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CTLA4Ig adenoviral gene transfer induces long-term islet rat allograft survival, without tolerance, after systemic but not local intragraft expression

Potiron, Nicolas
Boeffard, Françoise
Chagneau, Carine
Brouard, Sophie
Guillot, Cécile
Soulillou, Jean-Paul
Anegon, Ignacio
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Published in Human gene therapy. 2003, vol. 14, no. 6, p. 561-75
Abstract Genetic engineering using recombinant adenoviruses offers an opportunity to modify islet grafts in order to prevent allograft rejection. We have used an adenovirus coding for CTLA4Ig to compare its efficacy in preventing islet rejection depending on local or systemic production after gene transfer either into the islets or intramuscularly, respectively. Islet allograft survival was also evaluated using recombinant CTLA4Ig administered intraperitoneally or incubated ex vivo with islets prior to transplantation. Transduction of islets with 10(3) or 10(4) plaque-forming units (pfu) per islets of AdCTLA4Ig prolonged islet survival (mean +/- standard deviation [SD] days = 19.5 +/- 5.8 and 19.5 +/- 5.6, respectively, vs. 10.6 +/- 2.4 in control islets, p < 0.001), with low levels of circulating CTLA4Ig. In contrast, long-term survival (>60 days) was obtained after intramuscular injection of AdCTLA4Ig that resulted in sustained high levels of circulating CTLA4Ig. Islets incubated in vitro with CTLA4Ig did not show prolonged survival (10.3 +/- 2.5 days). Graft rejection was delayed after one injection of CTLA4Ig (23 +/- 7.6 days, p < 0.003 vs. control). Recipients of long-term surviving grafts after intramuscular AdCTLA4Ig gene transfer were not tolerant because second islet grafts of donor origin were rejected. These recipients also had a strong inhibition of humoral responses against nominal antigens, whereas animals receiving transduced islets showed normal responses. These data demonstrate that local production of CTLA4Ig after gene transfer was as efficient as a single injection of CTLA4Ig in preventing graft rejection. Furthermore, intramuscular gene transfer of CTLA4Ig was the most efficient way to induce long-term islet graft survival but no donor-specific tolerance was induced.
Keywords Adenoviridae/geneticsAnimalsGenetic VectorsGraft RejectionGraft Survival/immunologyImmunocompromised HostImmunoconjugates/analysis/geneticsIslets of Langerhans/pathology/physiologyIslets of Langerhans Transplantation/immunology/methods/pathologyIsoantibodies/bloodMaleMiceRatsRats, Inbred BNRats, Inbred LewRats, Inbred WFSpleen/immunologyTransduction, GeneticTransplantation Tolerance
PMID: 12718766
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LAUMONIER, Thomas et al. CTLA4Ig adenoviral gene transfer induces long-term islet rat allograft survival, without tolerance, after systemic but not local intragraft expression. In: Human gene therapy, 2003, vol. 14, n° 6, p. 561-75. doi: 10.1089/104303403764539341

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Deposited on : 2014-09-24

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