Question+Four

= What are the negatives of xenotransplantation? = ========

====So far, no xenotransplantations have been entirely successful due to the patient's immune system. The response is usually more severe in allotransplantations. Ultimately, the immune system rejects the xenotransplant, and in some cases kill the patient. There are several types of organ rejection xenotransplantation faces:====
 * ====Hyperacute rejection====
 * ====Acute vascular rejection====
 * ====Cellular rejection====
 * ====Chronic rejection====

====**Hyperacute rejection** is rapid and violent and occurs within minutes from the time of the transplant. It is mediated by the binding of XNAs (xenoreactive natural antibodies) to the donor endothelium, which causes the activation of the human complement system. This results in destruction of endothelial cells, platlet degtanulation, inflammation, coagulation, fibrin deposition, and hemorrhage. The epitope XNAs target is an α-linked galactose moiety, Gal-α-1,3Gal, produced by the enzyme α-galactosyl transferase. Most non-primates contain this enzyme, so evidently, this epitope is present on the organ epithelium. It is perceived as a foreign antigen by primates, who do not have the galactosyl transferase enzyme.====

There are several ways to prevent hyperacute rejection that are currently being investigated:
====1. **Interruption of the complement cascade**. The patient's complement cascade could be stopped through the use of cobra venom factor,soluble complement receptor type 1, anti-C5 antibodies, or C1 inhibitor. There are several disadvantages of this solution, including the toxicity of the venom, and most importantly it will cause the complement system to not function properly.====

====2. **Genetically alter organs**. The donor or the patient could be genetically altered to stop hyperacute rejection. Pigs could have the gene which codes for the enzyme responsible for expression of the immunogeneic gal-α-1,3Gal moiety removed. Those pigs are called 1,3 galactosyl transferase gene knockouts. Pigs could also be genetically modified to increase expression of H-transferase - an enzyme which competes with galactosyl transferase. Experiments shown that doing this reduces α-Gal expression by 70%. Another way is to increase expression of human complement regulators to inhibit the complement cascade. We could also perform plasmaphoresis on humans to remove 1,3 galactosyltransferase, which reduces the risk of activation of effector cells, complement pathway activation and delayed type hypersensitivity.====

====**Acute vascular rejection** is also known as delayed xenoactive rejection. This type of rejection occurs within 2 or 3 days if hyperacute rejection is prevented. This type of rejection is much more complex than hyperacute rejection and is not fully understood by scientists yet. Acute vascular rejection is caused by reactions between the xenograft's endothelial cells and host antibodies, macrophages and platelets and requires de novo protein synthesis. This results in an inflammatory infiltrate of macrophages, natural killer cells and a small number of T cells, intravascular thrombosis, and fibrinoid necrosis of vessel walls. Binding of XNAs to the donor endothelium may lead to the activation of host macrophages as well as the endothelium itself, and ultimately leads to the development of a procoagulant state, the secretion of inflammatory cytokines and chemkines as well as expression of leukocyte adhesion molecules.====

====Sometimes, when hyperacute and acute vascular rejection have not occured, accommodation is possible. Accommodation is the survival of the xenotransplant despite the presence of XNAs. The transplant is given a break from humoral rejection when the complement cascade is interrupted, circulating antibodies are removed, or their function is changed, or there is a change in the expression of surface antigens on the transplant. This allows the xenotransplant to up-regulate and express preotective genes, which help in resistance to injury.====

====**Cellular rejection** is based on cellular immunity and is mediated by natural killer cells which accumulate in the xenograft and damage it, and T-lymphocytes which are activated by MHC molecules through both direct and indirect xenorecognition. The strength of cellular rejection in xenografts is still unknown, though it is expected to be stronger than in allografts because of the differences in peptides in different animals. This leads to more antigens potentially recognised as foreign, therefore eliciting a greater indirect xenogenic response.====

Ways to prevent cellular rejections are:
====1. **Using haematopoietic chimerism**. This induces donor non-responsiveness. Donor stem cells are introduced into the bone marrow of the patient, where they coexist with the patient's stem cells. This produces cells of all haematopoietic lineages. The existence of donor stem cells in the recipient's bone marrow causes donor reactive T cells to be considered self and undergo apoptosis.====

====**Chronic rejection** is slow and progressive and is usually found in transplants which survive the initial rejection phases. Scientists are unsure of how chronic rejection works as xenotransplants usually do not survive past the initial acute rejection phases. What is known is that XNAs and the complement system are not primarily involved. The major cause of chronic rejection might be arteriosclerosis. Lymphocytes activate macrophages to secrete smooth muscle growth factors. This results in a build up of smooth muscle cells on the vessel walls, causing the hardening and narrowing of vessels inside the transplant. Chronic rejection leads to pathologic changes of the organ, which is the reason transplants must be replaced after a few years. It also might be possible that chronic rejections in xenotransplants might be more severe than in allotransplants.====

====Another problem with xenotransplants is that the pathogens from the donor species may infect the recipient. For example, many pigs carry a virus called porcine endogenous retrovirus, or PERV. In an experiment in which pig cells were transplanted into a diabetic mouse, the mouse was found to have been infected with PERV. However, out of the 200 patients who received pig xenotransplants during experiments overseas in the 90s, none have become infected with PERVs. In any case, if PERVs were to cross the species barrier into humans and become more contagious by a series of mutations, many humans could be infected.====