TY - JOUR
T1 - Regulatory cells potentiate the efficacy of IL-4 gene transfer by up- regulating Th2-dependent expression of protective molecules in the infectious tolerance pathway in transplant recipients
AU - Ke, Bibo
AU - Ritter, Thomas
AU - Kato, Hirohisa
AU - Zhai, Yuan
AU - Li, Jiye
AU - Lehmann, Manfred
AU - Busuttil, Ronald W.
AU - Volk, Hans Dieter
AU - Kupiec-Weglinski, Jerzy W.
PY - 2000
Y1 - 2000
N2 - We have previously shown that the tolerant state in allograft recipients can be maintained and perpetuated by an 'infectious' T cell-dependent regulatory mechanism. Hence, 1) treatment of LEW rats with RIB-5/2, a CD4 nondepleting mAb, produces indefinite survival of LBNF1 cardiac allografts; 2) donor-specific tolerance can be then transferred by spleen cells into new cohorts of test allograft recipients; and 3) putative regulatory CD4+ Th2- like cells are instrumental in this tolerance model. We now report on studies aimed at exposing mechanisms underlying the infectious tolerance pathway, with emphasis on the interactions between intragraft adenovirus-IL-4 gene transfer and systemic infusion of regulatory cells from tolerant hosts. Unlike individual treatment regimens, adjunctive therapy with adenovirus-IL-4 and suboptimal doses of regulatory spleen cells was strongly synergistic and extended donor-type test cardiac allograft survival to about 2 mo. RT-PCR- based expression of intragraft mRNA coding for IL-2 and IFN-γ remained depressed, whereas that of IL-4 and IL-10 reciprocally increased selectively in the combined treatment group, data supported by ELISA studies. In parallel, only adjunctive treatment triggered intragraft induction of molecules with antioxidant (HO-1) and anti-apoptotic (Bcl-x(L)/Bag-1) but not with pro-apoptotic (CPP-32) functions, both in the early and late posttransplant phases. Hence, systemic infusion of regulatory cells potentiates the effects of local adenovirus-IL-4 gene transfer in transplant recipients. Th2-driven up-regulation of protective molecule programs at the graft site, such as of anti-oxidant HO-1 and/or anti-apoptotic Bcl-x(L) and Bag-1, may contribute, at least in part, to the maintenance of the infectious tolerance pathway in transplant recipients.
AB - We have previously shown that the tolerant state in allograft recipients can be maintained and perpetuated by an 'infectious' T cell-dependent regulatory mechanism. Hence, 1) treatment of LEW rats with RIB-5/2, a CD4 nondepleting mAb, produces indefinite survival of LBNF1 cardiac allografts; 2) donor-specific tolerance can be then transferred by spleen cells into new cohorts of test allograft recipients; and 3) putative regulatory CD4+ Th2- like cells are instrumental in this tolerance model. We now report on studies aimed at exposing mechanisms underlying the infectious tolerance pathway, with emphasis on the interactions between intragraft adenovirus-IL-4 gene transfer and systemic infusion of regulatory cells from tolerant hosts. Unlike individual treatment regimens, adjunctive therapy with adenovirus-IL-4 and suboptimal doses of regulatory spleen cells was strongly synergistic and extended donor-type test cardiac allograft survival to about 2 mo. RT-PCR- based expression of intragraft mRNA coding for IL-2 and IFN-γ remained depressed, whereas that of IL-4 and IL-10 reciprocally increased selectively in the combined treatment group, data supported by ELISA studies. In parallel, only adjunctive treatment triggered intragraft induction of molecules with antioxidant (HO-1) and anti-apoptotic (Bcl-x(L)/Bag-1) but not with pro-apoptotic (CPP-32) functions, both in the early and late posttransplant phases. Hence, systemic infusion of regulatory cells potentiates the effects of local adenovirus-IL-4 gene transfer in transplant recipients. Th2-driven up-regulation of protective molecule programs at the graft site, such as of anti-oxidant HO-1 and/or anti-apoptotic Bcl-x(L) and Bag-1, may contribute, at least in part, to the maintenance of the infectious tolerance pathway in transplant recipients.
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U2 - 10.4049/jimmunol.164.11.5739
DO - 10.4049/jimmunol.164.11.5739
M3 - Article
C2 - 10820251
AN - SCOPUS:0034120177
VL - 164
SP - 5739
EP - 5745
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 11
ER -