Characterization of Human Cd55 and Cd59 Transgenic Pigs and Kidney Xenotransplantation in the Pig-to-Baboon Combination1

Abstract

New transgenic pigs expressing combinations of regulators of complement activation and other molecules are needed to resist xenograft hyperacute rejection (HAR) and to further analyze and treat xenograft rejection. Double transgenic pigs for human CD55 (hCD55) and human CD59 (hCD59) using the promoter of the human elongation factor 1 alpha gene were generated, and their kidneys were transplanted into nonimmunosuppressed baboons. hCD55 and hCD59 were mainly expressed by the endothelial cells, and these cells showed increased resistance to complement-mediated lysis. Baboons receiving kidneys from hCD55hCD59 pigs survived for 5 and 6 days, and displayed alterations in coagulation. Thrombocytopenia and platelet microthrombi were present within the kidneys. Nontransgenic kidneys showed HAR in less than 2 days. Kidneys from pigs expressing hCD55hCD59 displayed protection against HAR in the absence of immunosuppression. Rejection was associated with coagulopathy leukocyte infiltration and a rebound of anti-alpha Gal antibodies.

Role of Mouse Innate Immunity in Immunodeficient Mice for Xenotransplantation

“…This rejection is initiated by the binding of anti-galactose-α1,3-galactose (Gal) natural antibodies produced from primate cells to Gal on the pig vascular endothelium and sequential activation of the complement cascade [30]. Several genetically modified pigs [31][32][33], such as Gal-transferase-knockout pigs, have demonstrated partial success in the induction of immunological tolerance by regulating complement-dependent HAR. Taken together, these studies suggest that inhibition of complement activation could be a novel therapeutic strategy for xenotransplantation.…”

Les xénogreffes finiront-elles par être acceptées ?

“…En effet, loin d'être seulement un organe vital, l'organe humain greffé provient du don volontaire d'un humain à un autre humain, et est à ce titre précieusement investi. Réduit à une matière vivante animale, il simplifiera certainement les Transgénique pour une MRCh Sans traitement < une semaine Rein [27] Transgénique pour une MRCh IS classique Quelques heures à 3 mois Coeur [50,51], rein [27] Transgénique pour une MRCh IS novatrice 3 jours à 4 mois et demi Coeur [52,11] Transgénique pour une MRCh IS + « thymus-rein » Jusqu'à un mois Rein [40] Transgénique pour une MRCh Sans traitement < une semaine Coeur [23], rein [53] Gal KO IS classique 1 mois (n = 1) Rein [54] Gal KO IS classique+ « thymus-rein » Environ 2 mois et demi (n = 1) Rein [32] Tableau I. Survies de xénogreffes porc/primate en fonction des manipulations effectuées sur le donneur et/ou le receveur. MRCh: molécule régulatrice du complément humain (CD55, CD59, CD46); IS: immunosuppression.…”

Immunological Challenges and Therapies in Xenotransplantation

“…Several efforts have been made to eliminate the detrimental effect of the complement cascade's activation on the xenograft, including the use of specific soluble complement inhibitors, such as soluble complement receptor type 1 (Lam et al 2005), or the cobra venom factor (Kobayashi et al 1997), and the production of animals transgenic for human complement regulatory proteins (CRP), such as hCD55, hCD46, or hCD59 (Fodor et al 1994;Cozzi and White 1995;McCurry et al 1995;Cowan et al 2000;Loveland et al 2004;Menoret et al 2004). This approach represents an elegant strategy for down-regulating local complement activation on the xenograft while preserving systemic complement activity as a first line of defense.…”