij-->R/A combination, similar synergistic effects and permanent graft survival could also be obtained by oral A802715 (100 mg/kg/day) in combination with a low dose of CsA (2.5 mg/kg/day). In both strain combinations, long-term survivors accepted donor-type but rejected third-party second grafts in the absence of immunosuppression. This specific tolerance was not related to clonal deletion nor anergy, as recipient lymphocytes proliferated normally in the anti-donor mixed lymphocyte reaction. Instead, a defect in generating specific cytotoxic T lymphocytes was involved. CONCLUSIONS: A802715 synergizes with CsA in vivo to induce specific transplantation tolerance and hence should be considered as a promising new immunosuppressant.
ISSN: 0041-1337
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Pharmacology Section (-)
Laboratory of Nephrology
Laboratory of Experimental Transplantation
× corresponding author
# (joint) last author

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