title: Simultaneous blockade of co-stimulatory signals, CD28 and ICOS, induced a stable tolerance in rat heart transplantation.
abstract: An inducible co-stimulator (ICOS), a recently identified co-stimulatory receptor with a close structural homology of CD28 and CTLA4, is expressed on activated T cells. Anti-ICOS antibody was demonstrated to be effective on prolongation of graft survival after liver transplantation in rats. In this study, we investigated the potency of tolerance induction using the antibody combined with a recombinant adenovirus vector containing CTLA-4Ig cDNA (AdCTLA-4Ig) in rat heart transplantation model. Using a DA-to-Lewis rat heart transplantation model, an anti-rat ICOS antibody and AdCTLA-4Ig were simultaneously administered i.v. into recipients. The tissue specimens from the grafts were removed on various days after transplantation for histological evaluation. Donor-strain skin and heart grafts, and third-party heart allografts were challenged in the recipients with a long-term surviving graft. Splenocytes from the tolerance-induced recipients were used for adoptive transfer study. Anti-ICOS antibody alone did not prolong the survival of heart allograft. AdCTLA-4Ig monotherapy significantly prolonged the survival of heart allograft (Group 4). With a combination of Anti-ICOS antibody and AdCTLA-4Ig, all recipients were resulted in a long-term allograft acceptance for more than 200 days (Group 8). When challenged donor-strain skin grafts in the tolerant rats of Group 4, the skin was rejected, which also lead to a rejection of primary heart allografts. The recipients in Group 8 also rejected donor-strain skin grafts with no rejection of the primary heart grafts. These recipients accepted secondary heart grafts from donor-strain but not third-party. In Group 8 long-term survival recipients showed a high population of CD4+CD25+ regulatory T cell in peripheral blood, and in adoptive transfer study subtraction of these CD4+CD25+ T cells accelerate the rejection of heart graft in secondary irradiated recipients. The present results demonstrated that anti-ICOS antibody combined with AdCTLA-4Ig potently induces a stable immune tolerance after heart allografting in rat, which is mediated by the induction of CD4+CD25+ regulatory T cells. This strategy may be attractive for clinical employment to induce transplantation tolerance.
authors.affiliation: Laboratory of Transplantation Immunology, Department of Innovative Surgery, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya-ku, Tokyo 154-8567, Japan.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujino
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kimura
authors.forename: Naoko
authors.initials: N
authors.lastname: Funeshima
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kitazawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Harihara
authors.forename: Katsunari
authors.initials: K
authors.lastname: Tezuka
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Makuuchi
authors.forename: Seiichi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
mesh_terms: D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology* / Q000502:physiology; D018106:CD28 Antigens / Q000276:immunology* / Q000502:physiology; D015704:CD4 Antigens / Q000032:analysis; D005434:Flow Cytometry; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates / Q000235:genetics / Q000627:therapeutic use; D060889:Inducible T-Cell Co-Stimulator Protein; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D015375:Receptors, Interleukin-2 / Q000032:analysis; D016038:Skin Transplantation / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000737:chemistry; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D015704:CD4 Antigens; C556695:Icos protein, rat; D018796:Immunoconjugates; D060889:Inducible T-Cell Co-Stimulator Protein; D015375:Receptors, Interleukin-2; D000069594:Abatacept