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Discuss the immunological problems associated with xenotransplant rejection and recent advances (within the last 10 years) in improving the success of organ transplantation. Essay Example

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    Biology
  • Document type:
    Essay
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    Undergraduate
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Immunological Problems Associated With Xenotransplant Rejection

Introduction

At a time when the demand for transplantable organs far exceeds the supply, a growing number of scientists are investigating the possibility of transplanting animal organs or tissues into human beings. Although much more research is needed before cross-species transplants can be anything but experimental, investigators were making considerable progress in 1995 and 1996 (Kuwaki 2005).

Transplantation has made rapid progress in the past 10 years, and in many cases, transplant surgery has become the treatment of choice for end-stage organ failure (Townsend, 2005) Improved histocompatibility typing and surgical techniques, better patient selection, earlier and more accurate detection of rejection episodes and a greater understanding of the immune system have all combined to greatly improve patient and graft survival. While rejection of the graft remains the major stumbling block, we have seen substantial additions to the range of anti-rejection, or immunosuppressant drugs, available to transplant clinicians. The other major limitation is the chronic shortage of donor organs. About 3,000 transplants are carried out each year in the UK, but there are thousands of other patients on the waiting list and, despite several `Carry a Donor Card’ publicity campaigns, fewer organs are available (Prommool, 2000).

Indications and Procedures

The transplantation of organs from human donors to human recipients has been established practice in medicine since the first successful kidney transplant was performed in 1954 (Tan, 2002). Its applications have been limited, however, for two major reasons. First, the demand for human donated organs always exceeds the supply. Second, the human body naturally rejects transplants. When the immune system recognizes compounds on the surfaces of cells from any source that is «not self,» a chain reaction begins. Antibodies attack foreign proteins and mark them for destruction by white blood cells (Townsend, 2005). Enzymes attack the walls of blood vessels in a transplanted organ, destroying it within hours. To prevent rejection, transplant recipients must take immunosuppressive drugs for months or years. Blocking their immune response, however, makes transplant patients susceptible to infections, some of which can be deadly (Munson, 2004).

Xenotransplantation — the transfer of cells, tissues, or organs from nonhuman animal donors to human recipients for therapeutic purposes — might solve both of these problems. A large supply of organs can, in theory, be farmed in animals such as pigs. Also, theoretically, organs can be tailor-made to prevent rejection. Genetic engineering techniques should be able to replace animal proteins and sugars on the surfaces of cells with human ones, thus creating an organ that the recipient’s immune system is tricked into accepting as «self» (Munson, 2004).

Immunosuppressant drugs

The immune response to the transplanted organ involves mainly subsets of T-lymphocytes (T- helper cells and T-cytotoxic cells), with regulation by lymphokines (interleukins 1 and 2) and B-lymphocytes (Hornick, 2006). The immune response, if unchecked, leads ultimately to the destruction of the transplant graft by ischaemic necrosis. To prevent transplant rejection, the recipient is given immunosuppressant drugs to attenuate the immune response (McRae, 2006). The ideal immunosuppressant would protect the transplant from rejection but would have no other effects on the patient. This would involve drugs acting mainly against T-cell activation and proliferation. Unfortunately, none of the current immunosuppressant drugs are this selective, and suppression of B-cell production and other cellular activity also occurs (Hornick, 2006). This renders the patient more susceptible to infection and proliferation of malignant cells. Once the transplant has become established over a period of months, the immune system adapts to the continuing insult by a reduced immune response. This allows a gradual reduction in the doses of the anti- rejection drugs given to the patient

New advances

In view of the increasing number of patients on the waiting list, and the falling donor rates, novel methods of procuring donor organs are being investigated. One approach is xenotransplantation, where animal organs are used instead of human ones. The pig is considered the most suitable donor animal; its high fertility allows a rapid increase in herd numbers, and the size of adult organs is similar to that of humans. However, there are both scientific and ethical problems associated with this technique. The first of these is hyper acute rejection, where the grafted organ is rejected within minutes or hours of being transplanted (Cooper, 2002).

Another is cellular immunity, where the recipient mounts a cellular immune response to the xenograft greater than that to a graft from a human donor. The obvious solution to this is to subject the recipient to even greater immunosuppression. A third problem is that retroviruses may spread from pig to human tissues, or that parts of pig retroviruses may recombine with parts of human viruses to create a new virus (Cooper, 2002). This effect has been demonstrated in vitro. One approach to solving these problems is by cloning technology. This could provide consistent groups of donor organs which express the correct HLA antigens to prevent hyperacute rejection, and at the same time are known to be retrovirus-free. (Hanson, 2000).

Although cross-species transplants are appealing because of their potential to alleviate the shortage of suitable organs for transplant, scientists face a number of challenges in turning this hope into reality. Rejection of an organ by the recipient’s immune system remains one of the major problems with xenotransplants (Morris, 1998). Cells of the immune system may identify transplanted tissue as “foreign,” and attack and destroy it—sometimes within minutes or hours. To minimize this danger, physicians must give the recipient drugs that suppress the immune system.

Conclusion

Some scientists are turning their attention to the use of pigs as potential organ donors. They believe that if viruses are present in donor pigs, those microbes would be less likely to thrive in human beings than viruses harbored by baboons or other primates, which are genetically closer to human beings. Pigs have other advantages as well: They are easier to breed than primates, and their organs are similar in size to human organs (Prommool, 2000).

To further improve the likelihood of success, several teams of researchers have created genetically altered strains of pigs with organs that are less likely to be rejected by the human immune system. At the Duke University Medical Center in Durham, North Carolina, for example, researchers have injected human DNA into pig embryos (Prommool, 2000). The pigs that develop from the embryos have both pig and human DNA in their cells. Presumably, organs from such pigs would be less likely to be rejected by the human immune system. In 2002, researchers in Virginia announced that they had successfully bred pigs lacking a specific sugar molecule on their cell surfaces known to trigger the rejection response in humans. Xenotransplantation advocates hope that this and similar developments will spur further progress in the field.

Writer’s Surname

Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. (2000). Long-term survival in renal transplant recipients with graft function. Kidney Int; 57:307-13. 

 Tan M, Di Carlo A, Liu S, Tector A, Tchervenkov J, Metrakus P: (2002). Hepatic sinusoidal endothelium upregulates IL-1alpha, IFN-gamnm, and iNOS in response to discordant xenogeneic islets in an in vitro model of xenoislet transplantation. J Surg Res 102:229-236,

Hornick, P. & Rose, M. L. (2006), Transplantation immunology: methods and protocols, Humana Press, Totowa, N.J.

Townsend, Courtney M., Jr., et al., eds. (2005). Sabiston Textbook of Surgery. 17th ed. Philadelphia: Elsevier Saunders.

McRae, D. (2006), Every second counts: the race to transplant the first human heart, G.P. Putnam’s Sons, New York.

Kuwaki, K., et al. (2005). Heart transplantation in baboons using ±1, 3-galactosyltransferase gene-knockout pigs as donors: initial experience. Nature Medicine 11:29-31

Morris PJ (1998) Progress in the induction of tolerance to allografts. Transplantation Proceedings 30, 2427-2429

Prommool S, Jhangri GS, Cockfield SM, Halloran PE (2000). Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol; 11:565-73. 

Cooper, David K. C., and Robert P. Lanza. (2003). Xeno: The Promise of Transplanting Animal Organs into Humans. New York: Oxford University Press,.

Munson, Ronald. (2004).Raising the Dead: Organ Transplants, Ethics, and Society. New York: Oxford University Press,