Mechanism of action

From FETAL PRECURSOR CELL TRANSPLANTATION (FPCT)
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The mechanism of action of fetal cell transplantation is hypothetical. There are a few published but rather exceptional reports of autopsy findings where the implanted fetal cell transplants were found surviving at the implantation site (brain, under the kidney capsule). There are published data of animal experimentation with histological proof of survival of implanted cells at the implantation site. VI.BIBLIOGRAPHY [72]


But the authors of the most authoritative book on fetal cell transplantation in the treatment of diabetes mellitus VI.BIBLIOGRAPHY [109] feel that the majority of the clinical effect is a result of direct stimulation of the repair of patient's own cells and tissues by the transplanted cells, rather than the functioning of transplanted cells themselves. The cell therapy publications state that all implanted cells disappear very quickly from the implantation site, and the greatest portion of them ends up within 2 - 3 days in the organ or tissue ‘where the respective cell belongs’, i.e. all organs and tissues of the patient malfunctioning as a result of a disease, that are treated by the implantation of cells or tissue fragments of each such mal-functioning organ or tissue, following the rules of ‘organospecificity’. VI.BIBLIOGRAPHY [95, 108, 116, 117, 118, 119]


This hypothesis is supported now by the recent U.S. publications dealing with ‘homing’. VI.BIBLIOGRAPHY [19, 20, 21, 179, 180] If transplanted cells and tissues exert their effect mostly by direct stimulation of the corresponding malfunctioning organs and tissues of the patients, to which they are ‘homed’, the question is raised what is the basis of such direct stimulation: outright metabolic influence, paracrine regulatory effect, messenger function, etc.


Let’s look at the specific example, that of complications of IDDM. In case of complications of IDDM the answer is very difficult because of our lack of understanding of the cause of the microangiopathic changes underlying diabetic complications. It is not a result of lack of insulin. On the contrary there is a hypothesis that exogenous insulin is the cause of microangiopathic complications of IDDM. (15). Lately it has been believed that lack of C-peptide is the cause of microcirculatory pathology. VI.BIBLIOGRAPHY [16, 149]


We think, together with Alexis Carrell, that the problem of IDDM is not only a lack of insulin (Carrel: “Insulin does not cure a diabetic”) VI.BIBLIOGRAPHY [18], but also lack of some heretofore unknown factors produced by other cells of the Langerhans islets, besides a- and ß-cells. But, and most importantly, the chronic insufficiency of various factors normally produced by various cells of Langerhans islets places great undue demands on the regulatory system of the metabolism of carbohydrates and lipids, primarily the ‘hypothalamic/pituitary - adrenal axis’, and on the liver as the key organ of metabolism. This is forcing compensatory steps by all these organs, that after a certain period of time lead to an overload, and eventually an exhaustion, of these organs. The appearance of complications of IDDM is the signal that the system is starting to break down.


Hypothesis on the lack of immune response with BCRO method of fetal precursor cell transplantation.


After many discussions with deceased F. Schmid VI.BIBLIOGRAPHY [184] and several Russian scientists, a hypothesis developed about the lack of overt immune response after fetal cell transplantation.


A few introductory remarks ought to be made. Prior to the start of our IIBM project on fetal precursor cell transplantation in Russia, RITAOMH used a ‘monotherapy’ only, i.e. in the treatment of complications of IDDM they used only islet cell transplants and not a combination of cell transplants of various organs, as developed by the German cell therapy school, and adopted by BCRO, and thereby IIBM, from its inception. This was contrary to the past experience in U.S.S.R.


After Prof.Dr. Filatov, the father of the implantation of placenta fragments for therapeutic purposes, a treatment that has been taken by some 20 millions of patients worldwide during the past 90+ years, opened up the field of cell transplantation in the U.S.S.R., a lot of work was done in this area there.


Interestingly enough, although there was a deep animosity between Germany and U.S.S.R. between WW1 and WW2, and thereafter, and contacts were minimal, fetal cell transplantation was flourishing in U.S.S.R., and was following essentially the same principles as in Germany/Switzerland, and that included the use of combinations of cell transplants, i.e. ‘polytherapy’ rather than ‘monotherapy’.


The new leadership of RITAOMH in the 70-ies began to pay more attention to English than German literature and got ‘swayed’ away from traditions, and toward ‘monotherapy’. But the older generation of Russian physicians remembered the works of the followers of Prof.Dr. Filatov: Prof.Dr. Tushnov in 20 - 30-ies, Research Institute of Metabolic and Endocrine Disorders of the Ministry of Health of Russian Federation in Moscow under the direction of Prof.Dr. Kazakov in 30-ies, Prof.Dr. Rumi’antsev in 50-ies, and others, and so IIBM found a lot of intellectual cooperation and fertile ground for re-introducing German/Swiss/Soviet concepts of the use of combinations of fetal cell transplants. VI.BIBLIOGRAPHY [328]


The hypothesis of our team has been, that it is indeed the combination of fetal precursor cell xeno-transplants, the sources of which are many individual fetal rabbits, that is partly responsible for the diminution of the immune response to cell transplantation. It evolved logically from an everyday clinical observation of hundreds of children treated by fetal precursor cell transplantation for various untreatable chromosomal and genetic diseases every 4 months, with transplants of human fetal origin prepared by IIBM without a tissue culture, by a special technique, that included cryopreservation, VI.BIBLIOGRAPHY [37], with no immune reactions whatsoever despite a complete lack of immunosuppression.


Multiple discussions were carried out with scientists at RITAOMH, that used only cultured cell transplants, mostly of animal fetal origin, in their clinical practice, and who were amazed by such an absolute lack of immune reactions with non-cultured allo-transplants. Not only that there were no immune reactions in children treated by fetal cell transplantation every 4 months, on the contrary the deficiencies of their immune system function were corrected. VI.BIBLIOGRAPHY [144, 145]


Many of these treatments were carried out at the Central Clinical Hospital in Moscow, the same hospital used by President Yeltsin, where rules were extremely strict, and thus a large team, that included an anesthesiologist, had to be in attendance at every fetal cell transplantation that IIBM carried out there. One year later the hospital changed this rule, since it was recognized that no reaction ever took place after the treatment, and so the attendance of an anesthesiologist, ready for re-animation, was terminated.


Our experience is in agreement with reports that cell transplantation from multiple donors has resulted in induction of tolerance in experimental models. VI.BIBLIOGRAPHY [181] When small number of islets from multiple histoincompatible donors are combined into one graft, then islets of each donor induce only a minimal immune response, that significantly prolongs their survival , and the clinical effect is substantially improved without increasing the overall immunogenicity. VI.BIBLIOGRAPHY [182] The above stated facts together with the growing body of U.S. literature about the diminished immune reaction as a result of ‘co-transplantation’, i.e. simultaneous use of tissue fragments of more than one organ or tissue for fetal precursor cell xeno-transplantation VI.BIBLIOGRAPHY [6, 23, 24, 25, 26, 27] gives strong support to this hypothesis.