Complement activation and coagulation in xenotransplantation

Abstract

Xenotransplantation using porcine donors holds tremendous promise for alleviating the chronic shortage of human organ donors. However, transplantation from pigs into higher primates triggers a vigorous immune response involving complement activation and thrombosis. Hyperacute rejection can be prevented by using donors in which GalT, the gene responsible for the predominant target of anti-pig natural antibodies, has been deleted. Unfortunately, the adaptive response to GalT knockout (KO) organs has been difficult to immunosuppress. The focus has shifted to identifying additional genetic modifications that will extend xenograft survival beyond the several months currently achievable. Which gene(s) should be added to the GalT KO background is open to debate. Overexpression of a complement regulatory factor(s) seems a logical first choice, supported by recent in vitro data but not yet validated in preclinical models. The next obvious candidate would be an anticoagulant protein(s) to deal with the dysregulated coagulation that is almost invariably associated with xenograft rejection. Several potentially useful molecules have been identified, although this study is yet to be translated to the pig. Our understanding of the mechanisms of GalT KO xenograft rejection continues to grow, providing a rational basis for tailoring further genetic modification of the donor and immunosuppression of the recipient.

Antiinflammatory and Anticoagulant Effects of Transgenic Expression of Human Thrombomodulin in Mice

“…A parallel exists with the markedly beneficial effect of expression of complement regulators at therapeutic levels, that is, levels beyond those required to correct inter-species molecular incompatibilities, where HAR can be prevented even in the presence of undiminished anti-αGal–αGal interactions (36–38). Indeed, the parallel extends to the associated antiinflammatory effects of the regulators of complement and coagulation/thrombosis (39). …”

Tissue transplantation by stealth—Coherent alginate microcapsules for immunoisolation

“…In the context of small non-vascular xenografts (e.g., pancreatic islets and dopaminergic neurons), no donor endothelium is involved and hence endothelial activation is not a problem. Depending on cell type, strong xenoantigens may still be expressed, and pre-formed/induced antibodies may activate cell killing mechanisms with or without complement involvement [26,49]. For any xenograft that survives long enough, a direct T-cell mediated immunological response may occur several days to many weeks after transplantation.…”

Modifiers of complement activation for prevention of antibody-mediated injury to allografts

“…One such example is the coagulation pathway whose action is often intertwined with that of the complement system [117,118], and which is usually activated in the setting of AbMR [5, 68,69]. A large body of research has been performed examining the role of disordered coagulation, and its interaction with complement in the hyperacute and early phases of xenotransplant rejection [114,117,119,120]. Attempts to overcome the largely antibody-initiated process in this field have focused almost exclusively on genetic modification of the xenogeneic donor.…”