https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-6143.2011.03646.x

Complement Inhibition Enables Renal Allograft Accommodation and Long‐Term Engraftment in Presensitized Nonhuman Primates

Currently, the number of patients awaiting transplantation is continuously increasing, and shortage of available deceased organ donors is the major limitation for organ and cell allotransplantation. Research to develop alternative sources of tissues is ongoing and xenogeneic organs or cells represent an attractive solution. This review focuses on recent progress achieved in this field, including the development of newly genetically modified animal donors and new immunosuppressive approaches. As xenotransplantation is moving closer to clinical application, future perspectives must establish guidelines to ensure that future clinical trials are carried out ethically and safely.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-2277.2005.00124.x

Xenotransplantation: an update on recent progress and future perspectives

Background:  In pig-to-nonhuman primate solid organ xenotransplantation using organs from donors transgenic for human decay-accelerating factor (hDAF), the main type of rejection is antibody-mediated (acute humoral xenograft rejection, AHXR). This occurs despite the complement-regulatory function of the transgene, neutralization of natural antibodies to Galα1–3Gal (Gal) using soluble glycoconjugates, and chronic immunosuppression. As complement components play a major role in graft destruction after antibody binding, we evaluated the efficacy of chronic complement inhibition by soluble complement receptor type 1 (TP10).



Methods:  Life-supporting hDAF-transgenic kidney transplantation was performed in cynomolgus monkeys, using cyclophosphamide induction, and maintenance immunosuppression with cyclosporin A, mycophenolate sodium, and tapering steroids. Rejection was treated with bolus steroid injections: if not successful animals were terminated. Three groups were studied: in group 1 (n = 4) GAS914 (a soluble glycoconjugate comprising Gal on a poly-L-lysine backbone) was added before and after transplantation; group 2 (n = 2) received GAS914 as in group 1 and in addition TP10 before and after transplantation; in group 3 (n = 4) GAS914 was only given before transplantation and TP10 as in group 2. Monitoring included the regular assessment of anti-porcine antibodies, complement activity (soluble C5b-9), therapeutic drug monitoring, and graft histology.



Results:  Survival in group 1 was 6, 12, 31 and 37 days, respectively, and in all four cases graft histology showed AHXR. The two animals in groups 2 survived 3 and 15 days, respectively, and similarly showed AHXR in graft histology. In group 3 two animals showed AHXR (10 and 37 days survival, respectively), and two others did not show AHXR (20 and 32 days survival, respectively). The diagnosis AHXR included the deposition of complement activation products in the graft, which were present at lower intensity in animals treated with TP10. In all animals GAS914 effectively neutralized circulating anti-Gal antibody. Antibodies were detectable in the circulation of all animals using porcine erythrocytes in a hemolytic assay, although at lower levels than before transplantation. Soluble C5b-9 was not detectable in the circulation of animals receiving TP10, and circulating TP10 concentrations in these animals were in a presumed pharmacologically active range.



Conclusions:  The inclusion of TP10 in the immunosuppressive protocol does not clearly lead to improved xenograft survival. Despite effective neutralization of anti-Gal antibodies and effective inhibition of systemic complement activity, AHXR was apparent in four of six animals under chronic TP10 treatment, including deposits of complement activation products in the graft. Apparently, effective systemic complement inhibition by TP10 in combination with local complement regulation by the hDAF transgene product does not necessarily result in effective inhibition of complement activation at locations in the xenograft upon binding of anti-porcine antibodies to the grafted endothelium.

The effect of soluble complement receptor type 1 on acute humoral xenograft rejection in hDAF‐transgenic pig‐to‐primate life‐supporting kidney xenografts

Role of complement and perspectives for intervention in transplantation.

The shortage of human organs and tissues for transplant has led to significant interest in xenotransplantation of pig tissues for human patients However, transplantation of pig organs results in an acute immune rejection, leading to death of the organ within minutes The α-1,3-galactosyltransferase (GALT) gene has been knocked out in pigs to reduce rejection, yet additional genes need to be modified to ultimately make pig tissue immunocompatible with humans The development of pig induced pluripotent stem cells (piPSCs) from GALT knockout (GALT-KO) tissue would provide an excellent cell source for complex genetic manipulations (eg, gene targeting) that often require highly robust and proliferative cells In this report, we generated GALT-KO piPSCs by the overexpression of POU5F1, SOX2, NANOG, LIN28, KLF-4, and C-MYC reprogramming genes piPSCs showed classical stem cell morphology and characteristics, expressing integrated reprogramming genes in addition to the pluripotent markers AP, SSEA1, and SSEA4 GALT-KO piPSCs were highly proliferative and possessed doubling times and telomerase activity similar to human embryonic stem cells These results demonstrated successful reprogramming of GALT-KO fibroblasts into GALT-KO piPSCs GALT-KO piPSCs are potentially an excellent immortal cell source for the generation of pigs with complex genetic modifications for xenotransplantation, somatic cell nuclear transfer, or chimera formation

α-1,3-Galactosyltransferase knockout pig induced pluripotent stem cells: a cell source for the production of xenotransplant pigs.

At present, acute vascular rejection (AVR) remains a primary obstacle inhibiting long-term graft survival in the pig-to-non-human primate transplant model. The present study was undertaken to determine whether repetitive injection of low dose Yunnan-cobra venom factor (Y-CVF), a potent complement inhibitor derived from the venom of Naja kaouthia can completely abrogate hemolytic complement activity and subsequently improve the results in a pig-to-rhesus monkey heterotopic heart transplant model. Nine adult rhesus monkeys received a heterotopic heart transplant from wild-type pigs and the recipients were allocated into two groups: group 1 (n = 4) received repetitive injection of low dose Y-CVF until the end of the study and group 2 (n = 5) did not receive Y-CVF. All recipients were treated with cyclosporine A (CsA), cyclophosphamide (CyP) and steroids. Repetitive Y-CVF treatment led to very dramatic fall in CH50 and serum C3 levels (CH50 < 3 units/C3 remained undetectable throughout the experiment) and successfully prevented hyperacute rejection (HAR), while three of five animals in group 2 underwent HAR. However, the continuous suppression of circulating complement did not prevent AVR and the grafts in group 1 survived from 8 to 13 days. Despite undetectable C3 in circulating blood, C3 deposition was present in these grafts. The venular thrombosis was the predominant histopathologic feature of AVR. We conclude that repetitive injection of low dose Y-CVF can be used to continuously suppress circulating complement in a very potent manner and successfully prevent HAR. However, this therapy did not inhibit complement deposition in the graft and failed to prevent AVR. These data suggest that using alternative pig donors [i.e. human decay accelerating factor (hDAF)-transgenic] in combination with the systemic use of complement inhibitors may be necessary to further control complement activation and improve survival in pig-to-non-human primate xenotransplant model.

Improved suppression of circulating complement does not block acute vascular rejection of pig-to-rhesus monkey cardiac transplants.

RAGE antagonism with azeliragon improves xenograft rejection by T cells in humanized mice.

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Improved suppression of circulating complement does not block acute vascular rejection of pig-to-rhesus monkey cardiac transplants.

RAGE antagonism with azeliragon improves xenograft rejection by T cells in humanized mice.