title: CTLA-41g in combination with anti-CD40L prolongs xenograft survival and inhibits anti-gal ab production in GT-Ko mice.
abstract: The generation of GT-Ko mice has provided unique opportunities to study allograft and xenograft rejection in the context of anti-alpha1,3-Gal antibody (anti-Gal Ab) responses. In this study we used the allotransplantation model of C3H hearts into galactosyltransferase-deficient (GT-Ko) mice and the xenotransplantation model of baby Lewis rat hearts into GT-Ko mice to investigate the ability of CTLA-41g in combination with anti-CD40L mAb to control graft rejection and anti-Gal Ab production. Murine CTLA-41g or anti-CD40L monotherapy prolonged allograft survival, and the combination of these reagents was most immunosuppressive. However short-term treatment with murine cytotoxic T lymphocyte associated antigen-4 (muCTLA-41g) and/or CD40 ligand (CD154) monoclonal antibodies (anti-CD40L mAbs) was unable to induce indefinite allograft survival. CTLA-4-immunoglobulin fusion protein (CTLA-41g) or anti-CD40L monotherapy only marginally prolonged xenograft survival; the combination of human CTLA-41g and anti-CD40L significantly prolonged xenograft survival (74days), while the combination of murine CTLA-41g and anti-CD40L resulted in graft survival of >120days. CTLA-41g or anti-CD40L monotherapy or the combination of these agents inhibited the production of alloAbs, including anti-Gal Abs. CTLA-41g or anti-CD40L monotherapy partially controlled xenoAb and anti-Gal Ab production, while the combination was more effective. These observations corroborate our previous observations that humoral, including anti-Gal Ab, responses and rejection following allograft or concordant xenograft transplantation in GT-Ko mice are T-cell dependent and can be controlled by costimulation blockade.
authors.affiliation: Department of General Surgery, Rush Presbyterian St Luke's Medical Center, Chicago, IL, USA.
authors.forename: Dengping
authors.initials: D
authors.lastname: Yin
authors.forename: Lianli
authors.initials: L
authors.lastname: Ma
authors.forename: Jikun
authors.initials: J
authors.lastname: Shen
authors.forename: Guerard W
authors.initials: GW
authors.lastname: Byrne
authors.forename: John S
authors.initials: JS
authors.lastname: Logan
authors.forename: Anita S F
authors.initials: AS
authors.lastname: Chong
mesh_terms: D000069594:Abatacept; D000818:Animals; D000917:Antibody Formation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000627:therapeutic use*; D023201:CD40 Ligand / Q000276:immunology*; D060908:CTLA-4 Antigen; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D011917:Rats, Inbred Lew; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D023201:CD40 Ligand; D000069594:Abatacept; D005700:Galactosyltransferases