AdCTLA-4Ig combined with donor splenocytes, bone marrow cells and anti-ICOS antibody treatment induce tolerance in a rat heart transplantation model.
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.
Guo
Lei
L
Department of Innovative Surgery, National Research Institute for Child Health and Development, 3-35-31 Taishido, Setagaya-ku, 154-8567, Tokyo, Japan.
Fujino
Masayuki
M
Kimura
Hiromitsu
H
Funeshima
Naoko
N
Kitazawa
Yusuke
Y
Harihara
Yasushi
Y
Tezuka
Katsunari
K
Makuuchi
Masatoshi
M
Suzuki
Seiichi
S
Li
Xiao-Kang
XK
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
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