Co-stimulation blockade targeting CD154 and CD28/B7 modulates the induced antibody response after a pig-to-baboon cardiac xenograft.
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.
Wu
Guosheng
G
University of Maryland and Baltimore VAMC, Baltimore, MD 21201, USA.
Pfeiffer
Steffen
S
Schröder
Carsten
C
Zhang
Tianshu
T
Nguyen
Bao N
BN
Lea
William
W
Kelishadi
Sean
S
Atkinson
James B
JB
Schuurman
Henk-Jan
HJ
White
David J G
DJ
Azimzadeh
Agnes M
AM
Pierson
Richard N
RN
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*
D000906:Antibodies; D018122:B7-1 Antigen; D018106:CD28 Antigens; D004187:Disaccharides; C055075:galactosyl-(1-3)galactose; D023201:CD40 Ligand