At present, xenotransplantation in humans is extremely limited in scope. However, given the acute worldwide shortage in availability of human tissues and organs, it is being actively researched as an alternative source.
Pig has become the de facto donor, not so much for scientific as for economic and practical reasons. Pigs are already a major human food source plus they are considered physiologically similar enough. Now it’s also become ever easier and cheaper to generate cloned, gene knockout and transgenic pigs.
There are 3 main stumbling blocks to xenotransplantation in general, and for pig-to-human transplantation in particular:
- Human anti-pig immune responses.
- Proper physiological functioning of transplanted cell/tissue/organ in humans.
- Transfer of microbes from transplanted cell/tissue/organ to humans. Typically, the danger posed by viruses such as endogenous retroviruses. However, there are currently at least 13 peer-reviewed studies on small numbers of humans who were transplanted with pig cells or tissues, and no PERV (Pig Endogenous Retrovirus) transmission was observed in any of them. Follow-up ranged from as short as a few hours to as long as several months (look at Table 4 in reference 2 for details).
Human anti-pig immune responses
- Xenogeneic transplant is transplant between different species.
- Unlike allogeneic transplants*, xenogeneic transplants induce an extremely rapid form of transplant rejection called hyperacute rejection (HAR).
- Turns out the major immune response targets in xenogeneic transplants are the sugar molecules that decorate proteins and lipids.
- This is because protein and lipid-associated sugars, i.e., sugars in glycoproteins and glycolipids, respectively, are species-specific.
- When HAR was first observed, it was quite the surprise.
* Allogeneic transplant is transplant between genetically non-identical members of the same species.
How scientists are attempting to minimize human anti-pig immune responses
- Knock-out the pig gene for the enzyme, alpha-1,3-galactosyltransferase (GalTKO).
- Humans lack this enzyme and hence lack the sugar decorations on proteins and lipids that are added by it.
- However, this approach doesn’t eliminate all targets of HAR, only the major one.
- Over-express in pigs human enzymes that compete with alpha-1,3-galactosyltransferase for the same substrates. For e.g., H-transferase.
- Express in pigs human proteins that regulate complement. This will help prevent complement-mediated rejection.
- Express in pigs human immunomodulatory and/or immunosuppressive known to inhibit human T and B cells.
- Gock, Hilton, et al. “Genetic modification of pigs for solid organ xenotransplantation.” Transplantation reviews 25.1 (2011): 9-20.
- Denner, Joachim. “Xenotransplantation-Progress and Problems: A Review.” (2014).
- Satyananda, Vikas, et al. “New concepts of immune modulation in xenotransplantation.” Transplantation 96.11 (2013): 937.