title: Blockade of CD28-B7, but not CD40-CD154, prevents costimulation of allogeneic porcine and xenogeneic human anti-porcine T cell responses.
abstract: Despite increasing use of swine in transplantation research, the ability to block costimulation of allogeneic T cell responses has not been demonstrated in swine, and the effects of costimulatory blockade on xenogeneic human anti-porcine T cell responses are also not clear. We have compared the in vitro effects of anti-human CD154 mAb and human CTLA4IgG4 on allogeneic pig T cell responses and xenogeneic human anti-pig T cell responses. Both anti-CD154 mAb and CTLA4IgG4 cross-reacted on pig cells. While anti-CD154 mAb and CTLA4IgG4 both inhibited the primary allogeneic pig MLRs, CTLA4IgG4 (7.88 microg/ml) was considerably more inhibitory than anti-CD154 mAb (100 microg/ml) at optimal doses. Anti-CD154 mAb inhibited the production of IFN-gamma by 75%, but did not inhibit IL-10 production, while CTLA4IgG4 completely inhibited the production of both IFN-gamma and IL-10. In secondary allogeneic pig MLRs, CTLA4IgG4, but not anti-CD154 mAb, induced Ag-specific T cell anergy. CTLAIgG4 completely blocked the indirect pathway of allorecognition, while anti-CD154 mAb blocked the indirect response by approximately 50%. The generation of porcine CTLs was inhibited by CTLA4IgG4, but not by anti-CD154 mAb. Human anti-porcine xenogeneic MLRs were blocked by CTLA4IgG4, but only minimally by anti-CD154 mAb. Finally, CTLA4IgG4 prevented secondary xenogeneic human anti-porcine T cell responses. These data indicate that blockade of the B7-CD28 pathway was more effective than blockade of the CD40-CD154 pathway in inhibiting allogeneic pig T cell responses and xenogeneic human anti-pig T cell responses in vitro. These findings have implications for inhibiting cell-mediated immune responses in pig-to-human xenotransplantation.
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Lee
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: K L
authors.initials: KL
authors.lastname: Womer
authors.forename: E P
authors.initials: EP
authors.lastname: Pillsbury
authors.forename: K S
authors.initials: KS
authors.lastname: Allison
authors.forename: A E
authors.initials: AE
authors.lastname: Marolewski
authors.forename: D
authors.initials: D
authors.lastname: Geng
authors.forename: A D
authors.initials: AD
authors.lastname: Thall
authors.forename: J S
authors.initials: JS
authors.lastname: Arn
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.forename: M H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: J C
authors.initials: JC
authors.lastname: Madsen
mesh_terms: D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D019138:Antibodies, Blocking / Q000032:analysis / Q000494:pharmacology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D015478:Antigens, Heterophile / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000032:analysis / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D008969:Molecular Sequence Data; D013552:Swine; D013556:Swine, Miniature; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015478:Antigens, Heterophile; D018122:B7-1 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007519:Isoantigens; D008562:Membrane Glycoproteins; D016753:Interleukin-10; D023201:CD40 Ligand; D000069594:Abatacept; D007371:Interferon-gamma