The pathobiology of pig‐to‐primate xenotransplantation: a historical review

Abstract

The immunologic barriers to successful xenotransplantation are related to the presence of natural anti-pig antibodies in humans and non-human primates that bind to antigens expressed on the transplanted pig organ (the most important of which is galactose-α1,3-galactose [Gal]), and activate the complement cascade, which results in rapid destruction of the graft, a process known as hyperacute rejection. High levels of elicited anti-pig IgG may develop if the adaptive immune response is not prevented by adequate immunosuppressive therapy, resulting in activation and injury of the vascular endothelium. The transplantation of organs and cells from pigs that do not express the important Gal antigen (α1,3-galactosyltransferase gene-knockout [GTKO] pigs) and express one or more human complement-regulatory proteins (hCRP, e.g., CD46, CD55), when combined with an effective costimulation blockade-based immunosuppressive regimen, prevents early antibody-mediated and cellular rejection. However, low levels of anti-non-Gal antibody and innate immune cells and/or platelets may initiate the development of a thrombotic microangiopathy in the graft that may be associated with a consumptive coagulopathy in the recipient. This pathogenic process is accentuated by the dysregulation of the coagulation-anticoagulation systems between pigs and primates. The expression in GTKO/hCRP pigs of a human coagulation-regulatory protein, for example, thrombomodulin, is increasingly being associated with prolonged pig graft survival in non-human primates. Initial clinical trials of islet and corneal xenotransplantation are already underway, and trials of pig kidney or heart transplantation are anticipated within the next few years.

Immune Response Associated with Islet Xenotransplantation in Small and Large Animal Models

“…Pigs and rodents, along with most other mammals, synthesize the enzyme alpha 1,3-galactosyltransferase and produce alpha Gal, and so do not produce anti-Gal antibodies [22]. Some nonhuman primates and humans lack this enzyme, and therefore do produce anti-alpha Gal antibodies.…”

“…The carbohydrate alpha Gal is accepted to be the epitope responsible for immediate xenograft destruction of porcine islets in nonhuman primates [22].…”

A Comprehensive Profile of Mature MicroRNA in the Pig

“…The pig has become the most suitable candidate as a source organ for xenotransplantation to overcome the growing gap between the need and availability of human donor organs [6].…”

“…The xenotransplantation of organs from gene-modified pigs is associated with longer survival and less rejection [6]. Biopsy is the gold standard for diagnosis of conditions such as acute rejection (AR), disease recurrence, and drug toxicity [79].…”

“…The pig has been used as a model to study various issues, such as reproduction [4], and the neuronal system [5], and is employed as a source of organs and cells in xenotransplantation [6].…”