Transmission of infection

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Xenosis (or xeno-zoonosis) is a term for an infectious disease introduced into human through procedures involving transplantation of xenogeneic cells or tissues.

The disease producing potential of an infection is a function of the relation between the host and the infecting agent. The pathogenic potential of an infection can change in an unpredictable fashion when the infecting microbe is transmited from its natural host into a new species. The effect xenogeneic tissue may have on antigen presentation and the targeting of effective immune responses to new pathogens is not known. VI.BIBLIOGRAPHY [55]

Endogenous retroviruses, widely present in mammalian species, presumably originated as exogenous viruses that became permanently integrated into the host germ line: they are transmitted from mother to child now. In the host species they are benign. Endogenous viruses are frequently xeno-tropic: although the original host is refractory to infection, the viruses can infect other species. Endogenous retroviruses may recombine in humans after xeno-transplantation. Standard diagnostic tests are not available for most of these retroviruses. VI.BIBLIOGRAPHY [55]

In xeno-transplantation the spread of zoonoses could be minimized by using gnotobiotic or SPF animals as a source of cell xeno-transplants, but that would be impractical as their production is difficult and costly, and thus they would not be available in large numbers. Unrecognized endogenous viruses, passed from mother to offspring, are maintained as genomic material and are neither observed nor recovered from adult tissue. They would not be eliminated by use of gnotobiotic or SPF animals. Animals from closed colony suffice for this purpose. One has to accept the fact that infectious agents are universal, and that a clear understanding of the specificity of infectious agents is often lacking and/or is not clearly defined. An alien species infected by certain agents may change the virulence of that agent. Many agents are host-specific and not infectious when crossing species barriers. VI.BIBLIOGRAPHY [53]

Zoonoses are generally initiated in immunologically naive individuals, and are devastating to such population, and that applies to xeno-transplant patients. Infectious agents causing zoonoses are frequently of little hazard in the host of origin: infection is usually subclinical, recognized only by a production of antibodies. Overtly sick animal would not be considered for xeno-transplant donation. It is the latent infections, which are not discernible, which may be activated as a result of transplantation. Endogenous agents are also an unknown factor. Immunosuppression frequently permits non-pathogenic organisms to become pathogenic. Continuing need for immunosuppression and the conceivable danger of infection is the major negative feature of transplantation in general. Clinically significant infection occurs in 75% of all allo-transplant recipients and is the leading cause of death. VI.BIBLIOGRAPHY [53]

Fetal cell xeno-transplantation in around 5 million patients during the period of 85+ years has not cause a single fatality.

There is a potential for the co-infection of human recipient cells by porcine and human retroviruses, whereby they would form a chimeric virus with an unknown pathogenic potential. Recombination is common in cells infected by retroviruses. VI.BIBLIOGRAPHY [49] The development of encapsulation for immunologic isolation of xenogeneic tissue and creation of transgenic animals whose organs are intended to survive immune surveillance after transplantation may increase the potential for viral recombination or reassortment. VI.BIBLIOGRAPHY [55]

There is much less controversy with xenoses as compared with immunological issues. Despite the presence of many known potential pathogens among different donor species, there will almost certainly be less transmission of known infections by xeno-transplantation than by allo-transplantation. … Most investigators believe that xeno-transplantation is exceedingly unlikely to lead to the generation of new pathogens. These are actually quotes taken from an Internet press release by one of the U.S. companies. The above is particularly true if the animal source of fetal cell xeno-transplants is a domestic animal. Proximity of humans to domestic animals would have caused such an event already if it were likely to happen. VI.BIBLIOGRAPHY [150] When no immunosuppression is used the minimal chance of transmission of xenoses is further substantially diminished. The danger of transmission of zoonoses exists, but its degree can be controlled by following regulations, such as that of the Ministry of Health of USSR of 1984, as well as that of

U.S. FDA, to a great degree. Main concern are the future infections currently not known to us yet, such as a unique circumstance where a retrovirus of animal species would recombine with a human retrovirus.

Rabbits do not seem to present any potential problem as a source of xenoses in fetal cell xeno-transplantation today, as could be expected due to their phylogenetic and taxonomic distance from man. According to Dr. Grachev of Section on Biologics, World Health Organization, Geneva, Switzerland, an organization that supervises worldwide production of vaccines and sera, rabbit kidney cell cultures have been used extensively for vaccine production, and thus far have not shown that rabbits represent any potential danger for transmission of viral zoonoses. Thus rabbit was a good choice as a source animal for production of cell xeno-transplants.

Besides that rabbits are the only laboratory animals in which no endogenous retroviruses have been identified to-date. VI.BIBLIOGRAPHY [200, 201, 202] (See also Section on Manufacturing)

Review of infections transmitted by large and small laboratory animals shows that generally in rabbits the following infections can occur: campylobacteriosis (rare), leptospirosis (low prevalence in hosts, or as a zoonosis) , salmonellosis (low/moderate prevalence in hosts, unknown frequency as zoonoses) and dermatomycosis (low prevalence in hosts, low frequency of zoonosis). Plague and psittacosis have a broad host range, including rabbits. Rabbits are natural hosts for a parasitic disease trichostrongylosis. Rabbits are laboratory hosts for common skin mites and ticks VI.BIBLIOGRAPHY [54].

Detailed didactic review of viral diseases in rabbits discusses the situation worldwide. Under the column of ‘public health significance’ for each virus found in rabbits there is a statement such as ‘man is not susceptible to the myxoma virus’, and the same applies for fibroma virus, rabbit pox virus (close to the vaccinia virus), papilloma virus, oral papilloma virus, rabbit kidney vacuolating virus, adenovirus, herpes virus, etc. There are known natural cases of rabies infection in rabbits potentially transmissible to man. This is of no significance in newborn or fetal rabbits, however. Arborvirus infections have been isolated in hares, but no human diseases have been reported to-date. VI.BIBLIOGRAPHY [51] Besides that, arborviruses require a vector for transmission from one host to another and are not a transplant problem. VI.BIBLIOGRAPHY [53)]

Review of potential transmission of retrovirus infections by mammals and poultry produced for food failed to demonstrate an association between human disease and these viruses. Lack of antibodies in apparently exposed groups of persons suggests an absence of infection, and/or lack of immune responsiveness of humans to infection with these viruses. Rabbits per se are not even mentioned in this report. VI.BIBLIOGRAPHY [50]

In recent years the number of donations and clinical allo-transplants of cornea, bone, skin, heart valve, and other tissues have exceeded that of allo-organs, and there have been infection transmissions reported. A high rate of bacterial contamination was found with human fetal tissue donations, and two actual cases of infection from cryopreserved islet cell infusions were found. VI.BIBLIOGRAPHY [52]