Xenotransplantation – Does it have a Future in Clinical Medicine?

Kaushik Bharati, PhD

Transplantation generally means removal of tissue(s) or organ(s) from a recently deceased person (the donor), and replacing into a living person (the recipient) whose organ is non-functional i.e. defective or damaged.

Types of Transplantation

Immunologically speaking, transplantation is of three types – autologous transplantation, allogeneic transplantation, and xenogeneic transplantation. When a tissue is taken from one part of the body and transplanted into another site on the same individual, it is called autologous transplantation. When organs, tissues, bone marrow or peripheral blood stem cells are transplanted between the same species i.e. from one person to another, both of whom are genetically identical, it is known as allogeneic or homologous transplantation. When an organ or tissue is transplanted from a different species (genetically different), i.e. from an animal to a human, it is called xenogeneic transplantation or xenotransplantation.

Human Organ Transplantation

Generally speaking, transplantation refers to organ transplantation from a recently deceased person to a living person. Some of the common organs that are transplanted include heart, lungs, liver, kidneys, pancreas and skin. Besides organs, tissues such as corneal tissue from the eye is also transplanted. In certain cases, transplantation can be carried out from a living donor. This includes liver transplantation, where a small portion of the donor liver is required to be transplanted. The transplant grows into the full organ. The cut portion of the donor liver also regenerates, thereby making the liver full-sized again. Another example is kidney transplantation. Since there are two kidneys, and in a healthy person, one kidney is sufficient to carry out the excretory functions of the body, a person can donate a kidney to a close relative, whose tissue have been typed and matched properly.

The Indian Scenario – A Few Facts & Figures

In India, currently cadaver organ transplantation is carried out in 7 states, namely, Andhra Pradesh, Gujarat, Karnataka, Kerala, Maharashtra, Punjab, Tamil Nadu, and the union territory of Delhi-NCR. Commonly transplanted organs include heart, lungs, liver and kidney. So far, cadaver organ donation in India has been relatively low, peaking slightly in 2013. That year a total of 852 organs were retrieved from 313 multi-organ donors. This means that only 0.26 organs were donated per million of the Indian population (MOHAN Foundation, 2013). Therefore, it is clearly evident that there is a stark difference in the “demand” and “supply” for human organs in India.

Xenotransplantation – The Pros and Cons

In order to meet this huge deficit of human organs, other avenues like xenotransplantation is being explored. Attempts to clinically use non-human primates as donors has led to short-term success. A baboon liver and a chimpanzee kidney functioned for 70 days and 9 months respectively in human recipients. Although there may be some advantages in using the phylogenetically similar non-human primate species for human transplantation purposes, there are also major disadvantages. These include the impracticalities of the procedure, the elevated risk of transfer of pathogenic viruses, besides being mired by various ethical issues.

Can Pigs be used for Xenotransplantation?

Using pigs for supplying organs for xenotransplantation appears to be an attractive alternative to non-human primates. Pigs can be reared in pathogen-free conditions, produce high number of litters, have organs that are anatomically and physiologically similar to humans. Importantly, pigs have served as donors of cardiac valves for transplantation in humans for many years. However, there are major immunological hurdles in implementing xenotransplantation using pig organs. For example, if a porcine kidney was transplanted into a human, it would immediately undergo hyper-acute rejection, mediated by antibodies. This is due to the fact that the surface of porcine cells contain a disaccharide antigen called galactosyl-α-1,3-galactose (Gal-α-1,3-Gal). Since many microorganisms also contain this antigen, almost everyone has been exposed, and have pre-existing antibodies that cross-react with porcine cells, which are subsequently lysed by complement. Various strategies have been evolved to tackle this problem. These include adsorbing the antibodies in the blood onto solid supports, and the use of soluble Gal-Gal disaccharides to block antibody reactions. Genetically engineered pigs have also been developed in which galactosyl transferase, the enzyme that adds Gal-α-1,3-Gal to pig proteins has been knocked out. These galactosyl transferase gene knockout (GalT-KO) pigs have been used as kidney and heart donors for baboons, and have met with limited success. The mean survival time was 92 days, and the longest survival time was 179 days.

A major issue of using pig organs for xenotransplantation is the possibility of introduction of a highly pathogenic retrovirus into the human population that could lead to another AIDS-like pandemic. However, the propagation of pigs free from endogenous porcine retroviruses could circumvent this issue.

What Does the Future Hold?

Will pigs be used as donors anytime soon? Possibly, but not soon, maybe in the distant future. The day-by-day increasing demand for human organs, and the associated shortfall, is driving research in the area of xenotransplantation, in particular, the use of pig organs like kidneys for transplantation into humans. If the safety issues are met, and the efficacy is first proven beyond doubt in non-human primate model, only then clinical trials may be permitted in humans in a very stringent and highly supervised manner. Although many challenges still remain in the clinical use of xenotransplants, earnest efforts are underway to overcome these challenges and address the issues in a time-bound and strategic manner, in order to make xenotransplantation a reality.