title: Anergic lymphocytes generated by blocking CD28 and ICOS pathways in vitro prolong rat cardiac graft survival.
abstract: Regulatory cells may play a pivotal role in inducing and maintaining transplantation tolerance. We investigated the mechanism of anergic lymphocytes with regulatory cell potential generated in vitro by ICOS and CD 28 co-stimulatory blockades as a source of cellular therapy for treating allograft rejection. Anergic lymphocytes were generated by a mixed lymphocyte reaction consisting of DA splenocytes as the stimulator and Lewis splenocytes as the responder in the presence of anti-ICOS mAb and rCTLA-4I g. Immunoregulatory effects of these lymphocytes were evaluated by secondary MLR and using other various stimulations. DA heart was transplanted into 7.5 Gy-irradiated Lewis rat after intravenous administration of these cells and/or Lewis spleen lymphocytes. We observed that these lymphocytes were not only anergic to alloantigen and polyclonal stimulations but also exhibited regulative activity to inhibit the alloreactive T-cell response. Our adoptive transfer studies revealed that irradiated recipients that received both anergic lymphocytes and naIve Lewis lymphocytes had significantly prolonged DA cardiac graft survival (mean 17.5 days) compared with a group that received Lewis lymphocytes alone (mean 10.8 days). Furthermore, some of the recipients accepted the graft indefinitely after receiving anergic lymphocytes alone (>100 days). These results demonstrated that anergic lymphocytes with regulatory activities can be generated through blocking co-stimulatory signals, CD 28 and ICOS, simultaneously in vitro, and may advance a new immunomodulatory strategy for preventing allorejection in organ transplantation.
authors.affiliation: Laboratory of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Hara
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kitazawa
authors.forename: Naoko
authors.initials: N
authors.lastname: Funeshima
authors.forename: Mikiko
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Sato
authors.forename: Katsunari
authors.initials: K
authors.lastname: Tezuka
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kimura
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Hatakeyama
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; C556695:Icos protein, rat; D018796:Immunoconjugates; D007074:Immunoglobulin G; D060889:Inducible T-Cell Co-Stimulator Protein; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000069594:Abatacept