ILAR Journal Online, Volume 37(1) 1995: Perspectives on Xenotransplantation

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ILAR Journal V37(1) 1995
Perspectives on Xenotransplantation

Xenotransplantation and Infectious Diseases
S.S. Kalter and R.L. Heberling

S.S. Kalter, Ph.D., is President of Virus Reference Laboratory Inc. (VRL), in San Antonio, Texas. R.L. Heberling, Ph.D., is Vice President of VRL.

For want of a nail the shoe was lost... Herbert, G. 1651.

INTRODUCTION

Organ transplantation is now an accepted, and in many instances necessary, mechanism for the preservation of human life when disease has resulted in the loss of organ function. The exact number of organs required for transplants is probably unknown, but there is unquestionably an insufficient supply of human organs, and another source or method is required. Hilts (1993) estimated that approximately 60,000-80,000 lives could be saved if organs were available. According to the United Network for Organ Sharing, in 1994 there were over 37,000 registrants for organ transplants; approximately half will die for lack of an available organ. It has been suggested that improving the logistics of delivery and matching of supply and need would be helpful in supplying human organs. Mechanical replacement is currently an inadequate option, and it is not a permanent solution. With limited human organ sources, what are the alternatives?

Leaving social and ethical aspects aside, animals could create a potential supply of temporary or perhaps permanent organs for transplantation. Assuming that xenotransplantation is viable, numerous queries enter into such a decision. For example, are infectious diseases acquired from transplanted animal organs and are body fluids the major conceivable danger? Humans are susceptible to animal-associated diseases (zoonoses). As it would appear that there is little choice between human and animal organs for transplants, and that there is an insufficient supply of human organs, problems with animal organs must be resolved.

Of the animals under consideration as organ donors, nonhuman primates and swine are most frequently suggested. Currently, nonhuman primates, because of their phylogenetic relationship to humans, are preeminent as suitable organ donors. When contemplating the nonhuman primate, anxieties that continue to counter their usage are fears engendered by the possible presence of infectious agents. It would appear, however, that "the jury is still out" with regard to this concept. Brack (1987) provides a background of infectious agents present in nonhuman primates. A potential for humans to become infected as a result of heterotransplantation exists and has been discussed in numerous reports (see references). Conceivable transfer of infectious agents as a result of xenotransplantation using nonhuman primates or pig sources is reviewed in #cooper1"Cooper and others (1991), Kalter (1991), and more recently by Michaels and Simmons (1994). Hardy (1989) does not consider infectious diseases.

If animals are to be a source of organs, it has been suggested that the spread of infectious diseases may be minimized by employing germfree (gnotobiotic) or specific pathogen-flee (SPF) animals for xenotransplants. Because of the numbers needed, the use of germfree or SPF animals would be impractical. Further, such animals still harbor endogenous agents. Limited experience suggests that well-characterized animals born in captivity and allowed no contact with animals introduced from the wild may be a more practical source of organs for xenotransplants.

When considering the choice of an animal, disease potential is a moot point. Infectious agents are unfortunately universal. A precise understanding of the specificity of infectious agents is often lacking and in many instances is not clearly defined. An alien species infected by certain agents may change the virulence of that agent, such as B virus infection of humans (Herpesvirus simiae from Macaca sp.). Many agents are host-specific and not infectious when crossing species barriers. Two recently described highly fatal simian viruses, Ebola-Reston and Simian Hemorrhagic fever do not cause human disease. The simian immunodeficiency viruses (SIVs) are not known to cause human disease although infection is suspected (Khabbaz and others 1994). Other agents, such as measles and tuberculosis are not influenced by species barriers and can cause infection or disease in diverse host species. Although the exact epidemiology of the Marburg virus is unknown, it was fatal for both human and nonhuman primates (Kalter 1986). The human immunodeficiency viruses are considered to be derived from simian sources, and others may be forthcoming. It is not known if natural immunodepression is a cause of altered virulence of infection or disease in a new host.

Many mammals are also infected by agents of nonmammalian origin (such as arboviruses, bacteria, parasites, and fungi). Arboviruses require a vector for transmission from one host to another and are not a transplant problem. Infection and disease are complicated by a number of extraneous considerations: immunological status, age, nutrition, socioeconomic factors, and geographic locale. If history foretells the future, "new" strains of infectious organisms most certainly will be forthcoming and could be a source of human infection and disease. Such occurrences have been observed in the past.

Infectious agents that can cause zoonotic disease are frequently of little hazard in the host of origin; infection usually results in subclinical disease with antibody production. Zoonoses are generally initiated in immunologically naive individuals and are devastating as such to any population. A transplant patient, because of immunosuppression, is immunologically naive. Because overtly sick animals would not be considered for organ donation, it is unlikely an agent would be transferred from them. However, latent infections of donor or recipient, which are not discernible, may be activated as a result of the transplant. Endogenous agents are also an unknown factor, and their presence may need consideration. In pursuing possible sources of transplant organs for humans from nonhuman primates and swine, human contact with these animals over the years has not been overshadowed by human infection and disease. However, these contacts have been by immunologically "normal", not immunosuppressed, individuals.

Immunosuppression increases the susceptibility of an organ recipient to infection and frequently permits nonpathogenic organisms to become pathogenic. As a consequence, activation of dormant or latent infectious agents in the recipient should be anticipated. Similarly, transferring a nonpathogenic or latent infection from an organ donor to an immunosuppressed individual may also result in enhanced pathogenesis. Past infections of both organ donor and recipient may be detected by antibody surveys. The presence of antibody may serve as a protective mechanism in transplants (Peterson and others 1980). However, antibody surveys are not infallible as titers may fall below perceptible levels or inappropriate methodologies may be employed.

While there is reason to be concerned about the transfer of infectious agents from an animal source, experience has indicated thus far that infection has not been a major problem in heterotransplants. Infections from animal donors do occur, but as in human-to-human transplants where infections are recognized (Ho 1977; Michaels and Simmons 1994), careful selection of a donor may limit the spread of infectious agents. Human infection from swine has not been as extensively studied as from nonhuman primates.

Of all the nonhuman primate viruses, B virus has received the most attention because of its pathogenicity tot humans. This virus, which is closely related antigenically to human herpes simplex, is common to Macaca sp. B virus infection in the macaque simulates human infection with herpes simplex, while infection in humans is fatal. Macaques, however, are now not considered for xenotransplants largely because they are hosts for B virus, so the question of B virus transfer is irrelevant. SA8, a herpesvirus found in baboons that is related to B virus but not considered a human pathogen, frequently causes misinterpretation of serologic results because of its antigenic cross reactivity with B virus.

Among nonhuman-primate organ donors, apes and principally chimpanzees are most desirable. While apes other than chimpanzees (such as gorillas, orangutans, gibbons) have been considered, they are not available. Immunologically these apes are also more remote from humans than the chimpanzee and would be less enticing as donors. The availability of chimpanzees is extremely limited and for all practical purposes this animal cannot be considered as an organ donor because they are an endangered species. Development of chimpanzee breeding colonies, although intriguing, would be inappropriate because of cost as well as for ethical reasons. The baboon (Papio sp.), a monkey that is readily available and raised in captivity, is currently the most frequently used nonhuman primate considered for xenotransplantation. Of the nonprimates, considerable attention has been given to the pig (Sus scrofa). Both animals, the baboon and the pig, have a microflora.

FLORA AND FAUNA

The baboon and pig meet the various criteria established for donor animals: size, ease of breeding in captivity, a source of food (pig), phylogenetic relationship (baboon), and many other physiological, anatomical, and other similarities to humans. The major negative feature shared by both animals, but also a problem in human-to-human transplants, is the continuing need for immunosuppression and the conceivable danger of infection.

Nonhuman Primates

Baboons have been extensively studied, and preliminary data are available on their acceptance as organ donors for humans (Starzl and others 1964, 1993; Hitchcock and others 1964; Reemtsma and others 1964, 1969; Murphy and others 1970; Brede and Murphy 1972; Van der Riet and others 1987; Bailey and others 1985; Human and others 1987). The baboon is currently the nonhuman primate of choice for xenotransplants in the United States and South Africa, the major areas of xenotransplantation activity. Other nonhuman primates, particularly the chimpanzee, have been used in limited instances over the years. In South Africa, the Chacma (Papio ursinus) baboon is locally available. In the United States the much smaller yellow baboon (P. cynocephalus), derived from Kenya, Tanzania, and Ethiopia, is used. Breeding of P. cynocephalus in the United States is well established (Goodwin and Coelho 1982). For practical purposes there does not appear to be any major differences in the normal flora of both species (Human and others 1987; Michaels and others 1994). Baboons breed well in captivity, do not appear to be endangered, and are readily available. In areas of origin, baboons are considered agricultural pests.

An extensive bibliography is available on the baboon, and its overall microbiology has been reported (Kalter 1967; Brede and Murphy 1968, 1972; Kalter and Heberling 1971; Kalter 1973, 1986). Noteworthy are the studies done on the baboon immediately following capture in Kenya providing information on natural infections (Kalter 1973). As suggested above, the phylogenetic relationship of nonhuman-to-human primates emphasizes their common flora and fauna, including bacteria, fungi, parasites, and viruses and their enhanced susceptibility to many of these agents. In addition, most nonhuman primates have an extensive specific pattern of infectious agents that are related, but distinct from their human counterparts (Kalter and others 1980). Widespread geographic and species differences in flora and fauna among nonhuman primate species is recognized. When contemplating nonhuman primates as a source of organs, it would appear that the choice is limited. Apes, as indicated, cannot be considered. South American monkeys are generally too small, many species are restricted in availability, and all species have a definite viral flora that includes several oncogenic viruses. Of the Asian and African nonhuman primates, macaques are not desirable because of the presence of Herpes B virus. Of the remaining African species, none offer any advantages over the baboon.

Despite the large number of viruses and other organisms recovered from the nonhuman primate, as well as the recognition of disease among these animals (Benirschke 1986), there is little evidence to indicate that extensive human infection, other than B virus, has been recognized. B virus infection of humans following contact with macaques is well described (Keeble and others 1958; Hunt and Melendez 1969; Hull 1968). Information on human infection with nonhuman primate agents following xenotranplants is very limited and is unquestionably due to the restricted number of simian-to-human xenotransplants completed. If the practice of using nonhuman primates as organ donors on immunosuppressed recipients continues, infection and disease must increase.

In nontransplant situations, hepatitis A contracted from chimpanzees is well substantiated (Hillis 1961; Smetana and others 1970). In 1967 an outbreak of a highly fatal disease occurred among humans as a result of contact with African green monkeys (Cercopithecus aethiops) blood and tissues. Monkeys carrying the virus (Marburg virus) rapidly succumbed to the disease and would not have been considered as organ donors Kalter 1986). Monkeypox virus, a close relative of smallpox and vaccinia viruses, has infected humans following contact with monkeys (Kalter 1986). There are other examples of human infections resulting from nonhuman primate contact. Human vaccines (such as polio and adenovirus) made in monkey tissues have resulted in the transfer of SV40 virus, a monkey papovavirus, to human recipients. This virus is oncogenic in experimental animals, but human disease has not been observed (Shah and Nathanson 1976). Unquestionably, other viruses have also been transferred by this mechanism. Human-to-human organ transplants are known to result in infection (Fulginiti and others 1968; Ho 1977), principally with herpesviruses (cytomegalovirus). As a consequence, it must be assumed that similar infections may occur as a result of xenotransplants (Michaels and Simmons 1994).

Several antibody studies on donor baboons have been conducted and antibody to a number of viruses has been demonstrated (Van der Riet and others 1987; Human and others 1987; Michaels and others 1994). In the limited number of instances where xenotransplants were conducted, few adverse effects from infectious agents were noted (Hitchcock and others 1964; Starzl and others 1964; Reemtsma 1964; #Reemtsma 1969; Bailey and others 1985; Starzl and others 1993). Infections, possibly leading to death, have been observed as a result of agents other than viruses (Starzl and others 1964; Reemtsma and others 1964; Brede and Murphy 1968; Michaels and Simmons 1994). It is quite clear that until more xenotransplants have been performed, infection and disease resulting from the donor organs will not be known.

Table 1 provides a listing of virus antigens and the results of screening baboon candidates for xenotransplants from the South African and Pittsburgh transplant groups. An important consideration when selecting animals based on antibody detection is the source of antigen. In a recent comparative study in which two laboratories tested the same serum sample for antibody, it became apparent that there was a need to develop specific test antigens against the animal species used in the xenotransplant (Michaels and others 1994). It is evident that extensive additional information, not only about the donor but about test methodologies employed, is required before making any judgement on the development of infection and disease following xenotransplants.

A major virus family that must be regarded with suspicion and that is a possible cause for concern in xenotransplants, is the Retroviridae. Retroviruses comprise a large family of viruses divided into a number of subfamilies all with varied biologic and clinical characteristics. Certain retroviruses (HTLV-BLV group and the genus lendvirus), are considered to be associated with B-or T-cell leukemia/lymphoma as well as human AIDS. Simian-related viruses are known to produce a disease in nonhuman primates similar to human AIDS. Both endogenous and exogenous retroviruses are recognized, and they may be transmitted horizontally, vertically, or both. Oncoviruses, which have long been recognized as tumor-producing and are associated with both human and simian AIDS, have furthered concern about the disease potential of retroviruses.

The status of human infection with SIV is not clear. The precise relationship between human and simian immunodeficiency viruses, particularly HIV-2, has also not been clarified. Antibody development in "two human infections" along with other infection markers, but no disease, is of interest in this continuous concern over infectivity by simian retroviruses (Khabbaz and others 1994). Waning antibody obviously indicates lack of persistent infection. Existence of other SIV strains with differences in pathogenicity need consideration and one may speculate that human pathogens exist. However, until such pathogenicity is demonstrated or a sufficient time has passed in the case of the two seropositive individuals, SIV strains should not be considered as the cause of human disease. Antibody development, in response to a foreign antigen, is to be expected.

Foamy viruses (Spumavirus), another group of retro-viruses, are prevalent in nonhuman primates and other animal species. Thus far, foamy viruses have shown little indication that they are other than nuisances with no recognized disease production. Their continued presence in host animals, however, strongly suggests that their status continue to be monitored.

Little studied and generally ignored are the endogenous retroviruses. Both types C and D endogenous viruses have been recognized, usually in placental or embryonic tissue, by electron microscopic examination, but rarely seen in adult tissue. Genomic material of these viruses probably resides within all living animals, but expression varies from cell to cell. While such genes are difficult to detect, molecular probes may be of value in determining their presence. Although a number of type C and D viruses have been isolated, little is known of their pathogenicity with the exception of the baboon (type C) isolate. This virus, as a pseudotype containing the Kitsten murine sarcoma genome, produced metastatic disease in dogs and nonhuman primates (Heberling and others 1976). The potential for the baboon endogenous type C virus, which can replicate in human cell cultures, to acquire a sarcoma gene present in the transplant host, is unknown.

In addition to viruses, other organisms have been recognized in nonhuman primates: bacteria (Brede and Murphy 1968; McClure and others 1986), parasites (Toft 1986), and fungi (Migaki 1986). These agents may have a detrimental effect on nonhuman primates especially in the colony habitat. Proper colony management is an integral aspect of maintaining healthy animals and preventing transmission to humans. Breakdowns in disease control do occur, and require rapid and precise management to minimize the devastating effects of disease expansion. Many of these organisms are recognized as infectious for the human and a cause for concern in xenotransplantation (Michaels and others 1992). Usually, unless donor tissue is in direct contact with human blood, agent transmission is minimal. Blood dyscrasias require careful examination. Overtly ill animals would be rejected as donor candidates. Routine laboratory monitoring should detect most infections and disease including those due to agents other than viruses. Unfortunately current monitoring is dependent on available methodologies, but even more so on accessible reagents including recognized antigens. While some cross-reactions may indicate infection by agents other than those included in the test menu, dependence upon such a reaction is extremely limited and open to criticism. Previously unrecognized disease incitants cannot be included in monitoring programs until the etiological agent is isolated. Accordingly, in addition to continuous colony antibody surveys, the need for laboratory support in identifying disease outbreaks is essential.

The effects of immunosuppression on infection were realized in early heterotransplants even though the primary cause of failure was organ rejection. "The continued need for high-dose immunosuppressive therapy precipitates lethal infections in the majority of cases"(Starzl and others 1964). Contributing infectious agents detected were: Escherichia coli, Pseudomonas aeruginosa, Staphylocaccus aureus, Aspergillus fumigatus, Candida albicans, Herpesvirus varicella, and Klebsiella-Aerobacter. The epidemiology of these infections remains unknown. Was it caused by the baboon or activation of recipients organisms? Reemtsma and others (1964) did observe that their patient receiving chimpanzee kidneys, who had been immunosuppressed, died of infection without evidence of organ rejection. Whether infection will be a significant problem in xenotransplantation remains to be determined.

Nonprimates

Several small animals have been suggested as organ donors and a number have been used. Swine have received considerable attention and are involved in a number of studies (Cooper and others 1991). The pig shares a number of characteristics with humans including size, structure, physiology, and dietary habits. As would be expected, the pig also has a microflora, which includes bacteria, parasites, fungi, and viruses. Many of these are known to be associated with human infection and disease (Cooper and others 1991). Endogenous viruses are suspected in swine but have not been reported. As with nonhuman primate tissues, use of the pig is contingent upon development of a successful method for overcoming rejection. Breeding pigs is more efficient and offers a greater opportunity than breeding nonhuman primates, and their additional usage as a source of food is another possible advantage. The availability of large numbers of pigs permits further exploration into the development of transgenic swine that could be immunologically acceptable to humans (Sachs 1992). Would the same mechanism be applicable to the nonhuman primate? Fewer ethical considerations is another major factor when contemplating the pig as an organ donor.

SUMMARY AND QUESTIONS FOR CONSIDERATION

The need for a source of organs as support systems for humans in the immediate future is unquestioned. The supply of needed organs from acceptable human donors is extremely limited, and mechanical organ replacements are currently impractical. The venture into using animals as organ donors, with full recognition of their deficiencies, is based on the realization that there is an insufficient supply of human organs and no adequate mechanical replacement.

In this brief overview, the nonhuman primate (baboon) and the pig are examined as potential organ donors. For practical purposes, either animal would be acceptable, if, or when, the problem of rejection is solved. Is the phylogenetic position of the baboon (concordant) versus that of the pig (discordant) sufficient to recommend the baboon over the pig as the donor of choice? Pigs offer a number of positive considerations: they are easy to breed, are a source of food, share many characteristics with humans, and their use raises fewer ethical issues than the use of baboons. Careful analysis suggests that infection and disease, while they occur, thus far have been a minor factor in the few xenotransplants attempted. However, the influence of immunosuppression must be weighed. Immunosuppression, used to control rejection, is the major underlying cause for infection either as a result of reactivation or enhanced susceptibility. In human allotransplants, immunosuppression and infection are closely linked. #Rubin (1981) states that clinically significant infection occurs in 75% of all transplant recipients and is the leading cause of death.

Both baboons and pigs are known to harbor agents of human infection and disease, and careful colony husbandry may solve this problem. Conceivably, unrecognized endogenous retroviruses in the nonhuman primate and perhaps in the pig could be a source of disease. These agents, passed from mother to offspring, are maintained as genomic material and are neither observed nor recovered from adult tissues. Endogenous viruses would not be eliminated by use of either gnotobiotic or SPF animals. Some limited experimenal data suggest an oncogenic capability for the baboon type C endogenous viruses, but more information is needed. What are the potential dangers to organ transplant recipients with regard to lymphoproliferative diseases? Such diseases have been observed in nonhuman primates including baboons (Kalter 1991). The existence of a herpesvirus closely related to human herpes simplex and the macaque B virus, that is SA8, may alarm some baboon advocates. However, human disease with SA8 has not been recognized.

While the question of alternatives has been asked, mechanical substitutes are so far unacceptable. Even given the ability to eliminate rejection, using animals raises some social and ethical opposition, particularly if choosing a nonhuman primate. Without question apes, and particularly chimpanzees, would be inappropriate. Their supply is limited in the wild and we are unable to raise sufficient numbers in captivity. Any use of present populations, regardless of the purpose, would not only be unethical, but would constitute an irreplaceable loss. Would the same protest result from the choice of the baboon or pig?

Is prevaccination with a battery of antigens of value in protecting an individual? There is evidence to indicate that seronegative immunosuppressed individuals receiving organs from seropositive donors have a higher risk of disease (Peterson and others 1980). Effective vaccines require availability of immunizing antigens. Until desired antigens are provided, "protection" would be limited only to those antigens in the vaccine. Of concern would be the failure to provide protection against the unknown. It has been suggested that the use of immunosuppressive drugs have enhanced the survival of HIV-infected liver recipients (Jacobson and others 1991).

The major difficulty in xenotransplants still seems to reside in the inability of the human body to accept a foreign tissue. Progress in developing mechanisms to modify rejection by means of immunosuppressive drugs has been somewhat successful and continues to improve (Starzl and others 1993). Are molecular and transgenic modifications of the donor animal (or even the recipient) worthy of consideration? Transgenic animals could be developed providing organs that would be immunologically acceptable to humans (Sachs 1992). However, will development of transgenic donors result in the appearance of new "uncontrollable" diseases, from which human fatalities may result? Current infections apparently are under control.

Can ethical and social thinking about the use of animal organs for xenotransplants be revised by solving the problem of organ rejection, controlling infection, increasing survival rates, choosing an animal host other than a primate and that also serves as a source of food? Because of the limited supply of human organs, more than half of the needy individuals die. Providing organs from animal sources for the approximately 50,000 patients waiting for transplants, even if not a permanent solution, should subdue any opposition to the use of an animal source of organs.

ACKNOWLEDGMENTS

Data reported herein on serologic studies were in part supported by grants from the Small Business Innovation Research Program: I R43 Al 128604-01, I R43 A1 129317-01 and 5 R44 AI 293 17-03. We also wish to apologize to the many, many investigators whose studies were not included in this overview. Xenotransplantation is an expanding field. This overview is an attempt to indicate the potential and problems of infectious diseases and xenotransplants.

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Van der Riet, F. deSt. J., P. A. Human, D. K. C. Cooper, B. Reichart, J. E. Fincham, S. S. Kaher, P. J. Kanki, M. Essex, D. L. Madden, M. T. Lai-Tung, D. Chalton, and J. L. Sever. 1987. Virological implications of the use of primates in xenotransplantation. Transplantation Proc. XIX 4068-4069.

TABLE 1 Serologic findings on baboons; accumulated data

Herpesviruses
Herpes simplex	+ (16/20)**	DIAdot®
Cytomegalovirus	+ (52/65)	DIAdot
Epstein-Barr	+ (32/65)	IFA
Varicella-zoster	+ (7/24)	DIAdot
SA 6 (Simian CMV)	+ (24/34)	DIAdot
SA 8	+ (7/24)	DIAdot
Lymphotropic herpes	+ (?/30)	IFA
Retroviruses
SIV	+ (5/51)	DIAdot
STLV 1	+ (5/31)	DIAdot
SRV	+ (1/85)	DIAdot
Foamy virus	+ (30/31)	DIAdot
Type C	+ (?/30)	EM
Miscellaneous
Hepatitis A	+ (3/31)	ELISA
Hepatitis B	+ (0/31)	ELISA
Influenza A	+ (0/34)	DIAdot
Influenza B	- (0/34)	DIAdot
Measles	+ (23/55)	DIAdot
Rubella	- (0/34)	DIAdot
Mumps	- (0/34)	DIAdot
Simian hemorrhagic fever	- (0/31)	DIAdot
Marburg	- (0/34)	DIAdot
Ebola-Reston	- (0/30)	DIAdot
Lymphocytic choriomeningitis	- (0/65)	DIAdot
Reovirus (SA 11 )	+ (31/39)	DIAdot
Monkey pox	- (0/31)	DIAdot
Encephalomyocarditis (EMC)	- (0/30)	DIAdot

*Serologic studies on both groups of animals performed at the Virus Reference Laboratory, Inc® The presence (+) or absence (-) of antibody at a 1:5 or 1:10 serum dilution, ? - no accurate count.
**Numerator (number positive)/Denominator (number tested). DIAdot® DIA-dot immunobinding assay, IFA-immunofluoresence, EM-electron microscopy, ELISA-enzyme linked immunosorbent assay.

Note: Other groups of baboon have been found with antibody to many of these viruses (Kalter and Heberling 1971; Kalter 1986). The above data were obtained only from the two specifically referenced groups of animals. Antigens employed were derived from nonhuman primate sources and were highly specific. Cross reactions among the herpesviruses were observed, but distinguishable.