Inhibition of complement, evoked antibody, and cellular response prevents rejection of pig-to-primate cardiac xenografts.
Complement (C) inhibition alone using a recombinant soluble form of complement receptor type 1 (sCR1) prevents hyperacute rejection but not subsequent irreversible accelerated acute rejection of discordant pig-to-cynomolgus monkey cardiac xenografts, which occurs within 1 week. To inhibit accelerated acute rejection, which is associated with a rise in serum xenoreactive antibody (Ab) and a cellular infiltrate, triple therapy with standard immunosuppressive agents (cyclosporine, cyclophosphamide, and steroids [CCS]) was combined with continuous C inhibition using sCR1. Each of two monkeys that received sCR1 + CCS showed minimal evidence of rejection when killed on days 21 and 32 in comparison to a monkey that received sCR1 + subtherapeutic CCS (rejected at 11 days) and a control that received CCS alone (rejected at 38 min). Prolonged xenograft survival was associated with low Ab levels and a minimal cellular infiltrate, suggesting that combined inhibition of C, xenoreactive Ab responses, and cellular immunity may be a useful approach in overcoming the immune barriers to discordant xenotransplantation.
Davis
E A
EA
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Pruitt
S K
SK
Greene
P S
PS
Ibrahim
S
S
Lam
T T
TT
Levin
J L
JL
Baldwin
W M
WM
Sanfilippo
F
F
D000818:Animals; D000906:Antibodies / Q000097:blood; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D003169:Complement Inactivator Proteins / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008297:Male; D011951:Receptors, Complement / Q000276:immunology*; D013256:Steroids / Q000627:therapeutic use; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D000906:Antibodies; D003169:Complement Inactivator Proteins; D007166:Immunosuppressive Agents; D011951:Receptors, Complement; D013256:Steroids; C082885:soluble complement inhibitor 1; D016572:Cyclosporine; D003520:Cyclophosphamide