2. History, types and source animals for xenografting
3. Advantages and disadvantages of xenografting
4. Barriers to clinical success of xenotransplantation
5. Motivation for xenografting
6. Medical challenge posed by xenografting
7. Psychological effects of Xenografting
8. Religious challenges of Xenografting
9. Epistemological challenges of Xenografting
10. Legal Dilemma posed by Xenografting
11. Ethical challenges posed by Xenografting
12. Xenografting and issues of animal rights
13. Concluding remarks
Xenografting also called xenotransplantation is the transfer of organs, tissues and cells from species of a different kind to another. The concern of this book is on xenografting that involves, the transfer of organs and tissues from animals to humans. The use of animals as source of organs, tissues and cells for transplantation into humans has been practiced for some time now. This procedure (xenotransplantation or xenografting) started as far back as 1904-1906 with Mitt Carrel and Guthrie. They performed autogenous vein grafts, leg replantation in dogs, and the famous patch-grafts (Samdani http://emedicine.medscape.com/article/432418-o...). In 1906 Kidneys from goats, sheep and monkeys were transplanted into humans by Jaboulay. Also, in 1032, Neuhof transplanted a lamb kidney into a patient with mercury poisoning (Samdani website). Xenotransplantation has however, not been successful because of set-backs like; immune system rejection and the risk of introducing a novel infectious disease to humans. Few recipients of animal’s organs and tissues have survived more than a few weeks and many others have died in a matter of hours or less (Hughes 18).
However, in recent times there has been an upsurge of interest once again in xenotransplantation, due to improved technologies, that have provided better immunosuppressive drugs that would aid combat immune rejection and also the development of transgenic technologies, where animals like pigs are being genetically modified to produce organs and tissues that would be compatible with the human body. This renewed interest in xenotransplantation is also due to new researches that have shown little evidence that pigs which are main object of xenografting will not transmit new infectious organisms to humans. The interest is increased by the fact that the number of human organs and tissues available for transplants are in short supply. According to the most recent report from the United Network for Organ Sharing (UNOS) more than 107,241 Americans alone were on the waiting list for organ transplantation as at May 2010 (http://www.unos.org/). According to Healy, a worldwide shortage of human organs for transplantation causes about 20-35% of patients who need replacement organs to die on the waiting list (235). Xenotransplantation it is believed, would help bridge the gap between the number of patients in need of transplantation and the number of organs available.
There are therefore, three main motivations behind the recent interest in xenografting, there are
(1) There are better immunosuppressive drugs to combat the hitherto existing problem of immune rejection by the recipient immune system.
(2) There are better evidences showing that xenotransplantation would not lead to the introduction of a novel infectious disease to the human race.
(3) The number of human organs available for transplantation is far too small compared to the demand.
Other factors like the financial gain that will accrue from a breakthrough in xenotransplantation and the possible fame this breakthrough would bestow on the scientists could also provide the vehicle that drives researches on xenotransplantation. The most important driver of xenotransplantation could be said to be the desire to find better treatment for the teeming patients on their dying beds. Norman Levinsky avers that the use of animal cells or tissues could be beneficial in AIDS, Parkinson’s disease, diabetes, spinal cord injury, acute liver failure, psoriasis, muscular dystrophy, myocardial infection and other health conditions. The importance of xenotransplantation could therefore, not be totally and reasonably contested. Michler a medical surgeon in support of moral benefits of xenotransplantation asserts “as a cardiac surgeon, I am faced with people who die all the time. It’s abhorrent. My interest in xenografts is a direct response to a tremendous problem, the management of heart failure - the No1 cause of death in this century today. At least 45000 of those people could be saved by a heart transplant, but we can transplant only about 2000 because of the shortage of donor agents” (website). As we have said already this is one main driver of Xenotransplation – the desire to save lives. But the question is, is xenotransplantation an ethically acceptable means of achieving those ends? Should the Machiavellian principle of the end justifies the means be made the order of the day in biomedical technologies? Many answers have been given to these questions as shall be seen in the book. However, my thinking is that, the means is as important as the end, none could be sacrificed for the other. This implies that caution must be applied in the use of xenografting procedure.
Though, xenotransplantation has a lot of praiseworthy prospects for the health of humans, the problems that could accompany its advent would be catastrophic. Diseases such as AIDS, diabetes, Parkinson’s disease, acute liver failure, spinal cord injury, psoriasis, muscular dystrophy, myocardial infarction and other health conditions have plagued mankind for ages and have defied all attempts at cure. The news that organs, tissues and cells got from animals would cure these diseases is indeed a course for celebration. But the question is, is it a worthy celebration? Though, the emergence of xenotransplantation offers great hope to the human race, it nevertheless is surrounded with evil, which I believe is capable of drowning what little hope it has for us. Xenotransplantation carries in itself the potential to sink the world. It could introduce a new world plague. It is capable of destroying basic religious beliefs and values. It could destabilize the ecosystem and thereby, increasing the environmental problems that are already proving too much to manage. The animals’ existence would be threatened by xenotransplantation, thereby leading to a drastic reduction of the world’s biodiversity – a biodiversity that is already speedily being lost.
Xenotransplantation is not yet a clinical success because, of the problem of immune rejection. However, in the nearest future it might become a huge success like other forms of genetic engineering. When this time comes, efforts would be diverted from the present drive to create a sustainable environment to xenografting. Most of the problems xenografting is out to solve are problems that have their roots in environmental degradation. If the solutions to these problems are found in xenotransplantation, then, there is likely to be a drop in the motivation to take care of the environment. The motivation to take care of the environment, has hinged on the knowledge that environmental degradation affects human health negatively. But if xenotransplantation clears off this source of motivation, then the environment may totally degrade.
Other problems that could accompany xenotransplantation include:
(1) The risk of introducing new infectious diseases to humanity.
(2) It could reduce the dignity of humans
(3) It could lead to identity crises
(4) It questions God’s existence and His creative role.
(5) It could lead to abuse of human rights
(6) It could contribute to overpopulation
These and many other challenges facing xenografting are x-rayed in this book. The main aim of this book is to conduct a philosophical appraisal of the implications of xenotransplantation to humans and the environment at large. And in attempt to doing this the work focuses on the following:
(1) Showing the motivation behind xenotransplantation
(2) Showing that the apparent potential benefits of xenotransplantation could become insignificant when compared with its potential danger to humans.
(3) Showing that success in xenotransplantation could dissolve the current resolve to sustain the environment.
(4) Showing the ethical, religious, psychological, epistemological, legal and health dilemmas surrounding xenografting.
(5) Pointing to a better way at tackling human problems that would not destabilize the ecosystem.
It is hoped that the recommendations in the book would serve as sufficient reasons, for the government to regulate the activities of scientists as regards xenografting research.
At present xenotransplantation could arguably be said not to be a risk, which would imply that this research is not justified. However, it is good to note, that research efforts are seriously ongoing, implying that in the nearest future, there would be a breakthrough in xenotransplantation and it would become a clinical success. Better immunosuppressive drugs are being sought for and research is also making significant progress in genetic engineering of pigs (the most favoured animals for xenotransplantation), so as their organs would not suffer hyperacute rejection when used in humans. The possibility that researches would yield result necessitates this research. I believe that it is better to nip a problem at the bud than to combat it when it is already full blown. Now that xenotransplantation is not yet fully developed and its catastrophic effects are not yet evident, it is better to tackle it, so as to save mankind and the world at large from imminent danger. Prevention is always better than cure.
This work gives support to the already done research on the ethical implication of xenografting and also challenges the committee of philosophers and scientists to join in the cost-benefit analysis of xenotransplantation. It is not good to endanger our future, that of the animals and other beings just for temporary gains that xenotransplantation holds for us. The end should not be made to justify the means – both are important. The means and the end must be held in complementary relationship as Asouzu would advise – the means and the end forms one complementary horizon and none is absolute (Complementary Reflection 156).
2. History, types and source animals for xenografting
History of Xenotransplantation
Xenografting is a transplant procedure in which a human patient receives an organ (like kidney or liver) or living cells (such as brain cells) that come from a healthy animal instead of from a human donor. It is also used to refer to transplant between any two different species of animals. It is contrasted with allotransplantation, which is the procedure whereby cells, tissues and organs are transferred from members of the same species; like in transplantation of organs from one human to another. While allotransplantation is transplantation from the same species, xenotransplantation is transplantation across different species.
The living animal material that is transplanted into humans in xenotransplantation is called xenotransplant or xenograft.
Alexis Carrel is generally known as the founding father of experimental organ transplantation, because of his ground breaking work with vascular technique. Carrel and colleague Guthrie contributed tremendously to the science of transplantation. They performed autogenous vein grafts, performed leg replantation in dogs, and developed the famous patch-graft technique for widening narrowed vessels. They also performed heterotopic experimental transplantation; for instance, parts of a smaller dog were transplanted into the neck of a larger dog (Samdani http://emedicine.medscape.com/article/432418-o.).
Due to the remarkable success of Carrel and his colleague Guthrie, other scientists made several frantic attempts in transplantation with commendable success. These results gave confidence to scientists, that xenograft survival and functioning in humans was a possibility. Many attempts were therefore, made thereafter to cure ailments through the use of animal organs and tissues. For instance, in 1906 Jaboulay transplanted kidneys from goats, sheep and monkeys into humans. In 1910 Unger transplanted a nonhuman kidney into a man dying of renal failure. In 1932, Neuhof transplanted a lamb kidney into a patient with mercury poisoning (samdani http://emedicine.medscape.com/article/432418-o.) In 1984, a baboon heart was transplanted into a new-born infant, named Baby Fae, who suffered from hypoplastic left heart syndrome (Bailey 3322). Also Starlz et al reported how a baboon liver was transplanted to a human patient suffering from hepatitis failure (65). According to Rood and Cooper, Porcine islet cells have in several occasions been transplanted into patients to aid in the cure of Type 1 diabetes in children and young adult (1270). Also porcine skin has been purportedly grafted into burn patients and pig neuronal cells have been transplanted into patients with Parkinson’s disease and Huntington’s disease (Fink et al 274).
These attempts were highly unsuccessful, because of the problem of immune system rejection of the xenograft. The immune system fights against foreign elements in the body which include bacteria, fungi, viruses and other bodies that are perceived to be foreign to the body, including xenograft. Thus, when organs of animals are transplanted into humans, the human immune system detect these organs as foreign and thereby fights seriously against them, leading to the destruction of these transplanted organs. This is what is called immune system rejection. This has been the problem that for several years militated against the success and growth of xenotransplantation. The problem of immune rejection led to a decline in interest in xenotransplantation. This interest was rekindled after Michon and Hamioger successfully performed transplantation on twins without using immunosuppression. Michon and Hamburger successfully performed a living related donor kidney transplantation in Paris in 1952, between monozygotic twins and they survived (Michon et al1420).
The advent of immunosuppressive drugs for the prevention of immune rejection also contributed to the renewed interest in xenotransplantation. Thus, since 1990, there have been various transplantation of animal organs into dying patients (Erlick http://www.nelsonerlick.com/htm/xenofactsheet.html). In 1995, according to Erlick, a patient in the United States got a bone marrow from a baboon. Although, the immune system of the patient rejected the baboon bone marrow, the patient continued to live a normal life. There have also been significant successes in areas of cellular xenotransplantation. For instance, ten patient received cells from pancreas of pigs and none of the patients got sick from the transplanted pig cells. Also, cases that involved hooking up a patient up to a pig liver, functioning as a substitute liver, for a short time until a suitable donor organ is sought for have also been recorded.
Types of Xenotransplantation
Xenotransplantation procedure is categorized into; solid organ xenotransplantation, cell and tissue xenotransplantation, extracorporeal perfusion and human/animal hybrid.
Solid organ xenotransplantation: This is a procedure whereby an animal organ like kidney or liver is transplanted into human as a replacement of the original human organ.
Cell and tissue xenotransplantation: It is the transplantation of tissues and cells from source animals to human beings as replacement of the original tissues in humans.
Extracorporeal perfusion: This is a procedure whereby the blood of the patient is made to circulate outside of the human body through animal organs, such as a liver or a kidney, or through a bio-artificial organ produced by culturing animal cells on an artificial matrix.
Human/Animal Hybrid: This is a procedure where human cells are grown in a culture with non-human animal cells that are transplanted back into human patients.
Source Animals for Xenotransplantation
Chimpanzees were generally considered to be the best source animals for organ transplants compared to other primates because of their close affinity with humans, but due to their endangered status, attention were shifted to baboons. Baboons being the next most preferred source animals, though, existing in abundance, fared badly in captivity, have a long gestation period and are capable of few offspring. In addition, they and other nonhuman primates are believed to pose the greatest risk of transmission of disease to humans. Samdani notes that the risk of transmission of xenogenic infections from donors to human recipients is high in baboons and other primates because of their closeness to humans. This infections could then be passed from the recipient to his close contacts and from there propagation through the general human population. Because of these possible problems associated with the use of baboons and other primates, attention was shifted from primates to pigs. This realization made the FDA (Food and Drug Administration) committee known as BRMAC (Biologic Response Modifiers Advisory Committee), to recommend that nonhuman primates should not be used as sources of xenotransplantation, since they pose the greatest threat of transmitting latent, intracellular, or unidentified organisms, including retroviruses. The committee therefore, recommended that nonhuman primates should not be used as sources of xenotransplantation (US Food and Drug Administration. http://www.fda.gov/cber/rules/frigene011801.htm). This recommendation led to the search for other suitable animal donors of organs.
Most of the scientists are of the agreement that pigs have the potential to be the right candidate for organ donation. This is because pigs are in abundance, quick to mature, breed well in captivity, have large litters, and have vital organs that are roughly the same in size with that of humans. Their use is also argued to be less resentful to the society because they are already an accepted source for societal meat. Pigs are also believed to be less likely to introduce new diseases to human because of their distance to humans in the evolutionary chain. Other reasons why pigs are preferred include:
1. Pigs because of their ability to fare well in captivity, can be raised in a highly controlled way, thus, their organs are less likely to transmit infectious diseases to humans.
2. Pigs could be genetically engineered to contain human genes. This would make the animal organs or cells to be readily accepted by the patient immune system.
In spite of these advantages, pigs xenografts are believed to be capable of experiencing severe immunologic barriers than the nonhuman primates because of their distance from man in the evolutionary chain.
3. Advantages and disadvantages of xenografting
Xenotransplantation has many advantages over allotransplantation and other means of treating ailments. These advantages it has, made many to argue that it is a better alternative to other curative measures. Benefits of xenotransplantation include:
1. Xenografting is helpful in the total treatment of diseases. People with serious kidney, liver, heart disease, diabetes or Parkinson’s disease which have defied all known treatments could be treated through xenotransplantation. The presently available treatment for these diseases is not able to provide a total cure. Xenotransplantation it is believed, could bring a complete cure to these diseases, thereby enabling the patients to live normal lives. Cellular xenotransplants for instance could treat people suffering from diabetes, Parkinson’s disease and other diseases. The treatment involves replacing specific cells or tissues which do not work properly as a result of the disease. For diabetes these cells are the islet cells of the pancreas; for Parkinson’s disease they are brain cells. These cells are difficult to be obtained from human donors. People with liver failure could be treated with an extra-corporeal (outside the body) xenotransplant using a healthy pig liver. In this process, the patient’s blood circulation is made to pass through a pig liver that is kept outside the patient’s body. Sometimes this is meant to be temporary until a suitable human donor is sought for, but sometimes this is all that is needed to allow the person’s own liver to recover and start working again. People needing bone marrow transplants could also benefit from xenotransplantation.
2. Xenografting gives the surgeon enough time to eliminate potential pathogens. In allografting (human to human transplantation) organs which are usually transplanted from a brain dead patient are given little or no time for examination to ascertain their health state, due to the urgency involved. The transplant organ therefore, could come from a suboptimal donor with advanced age and chronic medical condition or from a carrier with undetected infectious agents or malignant cells. In contrast, in xenotransplantation, there is enough time to scrutinize the xenograft before transplantation. A donor pig or Chimpanzee as the case may be could even be raised under controlled conditions specifically intended for use as an organ donor. In this case, the donor animal can be extensively analysed to ensure that it is pathogens free.
3. In xenotransplantation, animal donors could be genetically modified to be resistant to many human pathogens specific to human tissues, such as HIV, hepatitis, and human cytomegalovirus. Xenotransplantation gives ample opportunity to scientist to rear genetically modified donor animals to be resistant to known human diseases that have defied all treatments. Since these animals’ organs and tissues are resistant to these diseases, when they are transplanted into humans, they cure those ailment which they have been genetically modified to resist. This procedure is not available for allotransplants, as human donors cannot be genetically modified because of ethical concerns.
4. Xenografting unlike allografting could go well with children. Xenografts are appropriate for infants who are physically too small to receive donations from adult humans. The organs from adults because of size difference may not fit well into children who need transplants. Since it is difficult to get children donors, it is difficult to get allograft for children. In this case, xenograft becomes the only option, since it is easier to get animals with different organs sizes to choose from.
5. Introduction of xenotransplantation would prevent ‘black market’ in human donor organs. Insistence on allotransplantation it is believed, could lead to illegalities in the acquisition of allografts. Due to the scarcity of human donor organs and the large number of patients on the waiting list for organ transplantation, human organs could be procured illegally. Some patients whose lives would have naturally been saved would be allowed to die by the doctors in order that their organs would be used for transplantation. Some patients could even be killed deliberately in order for their organs to be used for transplantation into a more important patient. Also, some brain dead patients’ organs and tissues could be smuggled without his/her consent or that of his/her family members. Xenotransplantation it could be argued would help stem this abuse. If animal donors are readily available and are safe for use, these cases would not exist, if at all there exist, there would be minimal.
6. Xenografting could save hundreds of thousands of lives and revamp the lives of many others. This is because, patients who otherwise would not have been eligible for transplantation because of shortage of human organ, would receive organs and tissues through xenotransplantation. Also, Xenotransplantation could eliminate poor quality of life situation for patients. Most people are not able to function optimally due to incurable ailments, xenotransplantation would improve the lives of such people.
7. Xenotransplantation could lead to national development. National development is a function of output of the people. If the per capita productivity of a country is low, that country’s development is bound to be slow. In contrasts, if its citizens are highly productive, the country will advance in development. For a people to perform optimally they need to be healthy, since xenotransplantation is capable of improving the health of a people, then it could be said to be capable of effecting national growth and development.
In spite of the numerous advantages that could accrue to humans, if xenografting becomes a clinical success, there are a lot of disadvantages that are associated with xenotransplantation. These disadvantages include:
1. The risk of introduction of xenozoonosis to the recipient: Xenozoonosis are diseases that are believed to be capable of being passed from animals to people by means of xenotransplants. It is the transmission of infectious agents between species via xenografts. Animal to human infection is normally rare, but has occurred several times in the past like in avion influenza, when influenza was passed from birds to humans (Beigel 1375). Xenotransplantation is believed to be capable of leading to disease transmission for 3 reasons:
a. Implantation breaches the physical barrier that normally helps to prevent disease transmission.
b. The recipients of the xenotransplant will be severely immunosuppressed to reduce the effect of immune rejection.
c. Human complement regulators expressed in transgenic pigs could serve as virus receptors and may also help to protect viruses from attack by the recipient immune system (Takeuchi & Weiss 504). This will give the viruses free way to operate in the recipients’ body.
The possibility of transmission of infectious agents raise questions regarding the safety of using xenotransplantation in humans, - this also places the general public at risk. Like humans, animals may also be infected with microorganism which could be specie specific (that is, it is not transmittable to other species). For instance, the transmissible virus of pigs causes diarrhoea in pigs but does not cause any sickness in humans. However, other kind of micro-organisms is not specie specific, which means some of them can infect animals and also cause disease in humans. An example of this is influenza. The flu first infected birds and pigs and though, it does not make these animal sick, when it passed to humans, it makes them sick. Another example is HIV, which was originally harmless in monkeys but when transferred to humans becomes very deadly.
The word xenozoonosis therefore, refers to zoonotic diseases that may pass to human through xenotransplant (Vanderpool 1311). Most mammals are known to have a kind of virus embedded in their DNA known as “endogenous retroviruses.” These viruses are passed from one generation to the next without causing havoc in the host species. All pigs are believed to carry such viruses called PERVs (Pig or Porcine Endogenous Retroviruses). These are normally inactive and thus do not cause disease to the pigs. The concern among scientists is that PERV may become active and infect the human cells. Viruses that could be transmitted by pigs include porcine herpesvirus, totavirus, parvovirus, and circovirus. Other unknown viruses as well as those that originally are not harmful to the pigs like PERV could also pose health risks to humans. Baboon and pigs are known to carry myriad transmittable agents that are not harmful to the animals themselves but could be toxic and deadly to humans
2. The xenograft may not work well especially if it is replacing an essential organ of human. Since the environment in which animal organs function are quite different from the one the human organ function in, it is feared that these organs may not function well in humans. For instance, the temperature which pig organs function in, is 39 degree Celsius which is different from the 37 degree Celsius of humans. Also the life span of a pig is roughly 15 years, which brings the fear as to whether or not pigs transplants in man would live more than 15 years.
3. The high level of immunosuppressive drugs needed to overcome immune rejection may be counterproductive. This may leave the patient susceptible to other infections. The immune system fights foreign agents that invade the body like bacteria, fungi and viruses. Thus, suppression of the immune system would leave room for easy invasion of the body by these micro-organisms, thereby causing many other sicknesses. Xenotransplantation therefore, could open room for other sicknesses to invade the recipient.
4. Xenotransplantation could potentially lead to a world plague. There are fears that xenotransplantation is capable of introducing novel infection to humans, which would be transmitted from man to man and thereby leading to a new world plague similar to HIV. This is a serious concern, considering the effort and money that have been invested in the fight against HIV.
5. Xenotransplantation could lead to a lot of ethical, moral and medical dilemmas. These dilemmas would be fully discussed.
4. Barriers to clinical success of xenotransplantation
Xenotransplantation has been largely unsuccessful because of various barriers. These barriers include:
1. Immune system rejection of xenografts. David Sachs in his work entitled “The Immunologic Response to Xenographs” argues that immunologic phenomenon is the greatest hindrance to a successful take-off of xenotransplantation. Without this immunologic phenomenon he argues, animals would accept transplant across varied breeds (http://ilarjournal.oxfordjournals.org/content/37/1/16). For instance, according to Manning, nude mice, have been shown to accept xenogenic skin grafts, to the extent that it can even grow chicken feathers (489). In theory therefore, Sachs believes that eliminating the immune response to xenografts would solve the puzzle and make xenografting a success story. Immune rejection occurs when a patient immune system fight against the newly transplanted organ or tissue and destroy it. A patient’s immune system will normally accept a transplanted organ (from a human or animal donors) only if it is a fairly close match with its own. But apart from identical twins, there are no organs or tissues that would be a perfect match with a patient organs and tissues. Thus, aside from organs from twins, the recipient organs would react against transplants either from humans or animals. However, the extent of rejection depends on how closely related the donor is to the patient. Human organs and tissues would however, experience not very serious rejection like animals. Also, organs from primates would receive less serious rejection than organs from not so closely related organs like that of pigs. The immune system response to xenografts ultimately results in rejection of the xenograft, Immune rejection of xenotransplantation is higher and more vigorous than that of allotransplantation and therefore more difficult to prevent. Allotransplants have few antigen disparities and this can be minimized through typing and matching. That is, disparities can be minimized by choosing organs that match, for instance, the organ from a twin, would more likely be more acceptable by the immune system than an organ from a far relation. Pig tissues and tissues of other animals express multiple antigens that cannot be matched to human recipients. These antigens result to multiple reactions, through the adaptive immune system and the innate immune system. Therefore, strategies that are very effective with allograft will not be effective with xenografts. Also, the rejection barrier of vascular xenografts (heart, kidneys, livers, lungs) is greater than for cellular grafts (islets, hepatocytes, neurat tissue). With vascular grafts, injury to the endothelial cells lining the vessels leads to thrombosis, hemorrhage, and prompt loss of the graft. This is as a result of the endothelial cells that line the blood vessels, which become activated. Thus, xenografts are lost to an immediate hyperacute and acute vascular rejection days after transplant. There are therefore, three basic types of immune rejection: hyperacute, acute and cellular rejection. Hyperacute rejection is a rapid and violent type which occurs within minutes to hours from the time of the transplant. It is mediated by the binding of XNAs (Xenoreactive Natural Antibodies0 to the donor endothelium, causing activation of the humancomplement system, which results in endothelial damage, inflammation, thrombosis and necrosis of the blood in neonates, after colonization of the bowl by bacteria with galactose moieties on their cell walls. Most of these antibodies are of the IgM class, but also include IgG, and IgA (Taylor, http://www.emedicine.com). The binding of XNAs, initiate complement activation through the classical complement pathway. Complement activation causes a cascade of events leading to; destruction of endothelial cells, platelets degranulation, inflammation, coagulation, fibrin deposition and harmorphage. This would result to thrombosis and necrosis of the xenograft (Taylor http://www.emedicine.com). Strategies have been proposed to combat the problem of hyperacute rejection, there include:
a. Interruption of the complement cascade: the recipient’s complement cascade can be inhibited through the use of cobra venom factor which depletes soluble complement receptor type 1, anti C5 antibodies or C1 inhibitor (C1-1NH). This procedure according to Dooldeniya, would deprive the individual of a functional complement system.
b. Developing transgenic organs through source donors. This is a process whereby source animals are genetically engineered so as their organs would not be perceived as foreign to the body by the immune system. The immune system attacks organisms and objects perceived to be foreign to the body. It attacks bacteria, fungi, viruses and also xenograft. However, when xengrafts are genetically engineered through donor animals, there are less likely to be perceived as foreign to the body by the immune system.
Acute vascular rejection is also known as xenoactive rejection, this type of rejection occurs within two or three days, if hyperacute rejection is prevented. The process that leads to acute rejection is not fully understood. It requires de novo protein synthesis and is driven by interaction between the graft endothelial cells and host antibodies, macrophages, and platelets (Candinas 64). The sticking of XNAs to the donor endothelium leads to the activation of host macrophages as well as the endothelium itself. This binding of XNAs leads to the development of a procoagulant state, the secretion of inflammatory cytokines and chemokines, as well as expression of leukocyte adhesion molecules such as E-selectin, intercellular adhesion molecule-1 (1CAM-1), and vascular cell adhesion molecule-1 (VCAM-1) (Taylor 2).The use of immunosuppressive drugs combined with a wide variety of approaches is necessary to prevent acute vascular rejection. These approaches include:
1. Administering a synthetic thrombin inhibitor to modulate thrombogenesis.
2. Depletion of anti-galactose antibodies (XNAs) through techniques like immunoadsorption, to prevent endothelial cell activation.
3. Inhibiting activation of macrophages and NK cells (Candinas 64).
Cellular rejection is based on cellular immunity, and is mediated by natural killer cells, which accumulate in and damage the xenograft and T-lymphocytes which are activated by MHC molecules through both direct and indirect xenorecogniton. In direct xenorecognition, antigen presenting cells from the xenograft present peptides to recipient cells. Indirect xenorecognition involves the presentation of antigens from the xenograft by recipient antigen presenting cells to CD4 T cells (Abbas and Lichtman 81). Though the strength of cellular rejection is uncertain, it is believed to be stronger in zenografts than in allografts due to differences in peptides in animals. An approach to reduce cellular rejection is inducing donor non-responsiveness using hematopoietic chimerism. This is a process where donor cells are introduced into the bone marrow of the recipient, where they coexist with the recipient’s stem cells. The bone marrow stem cells give rise to cells of all hematopoietic lineages, through the process of hematopoiesis. Lymphoid progenitor cells are created by this process and move to the thymus where negative selection eliminates T cells (Dooldeniya 113).
2. Size incompatibility: Differences in organ size limit the range of potential recipients of xenotransplant. Most organs of animals are not the same size with that of humans, making compatibility difficult. The difficulty of getting organs of the right size for transplantation to a patient is a serious barrier to the successful clinical take-off of xenografting. Pigs are believed to have organs roughly the same size with that of humans, but roughly the same is not exactly the same. There are fears that these minute differences in size could lead to incompatibility problems in the recipients. Erlick asserts that apart from identical twins, each person’s cells are a little bit different from everyone else’s. This is why there must be a test to ensure the organ of the donor matches with that of the recipient before there is a transplant (http;//www.nelsonerlick.com/html/xenofactsheet.html). If this is so with humans to humans, then the disparities between animal organs, tissues and cells with that of humans is greater. A perfect match according to him is almost impossible, thus many times the recipient gets an organ that is as close as possible to his/her own. Because of this slight difference in cells and organs, the recipient immune system recognises the donor organs as foreign and would therefore try to destroy these cells as it would destroy bacteria or viruses.
3. Longevity differences: The life of most animals is shorter than that of humans. Pigs that are the most preferred source animals have about 15 years life span. It is therefore, a cause of concern to scientists, as to whether or not a xenograft from a pig would last longer than 15 years in a human. Since no xenograft recipient has lived up to 15 years yet, it is difficult to ascertain whether pigs’ organs could exceed 15 years in an individual. Would xenotransplantation reduce the lifespan of the recipient? This is a question that is presently hard to answer, but is a strong contributor to the slow growth of xenografting.
4. Hormone and protein differences: Some proteins of animals will be molecularly incompatible with that of humans, which could cause malfunctioning of important regulatory process. This leads to the malfunctioning and eventually death of the xenografts in the human body.
5. Differences in environment: The organs and tissues of animals work in a different anatomical site and under different hydrostatic pressure. Thus, it is the belief of some scientists that these organs and tissues would not work well in a human anatomical environment that is so different from that of animals. This discourages research in xenotransplantation.
6. Temperature differences: The temperatures of animal bodies differ from that of that of humans. The body temperature of pigs for instance is 39 degree Celsius which is 2 degree above the average human body temperature. Though the implication of this difference on the activity of important enzymes is not known, it is feared that this may have a serious implication for the survival of the xenografts (Candinas 64).
7. Physiological challenges. Physiological challenges also hampers the successful clinical implementation of xenografting. There are physiological differences between the animals and the bodies, which often leads to incompatibilities of the xenografts with the host body. For example, the cells surfaces of the xenogenic tissues may be physiologically incompatible with that of the recipients. Also, the red cells of the recipient may be incapable of transmitting oxygen to xenogenic tissues or may even be unable to negotiate through xenogenic capillaries
8. Strict regulations. Due to the concerns raised by ethicists, moralists and other scholars, most of whom strongly called for a moratorium on xenotransplantation, the government and other international regulatory bodies have tended to apply strict regulations on research on xenografting. These regulations have no doubt inhibited and discouraged some scientists from undertaking a research in xenografting. The guidelines provided by the International Xenotransplantation Association Ethics Committee, demands that for any xenografting to be ethical, it must consider the risks to the patients and the society; this risk should be minimal. This implies that, preclinical data, including non-human primate data, must adequately support the possibility of a successful outcome. Samdani advises that, to meet this guideline, animals used for xenotransplantation should be reared in captivity and in close colonies, so as to ensure that known potential pathogens to humans are removed from the colony. The committee also demands that the recipient of the xenografts must be placed in monitoring at least for 50 years. In addition to a lifelong monitoring, the patient would also have to agree not to donate blood and inform close contacts about the xenotransplantation he has gone through and of its potential risk for spreading zoonotic infections. This is not an easy thing to do for both the scientists and the recipients. Lifelong monitoring would be strenuous to the scientists and will effectively deny the patients the right to withdraw from the study at any time. This right (to withdraw from study at any time) according to the Declaration of Helsinki and the US Code of Federal Regulation, is a fundamental right of the individual that cannot be violated (76). In addition to this, from a public health perspective, the patient notification of close contacts of his xenotransplantation and its potential infections risk would violate the principle of confidentiality. Another challenge as noted by Sandani, is that close contacts of xenotransplants recipients could be expected to desist from blood donation and subject themselves to monitoring if it becomes necessary. This is because infections from xenotransplantation recipients may be transferred to their close contacts, thus they along with the recipient need to be closely monitored. Samdani concede to the fact that this would be no easy task to accomplish, because the recipient’s close contacts may continually change. This requirement of monitoring of xenografting recipients along with their close contacts, may invariably lead to an international monitoring, due to the fast way people travel these days. Samdani believes therefore that, there is a need for an international awareness of the potential risk of xenotransplantation. This international awareness would elicit an international monitoring to ensure that infections are not transmitted across borders. According to him, the ethical principle of justice requires that all nations must be responsible for the control of potential infectious diseases from xenografting or xenotransplantation. This however, would not be easy because it would require an international treaty that will carry a uniform immigration surveillance system to monitor the entry of potentially infectious pathogens. He points out that federal regulation on xenotransplantation was based on speculation that hold that, if xenotransplantation was done on a large scale, recombination of the PERV subtypes would produce a new virus that was contagious and thus, could spread among human population. The federal guidelines therefore, stipulated that a recipient should be monitored for up to 50 years and they should be restricted from many things especially travelling. This is not an easy thing to do he claims and thus is a great barrier to xenotransplantation researches.