title: AdCTLA-4Ig combined with donor splenocytes, bone marrow cells and anti-ICOS antibody treatment induce tolerance in a rat heart transplantation model.
abstract: It is difficult to induce rat cardiac allograft tolerance by co-stimulator blockade of the B7-CD28 pathway with CTLA-4Ig monotherapy alone. However, combined therapies of AdCTLA-4Ig plus donor-specific spleen-cell infusion, bone marrow cell infusion, and anti-ICOS antibody have been demonstrated to effectively induce indefinite acceptance of rat cardiac allografts. In this report, we compared the tolerance of cardiac allograft tolerant recipients induced by the above three strategies. The results show that treating Lewis recipients of a DA cardiac allograft with a combination of AdCTLA4-Ig and anti-ICOS antibody, donor splenocytes or bone marrow cells produced indefinite graft survival. Second transplantation of donor type skin or heart grafts could not affect the survival of primary heart graft in anti-ICOS treated groups, but results in rejection of primary heart grafts in other two groups, and that co-stimulator blockade, CD28 and ICOS simultaneously with CTLA-4Ig and anti-ICOS antibody, facilitates the development of CD25+ CD4+ regulatory T cells and induces stable transplantation tolerance in the rat cardiac allograft model. This also provides an effective therapy in clinical transplantation for promoting permanent graft survival by generating regulatory T cells.
authors.affiliation: Department of Innovative Surgery, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya-ku, 154-8567, Tokyo, 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 / Q000494:pharmacology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D017690:Cell Transplantation; D005822:Genetic Vectors; D006085:Graft Survival; D016027:Heart Transplantation; D018796:Immunoconjugates / Q000494:pharmacology*; D060889:Inducible T-Cell Co-Stimulator Protein; D008297:Male; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D016038:Skin Transplantation; D013154:Spleen / Q000166:cytology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014019:Tissue Donors; D023001:Transplantation Tolerance
chemical_list: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; C556695:Icos protein, rat; D018796:Immunoconjugates; D060889:Inducible T-Cell Co-Stimulator Protein; D015375:Receptors, Interleukin-2; D000069594:Abatacept