Induction of donor-specific allograft tolerance by short-term treatment with LF15-0195 after transplantation. Evidence for a direct effect on T-cell differentiation.
A 20-day treatment with LF15-0195, a deoxyspergualine analog, induced long-term heart allograft survival in the rat without signs of chronic rejection. LF15-0195-treated recipients did not develop an anti-donor alloantibody response. Analysis of graft-infiltrating cells, IL10, TNFalpha, IFNgamma mRNA and iNOS protein expression in allografts, 5 days after transplantation, showed that they were markedly decreased in allografts from LF15-0195-treated recipients compared with allografts from untreated recipients. Surprisingly, spleen T cells from LF15-0195 recipients, 5days after grafting, were able to proliferate strongly in vitro, when stimulated with donor cells, but had reduced mRNA expression for IFNy compared with spleen T cells from untreated graft recipients. Furthermore, when T cells from naive animals were stimulated in vitro, using anti-CD3 and anti-CD28, LF15-0195 also increased T-cell proliferation in a dose-dependent fashion: however, these cells expressed less of the Th1 -related cytokines, IFNgamma and IL2, compared with untreated cells, suggesting that LF15-0195 could act on T-cell differentiation. In conclusion, we show here that a short-term treatment with LF15-0195 induced long-term allograft tolerance, decreasing the in situ anti-donor response, and we illustrate evidence for the development of regulatory mechanisms.
Chiffoleau
Elise
E
INSERM Unité 437 and Institut de Transplantation et de Recherche en Transplantation, CHU Hotel Dieu, Nantes, France.
Bériou
Gaëlle
G
Dutartre
Patrick
P
Usal
Claire
C
Soulillou
Jean-Paul
JP
Cuturi
Maria Cristina
MC
D000818:Animals; D000906:Antibodies / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D016207:Cytokines / Q000187:drug effects; D006084:Graft Rejection / Q000517:prevention & control*; D006146:Guanidines / Q000494:pharmacology*; D016027:Heart Transplantation / Q000276:immunology; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects*
D000906:Antibodies; D016207:Cytokines; D006146:Guanidines; D007166:Immunosuppressive Agents; C434185:LF 150195; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat