title: Co-stimulation blockade targeting CD154 and CD28/B7 modulates the induced antibody response after a pig-to-baboon cardiac xenograft.
abstract: BACKGROUND
  The induced antibodies against Galalpha1,3Gal (Gal) and non-Gal epitopes may contribute to delayed xenograft rejection (DXR). We asked whether blockade of the CD40/CD154 and CD28/B7 co-stimulatory pathways modulates the baboon elicited antibody response to pig Gal and non-Gal antigens.
  
  
  METHODS
  Eighteen baboons received heterotopic heart transplants from pigs transgenic for human decay-accelerating factor (n = 13) or membrane cofactor protein (n = 5). Ten reference ''conventional therapy'' animals received cyclosporin A, cyclophosphamide and mycophenolate mofetil, with (n = 4) or without (n = 6) anti-CD20. Eight ''co-stimulation blockade'' animals received anti-CD154 mAb (IDEC-131) and anti-thymocyte globulin, with (n = 4) or without (n = 4) anti-CD20; two of these animals also received CTLA4-Fc. Anti-alphaGal IgG and IgM, anti-non-Gal antibodies and graft histology were assessed serially.
  
  
  RESULTS
  Excluding two early graft failures, median graft survival with conventional therapy was 15 days (range 6 to 36 days, n = 8). Anti-Gal IgG antibody remained low through day 6 to 10, only one graft failure was accompanied by significant rise in anti-Gal IgG, and the anti-non-Gal response was weak (n = 2) or absent (n = 7). However many recipients succumbed with infection (n = 4) or coagulopathy (n = 2); DXR and ICOS+ T cells were prevalent in long-surviving grafts. With co-stimulation blockade, excluding three early graft failures, median graft survival was 7 days (range 6 to 11 days, n = 5). This regimen was very well tolerated, but increased anti-Gal antibody titer within 14 days was associated with graft failure in four of six animals. Although an anti-non-Gal response was present in three of six animals during IDEC-131 monotherapy (one strong, two weak), it was absent in both cases with additional CTLA4-Fc treatment.
  
  
  CONCLUSIONS
  As used here, CD154 blockade alone does not completely prevent induction of Gal and non-Gal anti-pig antibodies. Our preliminary data suggest that other co-stimulation pathways, including CD28/B7 and ICOS, are sufficient to mediate high-titer anti-non-Gal antibody to porcine antigens in baboons, and contribute significantly to the pathogenesis of DXR.
authors.affiliation: University of Maryland and Baltimore VAMC, Baltimore, MD 21201, USA.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Wu
authors.forename: Steffen
authors.initials: S
authors.lastname: Pfeiffer
authors.forename: Carsten
authors.initials: C
authors.lastname: Schröder
authors.forename: Tianshu
authors.initials: T
authors.lastname: Zhang
authors.forename: Bao N
authors.initials: BN
authors.lastname: Nguyen
authors.forename: William
authors.initials: W
authors.lastname: Lea
authors.forename: Sean
authors.initials: S
authors.lastname: Kelishadi
authors.forename: James B
authors.initials: JB
authors.lastname: Atkinson
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Schuurman
authors.forename: David J G
authors.initials: DJ
authors.lastname: White
authors.forename: Agnes M
authors.initials: AM
authors.lastname: Azimzadeh
authors.forename: Richard N
authors.initials: RN
authors.lastname: Pierson
mesh_terms: D000740:Anemia / Q000209:etiology; D000818:Animals; D030801:Animals, Genetically Modified; D000906:Antibodies / Q000097:blood / Q000494:pharmacology*; D000917:Antibody Formation; D018122:B7-1 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D004187:Disaccharides / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000473:pathology; D006085:Graft Survival; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology*; D007150:Immunohistochemistry; D007970:Leukopenia / Q000209:etiology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010215:Papio; D013552:Swine; D013921:Thrombocytopenia / Q000209:etiology; D014183:Transplantation, Heterologous / Q000009:adverse effects / Q000276:immunology*
chemical_list: D000906:Antibodies; D018122:B7-1 Antigen; D018106:CD28 Antigens; D004187:Disaccharides; C055075:galactosyl-(1-3)galactose; D023201:CD40 Ligand