Transplantation of cells, tissues, organs from one species to another is called xenotransplantation.

INTRODUCTION:

The success of organ transplantation has led to an ever-increasing shortfall between the demand for organs and the supply. This has led to an extensive investigation of the possible use of animals, especially the pig, as organ donors. However, a number of major barriers to successful xenotransplantation exist. These include immunological, physiological, anatomical, infectious and ethical problems. Of these hyper-acute rejection is the most common barrier in xenotransplant patients.

Alpha gal is a carbohydrate molecule found in mammalian cell membrane. Humans lost GGTAL gene during evolution. Hence humans identify alpha gal as foreign and produce antibodies to destroy it causing rejection. Scientists also added a human gene to the pigs to produce a protein called CD46 to slow the recipients immune response “Gal-safe pigs”

TYPES:

• Solid organ xenotransplantation
• Cellular or tissue xenotransplantation
• Human or animal hybrid xenotransplantation
• External therapies

DONOR SPECIES:

Concordant → similar / closely related species
Discordant → Distantly related / dissimilar species

IMMUNOLOGICAL BARRIERS:

1. Hyper-acute xenograft rejection:

Due to xenoreactive natural antibodies against xenoantigens. To overcome this, it is suggested to alter the organs through genetically engineered pigs or alter the recipient by depleting naturally occurring antibody against alpha gal to xenograft recipient.

2. Acute vascular rejection:

If  hyperacute rejection can be prevented in the first 24 h, then acute vascular rejection will occur. This is primarily due to endothelial activation leading to a procoagulant phase and is mediated by anti-Gal antibody. This can be prevented by thrombin inhibitor ( to modulate thrombogenesis), immuno-adsorption column to deplete antigalatose antibodies, inhibiting activation of macrophages and natural killer cells.

3. Cellular xenograft rejection:

Overcoming this barrier can be done with the mechanism of tolerance where donor stem cells are introduced into the bone marrow of recipient. The bone marrow stem cells produce all types of hematopoitic lineages by hematopoiesis. Lymphoid progenitor cells from hematopoiesis enters into thymus, eliminates T cells which are self reactive. Existence of donor stem cells in recipient bone marrow causes donor reactive T cells to consider self and undergo apoptosis.

4. Chronic xenograft rejection:

Little is known about this form of rejection in the xenograft model, but it seems likely that if the early forms of rejection are suppressed, then chronic rejection changes are inevitable and these will not be prevented by current immunosuppression, especially if they result from reactions produced by the anti-Gal antibody.

PHYSIOLOGICAL BARRIERS:

Many foreign proteins produced by surviving xenotransplants will be incompatible with their human ligands. Furthermore, there is very likely to be an immune response to any foreign protein produced by the xenogeneic organ.

ANATOMICAL BARRIERS:

Size will obviously be important in choosing organs for human use but, in this respect, the pig should be reasonably satisfactory in most instances 

INFECTIOUS BARRIERS:

Porcine endogenous retrovirus is pigs (PERV) which is dominant can be activated in human recipient and cause death. A novel swine hepatitis E virus has been described which also might have implications for the use of pigs as donors. Thus the possible transmission of viruses from xenogeneic donors to immunosuppressed recipients remains of considerable concern in future clinical trials of xenotransplantation. 

SOCIAL AND ETHICAL BARRIERS:

Although some people would find the use of any animals ethically unacceptable, most would probably accept the use of a species that was bred as a food source e.g. pig, sheep and cattle. There is no currently guidelines in place  to detect legal regulations of pig to human xenotransplantation. Major difference in cultural and religious belief will make it particularity challenging to build guidelines on xenotransplantation. One major ethical consideration is  a consent for animal rights and anthropocentric view of putting humans above other animal species.

REFERENCES: 

1. Hamilton D. Kidney transplantation: a history. In: Morris PJ, ed. Kidney Transplantation: Principles and Practice, 4th edn. Philadelphia: Saunders, 1994: 1-7
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3. Auchincloss H. Xenogeneic transplantation. A review. Transplantation 1988; 46: 1-20
4. Auchincloss H. Xenografting: a review. Transplant Rev 1990; 4: 14-27
5. Bach FH, Dalmasso G, Platt JL. Xenotransplantation: a current perspective. Transplant Rev 1992; 6: 163-75
6. Bach FH, Auchincloss H, Robson SC. Xenotransplantation. In: Bach FH, Auchincloss H, eds. Transplantation Immunology. New York: Wiley-Liss, 1995; 305-38
7. Bach FH, Ferran C, Soares M et al. Modification of vascular responses in xenotransplantation: inflammation and apoptosis. Nat Med 1997; 3: 944—8
8. Patience C, Patton GS, Takeuchi Y et al. No evidence of pig DNA or retroviral infection in patients with short-term extracorporeal connection to pig kidneys. Lancet 1998; 352: 699-701

Dr. Prathibha Thangadurai
DrNB Nephrology
Kauvery hospital, Alwarpet

Dr. Balaji Kirushnan
Nephrologist
Kauvery hospital, Alwarpet