Physiological Side Effects of Cellular Implants

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Besides possible recognisable side effects on the psyche, the newly structured organisation of the brain by neurotransplantation may also result in unwanted physiological effects. Neurotransplantation in the intact brain of rodents has been shown to alter physiology. Three examples from the literature on transplantation in animals illustrate this: i) the increase in cognitive capacities of aged rats following implantation of fetal septal brain grafts in the hippocampus (Gage et al. 1984), ii) the increase in masculine and feminine sexual behaviour of female rats following neonatal implantation of male preoptic brain tissue (Arendash and Gorski 1982) and iii) the change in circadian rhythm by rat inter-species grafting of the fetal suprachiasmatic nucleus (the biological clock of the brain; Ralph et al. 1990).

The recent notion that in PD patients who received an intrastriatal human fetal mesencephalic graft dyskinesias occurred more frequently than in sham-controlled subjects (Olanow et al. 2003; Freed et al. 2003) indicates that the grafted dopaminergic cells or the other nerve cells in the graft also have such physiological effects other than those wanted to restore the symptoms. The grafted tissues have re-arranged or re-structured the neuronal circuitries of the striatum so that control of motor functions is set differently and steering of body movements deviates from the intact situation of non-PD persons. This side effect, only recognised after a long history of dopaminergic cell grafting in PD patient (Hagell et al. 2002; Freeman et al. 2001) indicate once more that negative symptoms are sometimes hidden. It also re-emphasised that findings in animal models can never completely predict the results of the same approach in the diseased human and that unexpected side effects may show up in the clinical trial. Such an observation clearly sends the clinical neuroscientist back to their animal experiments to find out the cause of this side effect and to design new strategies for improved experimentation in human beings, if at all feasible. Meanwhile, some studies seem to indicate that the uneven distribution of reinnervation of the stratum in dopaminergic cell engrafted PD patients may be the cause of the disturbing dyskinesias (Maries et al. 2006).

2.8.3 So Far Risks of Cell Implants for the Psyche Appeared Limited or Barely Recognisable

Neurotransplantation adds small neural cell masses to the recipient brain, either as cell replacement therapy or as a source for substances that are beneficial to dysfunctional or damaged neurons. It does not, and cannot, replace large parts of the CNS with similar parts from donor brains and cannot replace entire neuronal circuits. It is unlikely that the micro-implants which are currently applied experimentally in patients would create a complete new brain with a new set of neuronal circuits, bringing about a different personal identity or, in the case of nervous xenografts, a non-human identity. Identity is not linked to a single, clearly defined, brain structure. Identity, as a reflection of declarative information on self, others, time and the environment, is stored in the entire brain and its networks in a dynamic fashion. The brain is not static but continuously changing and adapting its neuronal cell function and sensitivity and its cellular connectivities. However, as indicated above, small changes in the nervous system can definitely reflect personality changes from functional neuroteratology studies as well as neurografting studies in intact animals. When personality changes occur as the result of neurological and psychiatric diseases, particular brain surgical interventions may bring about additional changes beyond the ones that had to be cured and thus should be called side effects. The altered regional cellular and molecular make-up will change neural functioning of a particular neuronal network or of a series of networks in the CNS which then become active at a different level of homeostasis and, therefore, result in altered behavioural performance in daily life. Such personality changes are almost always subtle in the few studies on personality changes in programmes of experimental restorative neurosurgery with fetal dopaminergic neurons in PD, the test bed disease for many types of interventions (Sass et al. 1995; Diederich and Goetz 2000; McRae et al. 2003). Thus, no major complications for the psyche of a patient are reported that would balance out the gains in terms of therapeutic effects. However, one has the problem to distinguish the alterations due to the progress of PD itself, the changes induced by ongoing drug intake, those of the mechanical lesion from the surgery (penetration of a grafting cannula) as well as of the implanted dopaminergic cells. Though little research has been reported, Diederich and Goetz (2000) concluded, on the basis of various available neurophysiological and behavioural studies in PD patients subjected to with various treatments that fetal tissue, that transplantation does not induce significant cognitive changes or long term psychiatric complications. Unwanted side effects such as major contraindicative changes in personality or altered identity have so far not appeared to be major risks when the brain is locally treated with cell supplementation.

2.8.4 Transfer of Personality by Neuronal Grafting is Erroneously Brought Up

The transfer of personality has been put forward as a possible, unwanted side effect of neurotransplantation of human or pig fetal brain tissue (Walters 1988; Polkinghorne 1989; Linke 1993). Personality, as stated above, is not located in a single neuronal cell type or in a small brain area, but comes to expression from the activity of the neuronal networks of the brain, with all their inputs and outputs from and to other networks in the brain and elsewhere in the body. Personality is acquired and based on the formation and strength of these networks, the backbone of which is established by the genetic programme of human nuclear DNA during early and late (up to puberty) brain development in interference with external conditions, but which remain adaptable throughout someone's life (through mechanisms of neural plasticity, see before). Thus, transfer of personality from (minced or suspended) fetal donor tissue to the host brain is erroneously put forward as a possible drawback in neurotransplantation. The maturing and functional integration of the implanted fetal neurons will, moreover, be directed by the adult conditions of the site of implantation in the host, which are totally different from those in the fetal and immature brain.

2.8.5 Safety Aspects of Cell Implants

Cellular and gene therapeutic interventions in the brain of course also have several safety implications that need intensive control. Transmissible Diseases and Tumor Formation

Before implantation of cells from human sources, the presence of transmissible diseases should be checked. In case of a short time interval between the retrieval of the tissue from human abortion remains and the actual surgery, this requires informed consent of the woman involved, as (time-consuming and blood-based) tests have to be performed on her bodily fluids prior to donation and use of the aborted fetal tissue. This is routine procedure in all existing protocols of neurotransplantation involving embryonic mesencephalic tissues. The EC Directive of the European Parliament and Council on setting standards of quality and safety for the donation, procurement, testing, processing, storage and distribution of human tissues and cells (2003), requires serology tests for HIV 1 and 2, hepatitis B and C, Treponema pallidum and HTLV-I and II. Contaminations preclude the direct use of these tissues for implantation. More tests are sometimes added to these standard procedures. For example, in France the law requires additional tests for toxoplasmosis, EBV, CMV, VZV together with a risk-benefit assessment by the doctor (it is also mandatory that blood samples, taken from the patient before and after grafting surgery, are stored for checking the serology of immunological status of the host. Similarly, seroconversion had to be checked for EBV, CMV and VZV). Storage and hibernation of the abortion remains would make it possible to carry out these tests without blood sampling from the woman. However, in the case of primary neural cells, this is done at the expense of neuronal cell survival following grafting (Frodl et al. 1994).

The tests described above are, of course, also necessary when allogeneic ESCs, EGCs, fetal neuroprogenitor cells or SSCs are to be used as implants, or when cell lines from human embryonic teratocarcinoma are to be applied. Cell cultures can be tested for pathogens during the proliferation, differentiation and storage phase before final use. Control for the presence of infectious organisms will then be part of the "good laboratory practice" (GLP) of the cell line production facility. Cell lines derived from human ESCs appeared to be sensitive to mutations (Maitra et al. 2005), which may perhaps make them unusable for therapeutic purposes such as late-passage cell lines and highlights the need for periodic monitoring for genetic and epigenetic alterations. A major problem, however, is the frequent occurrence of brain tumors in animal studies when ESCs, either undifferentiated or differentiated into neuronal phenotypes, are used as neurografts. Causing a tumor is in fact the most feared complication of any stem cell-based therapy. ESCs injected in an undifferentiated state and not given proper guidance, can form a tumor in virtually any location (Asano et al. 2006). Experimental human application should therefore not be started until this event is better understood and can be controlled. Further research is needed on this. As i) there is no evidence to date that cancer is caused by bone marrow-derived SSCs, whereas ii) it can be used as autograft and iii) it is not ethically controversial, research in this field of stem cell therapies focuses more and more on the use of SSCs. However, as claimed above, the ESC may, in the end, be the cell that is needed because of its genuine totipotent character. Xenografts

For pig xenografts, proposed as an alternative for human allografts as pig nerve cells (as well as those from other mammals) can integrate and function perfectly to repair the injured brain in other mammals (Huffaker et al. 1989; Isacson et al. 1995; Galpern et al. 1996; Belkadi et al. 1997), screening is needed not only for animal-to-human transmissible diseases but the chances of zoonosis occurring must also be considered. This is a great concern as world wide attention is given nowadays to the fact that not only viruses, but also prions, may jump the species gap (Butler 1998). Large disease outbreaks in humans of the Ebola and Marburg monkey viruses, of the simian-derived HIV AIDS virus and, more recently, of bird flu seem to ward against any use of xenografts in human. Barker et al. (2000) still formulated a series of criteria that should be fulfilled in case pig xenografts are to be used in humans: i) microbiological specification of the pig strain, ii) biosecurity of animal production, iii) sterile tissue collection, iv) creation of a tissue archive and safety database, and v) an investigation of porcine endogenous retroviruses (PERVs). Even assuming that the use of domestic pigs - which have been in contact with humans for long periods of time - as source animals for cells will be less dangerous, the potential occurrence of zoonosis cannot be completely avoided by pathogen-free breeding. PERVs are integrated into the genome, as are retroviral DNA sequences in the human genome, and other mammalian species (Weiss 1998). Zoonosis could, therefore, also be a result of DNA recombination and adaptation, leading to the expression of known, or newly formed, retroviruses. Though not directly pathogenic for humans, pathogenicity of porcine viruses can change unpredictably when they cross species. The chance of cross-species infection (Patience et al. 1997) increases with the closeness of contact of grafted and host cells following neurotransplantation, and the reduced competence of the immune system in patients taking immunosuppressant drugs following grafting surgery. In a worst-case scenario, xenotransplants could introduce a highly infectious, or possibly lethal, pathogenic virus that would not only affect the graft recipient but could also (through human-to-human contacts) lay humanity open to a new plague (the "Trojan xenotransplant") (Butler 1998; Bach et al. 1998).

To the xenograft recipient, the benefit of a successful transplant will certainly outweigh the risk of any subsequent, unwanted effect of infection by a pig virus. To society in general, however, the possibility of setting off a new human epidemic requires fundamental virology studies before any ethical judgments are passed.

So far, patients who have received pig organ or tissue transplants (Nasto 1997; Stoye et al. 1998; Heneine et al. 1998) or who have undergone dialysis using pig kidneys (Patience et al. 1998) have shown no signs of porcine virus-induced pathogenesis. Clinical studies with porcine embryonic mes-encephalic dopaminergic grafts in the brain should always include long-term, post-operative screening on the expression of PERVs in serum samples (Isacson and Breakefield 1997). Possible consequences for the patient when hazardous viruses do show up have hardly been considered in the neurotransplantation field. If it affects just the patient, it is to be regarded simply as a side effect. If it becomes a highly transmittable, life-threatening disease, it could require, in extreme cases, the isolation of the person receiving the xenotransplant. Tissue Rejection

The brain is regarded as an immunological privileged organ in which tissue rejection is mild or absent. This knowledge stems from intra-species neuro-grafting (allografting) in mammals, including non-human primates. The immune system reaches the brain without hesitations if interspecies neuro-grafting is applied (xenografting), indicating that foreign body rejection can act in the CNS, as it can when bacterial or viral infections occur. Clinical trials with allografts are performed with or without immune suppression treatments. The disadvantages of life-long term immune suppression are known from organ transplantation surgery. Omitting immune suppression following neural grafting remains a subject of controversy, as do the results. Claims of long term dopaminergic cell survival in PD patients following neurotransplantation were presented, but a good correlation between cell survival and functional motor recovery was only reached in patients that had an ongoing immunosuppressive treatment.

Immunological responses can be prevented when the cells for implantation are encapsulated in semi-permeable membranes. Then, even cells from non-human species can be used as implants (Aebischer et al. 1996). However, the implant is then, and will only be, useful as an intracranial or sub-arachnoidal biological drug delivery device generating a missing compound in the brain and releasing a trophic protein following genetic modification of the encapsulated cells to fight or ameliorate neurodegeneration (the use of artificial cells as a vector for gene therapy). Supplementation of lost neurons or glial cells to reconstruct neuronal pathways in neurodegenerative diseases is impossible with such an approach.

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