title: 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.
abstract: 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-gamma 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 anti-oxidant (HO-1) and anti-apoptotic (Bcl-xL/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-xL and Bag-1, may contribute, at least in part, to the maintenance of the infectious tolerance pathway in transplant recipients.
authors.affiliation: Dumont-University of California Los Angeles Transplant Center, Department of Surgery, University of California Los Angeles School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: B
authors.initials: B
authors.lastname: Ke
authors.forename: T
authors.initials: T
authors.lastname: Ritter
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: Y
authors.initials: Y
authors.lastname: Zhai
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Lehmann
authors.forename: R W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: H D
authors.initials: HD
authors.lastname: Volk
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000276:immunology; D018014:Gene Transfer Techniques; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007108:Immune Tolerance / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000637:transplantation*; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D001616:beta-Galactosidase / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D015847:Interleukin-4; D001616:beta-Galactosidase