Animal sources for fetal precursor cell transplants

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“Because transplantation bypasses most of the patient’s usual protective physical and immunological barriers, transmission of known and/or unknown infectious agents to humans through xenografts may be facilitated.” (U.S. FDA regulation of January 19, 2001) The same concerns led to the ultimate selection of rabbits as the animal source for xeno-transplantation in the described method. (They were selected also because they are abundant. Besides that the dissection of the fetal and newborn rabbits is technically much easier as compared with larger animals that have also been used as a source of fetal cell transplants.)

The lack of transmission of any infection by BCRO fetal precursor cell transplantation with fetal and newborn rabbits as the source of cell transplants in author’s personal clinical experience of 18 years on thousands of patients has been the reason for the claim that the benefit/risk ratio of BCRO fetal precursor cell transplantation is very high.

Rabbits would be useless as a source of organ xeno-transplants due to their small size but are an excellent source of fetal precursor cell xeno-transplants for two key reasons:

A/ It is a common knowledge in veterinary and human medicine that none of the known viral diseases of rabbits are transmissible to man.

As this is a major issue nowadays, let’s elaborate on it, in particular on the transmission of retroviruses and prions.

No one argues the fact that there are rabbit retroviruses in Nature but the truth is that they have not been recognized to this date. According to the following references:

1/ Murphy F.A., Fauquet C.M., Bishop D.H.L., et al: Virus Taxonomy, (Sixth Report of the International Committee on Taxonomy of Viruses), Springer Verlag, Vienna - New York, 1995, Chapter: Families of Reverse-Transcribing Viruses, pages 23 - 42, and the very recent updates (the above Committee meets every 5 years), VI.BIBLIOGRAPHY [200]

2/ Fauquet C.M., Pringle C.R.: Abbreviations for vertebrate virus species names, Arch. Virology 1999; 144: 1865 - 1880, VI.BIBLIOGRAPHY [201] and

3/ Murphy A.F., Gibbs E.P.J., Horzinek M.C., Studdert M.J.: Veterinary Virology, Academic Press, San Diego, New York, London, 1999, pages 273 - 278, VI.BIBLIOGRAPHY [202]

there are no viruses of the Genus Retroviridae have been classified or taxonomically recognized in rabbits yet.

There are three articles by Bedigian H.C. et al., published 24 years ago, that are considered by some to be the sole available proof of existence of retroviruses in rabbits. These three articles are apparently not recognized by the virological community as no one has duplicated the findings of the authors in so many years. It should be pointed out that all three papers were written by the same authors working in the same laboratory, at the same time, and with their own WH/J strain of rabbits that served as a model for hereditary lymphosarcoma and immune hemolytic anemia associated with thymoma.

As per three papers by Bedigian et al. no RNA-directed DNA polymerase was found in rabbit fetuses older that 10 days, (and in such early embryos the retroviruses may have a physiologic purpose, as the authors of the paper stated themselves), or in any normal cells of adult rabbits even from the artificially created strains of rabbits with high incidence of malignancy, such as WH/J strain.

On the page 4694 of article # 2, submitted for publication on the same day as article # 1, the authors stated that ‘particles associated with RDDP (RNA-directed DNA polymerase) were detected in the extracts prepared from tumorous spleens, nodes, and kidneys, but not in tissues of unaffected rabbits’, i.e. obviously of the same artificially created WH/J strain.

In the last paragraph on pages 491-2 of article #1 authors wrote: “To date we have been unable, utilizing a wide range of mammalian cell lines, to demonstrate infection and replication of a rabbit oncornavirus.” ...“ The possibility exists that the viral information is defective and that a virus is therefore unable to replicate. A 2nd possibility may be that a permissive host has not yet been found that allows for the infection and replication of a rabbit type C RNA virus.” And further on: “The role of the type C particles that appear in the early gestation is not clear. Their presence may be due to a hormonal influence early in gestation, or they may be involved in some normal physiological process such as information transfer from parent to offspring (see reference by Daniels, footnote # 2, page 4687)”. The point here is that the authors found the RDDP reaction in the placenta and uterus during the first 10 days of gestation only and not thereafter.

Since the described method of manufacturing recommends to use rabbit fetuses at 28 days of gestation, and the gestation of rabbits takes 30 - 31 days, the findings of Bedigian et al. are not pertinent at all.

There is a recent article by Maudru T. and Peden K., in which authors describe their exceptionally sensitive test for detection of RNA-dependent DNA polymerase activity. No one has identified such activity in rabbits even with such test. Besides the authors state that their assay “can detect RNA-dependent DNA polymerase activity in DNA polymerases that are not retroviral reverse transcriptases.(!)”, thus “the usefulness of the PBRT assay to reveal the presence of low level of retrovirus in biological products or in patient material may be limited.” (p. 260)

One can understand the concern of some scientists in view of the discovery that porcine endogenous retrovirus is capable of infecting human cells in vitro, and that there is a possibility of mutations, or its recombinations with human retroviruses, that could create new pathogenic viruses. The fact remains that pig was domesticated five millenia ago, and even after eating pork for 5,000 years no human has been infected by any such virus yet, and it stays so as long as the ‘pork-producing industry’ continues to follow the ecologically sound principles, unlike what happened in the ‘beef-producing industry’, that caused the “Mad Cow Disease”.

Even if in the future the rabbit retroviruses are found, it will not change the scientific fact that they are not infectious to human or any other animal. Not even under extreme experimental conditions could hares be infected by the virus of haemorrhagic pneumonia of rabbits, and likewise the virus of the haemorhagic pneumonia of hares cannot be transmitted to rabbits, and so it is not surprising that humans or other animals could not be infected either. VI.BIBLIOGRAPHY [196]

At this moment there is no reason to think about prions in relation to rabbits. Since no one has come up with an idea to feed rabbits a food of animal origin, it is highly doubtful that any prions will ever be found in rabbits.

B/ It is a scientific fact beyond any doubt that the xenotransplantation between discordant species causes much less severe immunological reactions than xenotransplantation between concordant species. Rabbits are phylogenetically distant from man, i.e. ‘discordant’. That is probably, besides the procedure of preparation of fetal precursor cell transplants by the described method of tissue culture, a part of the reason why there is no need for immunosuppression when BCRO fetal precursor cell transplants prepared by the described method are used for implantation in clinical practice.

Many physicians feel that the immune reactions after fetal precursor cell xeno-transplantation are not of importance anymore because of the availability of excellent and powerful immunosuppressants. The reality is that all immunosuppressants have multiple side effects and their chronic use leads to potentially life-threatening complications, and if they have to be used with fetal precursor cell xeno-transplantation, then such treatment is fraught with a great risk, and of limited value in everyday clinical practice. When BCRO fetal precursor cell xeno-transplants are prepared by the described method, no immunosuppression is necessary, and their transplantation is less dangerous than taking an aspirin. The ability to minimize immune reactions after fetal precursor cell xeno-transplantation so that no immunosuppression is necessary in clinical practice is of crucial importance for the patient and for therapeutic success.