Reprinted by permission from:
edited by
 J.A. Aarli, W.M.H. Behan & P.O. Behan, pp. 500-505,1987.Blackwell Scientific Publications, Oxford.

Neuroimmunomodulation: An approach to the
therapy of neurological diseases

W. Pierpaoli
Neuroimmunomodulation (NIM) has assumed its name and significance and received acceptance only recently (Spector 198o, Spector & Korneva 1981) but it is not a new medical discipline. The term 'psychoneuroimmunology' (PNI) has also been proposed (Ader 19 8 1), but this is in fact more restrictive, because the eponym 'neuro' can include psychological and behavioural aspects, while that of a 'psycho' induces one to believe that the subject concerns only the relationship between strictly psychological and behavioural disorders, and immunological abnormalities. In addition, the orientation and approach of investigators working in this interdisciplinary field of research, differ profoundly, depending on their original scientific training as a scientist or clinician in immunology, biochemistry, endocrinology, neurophysiology and so on. Thus the task of defining NIM is difficult. In the last analysis, the recent acceptance of NIM as a valid integrative science is based on clear-cut evidence of a bilateral connection between hormones and factors of the central and peripheral neuroendocrine system, and those tissues and cells of the immune system which lead to humoral and cell-mediated immune responses. For an overall view on NIM, the reader is referred to recent publications and reports (Ader 19 8 1, Guillemin et al. 19 8 5).
The immunological dogma of specificity
An immunologist's view of NIM can be quite different to that of an endocrinologist ora neurologist. The accepted, fundamental concepts in immunogenetics and cellularimmunology have led to an obvious scepticism towards NIM. In fact, while hormonesand 'factors' are certainly needed for amplification and the final expression of an immune reaction (e.g. the proliferation to T- and B-cells, the blastic transformation of lymphocytes, the secretion of lymphokines and so on) they do not induce, according to an immunologist's view, the appearance or formation of sterically and/or chemically-defined "receptors' on antigen-reactive cells. The appearance of antigenic determinants on specific antigen-sensitive cells is genetically programmed in a germ-line fashion. Hormones, on the other hand, simply modulate or condition the second-stage phase (differentiation, proliferation) of the hormone-independent, genetically determined, specific immunocytes (Cohn 1985, Pierpaoli et al. 1970). In the labyrinth of this semantic problem, the  immunologist's view is that a primary immune reaction may, in fact, take place in vitro without any connection with the central nervous system (CNS) (Cohn 1985). This, however, is a deceptively simplistic view which leads to the conclusion that, if a lymphocyte can react to an antigen, mature to a plasma cell in vitro and produce immunoglobulins, NIM is unnecessary for the expression of an immune response. Unfortunately, sensitization to antigens in vitro requires the presence of hundreds of 'factors' or 'hormones' which are in the medium. in which the immune cells are cultured. Those 'factors' are just those preformed products of the neuroendocrine system which are supplied 'ready for use' in the calf-serum added to the culture medium, and which allow a 'primary' immune response to take place (Ambrose 1970). In addition, it is most likely that emergence of germ-line antigenic determinants on precursors of immune cells also needs hormones. It may be, although this is not certain, that only binding of antigens to specific' receptors on immune cells does not require the presence of hormones (Ambrose 1970, Pierpaoli et al. 1970).

These considerations automatically lead the non-immunologist to conclude that the immune response is completely generated, expressed and amplified by the neuroendocrine microenvironment and the assumption that hormones constitute 'non-specific' participants of an immune response is a paradoxical assertion because, in fact, it has been known for many years that an immune response generated in vitro (primary immunization, inductive phase) cannot be evoked at all without the presence of at least some of the elements of the neuroendocrine system, the number of which is increasing daily. It is thus evident that the immune and neuroendocrine systems cannot co-exist, from conception to death, without constant interdependence (Jankovic et al. 1981, Pierpaoli 1981). This is demonstrated by the fact that antigenic confrontation with genetically different immune cells during ontogeny irreversibly changes neuroendocrine and immune recognition and regulation (Pierpaoli et al. 1977). Thus the assumption that there is dissociation between 'specific' and 'non-specific' elements in the development and performance of the immune system, is blatantly naive.
An immunologist's view of neuropathology
One of the questions we can ask is whether or not, in those syndromes or diseases of the central or peripheral nervous system in which immune reactions or autoimmune disorders are recognized, the immune or autoimmune manifestations precede or followed the onset of the symptoms and the overt clinical expression of the disease. From the NIM point of view, this is a crucial point for understanding the aetiology and pathogenesis of multiple sclerosis (MS), systemic lupus erythematosus (SLE) and many other diseases in which an immune or autoimmune component is recognized or suspected. Of course, the presence of active immunological processes is proof that the disorder is, in fact, an autoimmune disease, but it does not reveal anything about its aetiology.
Therefore, we must intervene with immunosuppressant, anti-inflammatory drugs and corticosteroids. Generally, the immunologist confines his attention to the actual immunological symptoms and does not consider those derangements and alterations which are combined with the neurological and immune disorders or may even have produced them. This is not to blame him, but is hardly useful in the cure or prevention of a disease. In fact, the 'immunological cure' would be, not the elimination of symptoms but the eradication of the cause, by, for instance, the induction of specific tolerance to auto-antigens, a kind of 'reversal' of the cause of the disease. Thus, we must try to understand whether the 'immune' disease is indeed a side-effect or a by-product of another, or several, concomitant acute or chronic derangements of other organs, tissues or cells.
Neuropathology from the viewpoint of neuroimmunomodulation
lf we hypothesize that some or most neurological diseases may be derived from other than primary disorders of the immune system, we might be able to evaluate those diseases from a new viewpoint. How far are pathological affections of the nervous system with immunological disorders only a consequence of primary disorders of other systems? Very often, in neurological diseases there is an enormous variety of symptoms and alterations which affect other organs. All this constellation of diseases with a huge variety of symptoms can hardly be attributed to a primary immune disorder. Thus, the best confirmation for the validity of the NIM approach to neurological diseases is the pathological picture. The fact that an immune or autoimmune process is recognized as such is not proof for classification of the disease as 'autoimmune'. This applies to most neurological affections like MS and to diseases of the skin like SLE, psoriasis and others. Strangely enough, in most cases immunological alterations have been viewed as the cause and not the consequence of a neurological disease. In fact we think that, as is commonly the case in other systemic diseases with immune alterations which are cured by immunosuppressíve drugs and corticosteroids, e.g. SLE and rheumatoid arthritis, many neurological diseases may be initiated by a primary derangement of neuroendocrine regulation which is unobserved and yet determines the onset of the immune disorder. Most patients go to the doctor when they already have symptoms and, as mentioned in the previous section, the symptoms are then analysed and treated, mainly with drugs aiming at eliminating the actual pains and the local or general manifestations. Put differently, however, a clinician could not act otherwise. The same is true when we cure  cancer, arteriosclerosis or even infectious diseases.

The NIM view of neurological diseases is different. Why should we cure only the symptoms? What prevents us from trying new therapies based on observations of animal models of accompanying family alterations, and of all those anomalies which precede onset of the disease? The timing of appearance of a neurological disease among the members of the same family may help us to recognize those symptoms which precede the manifestation of the disease. Why do we not consider more carefully the fact that the immune system is totally dependent on neuroendocrine regulation? Why do we not analyse systematically the possible derangements of hypothalamic, pituitary, adrenal,  gonadal or thyroid function? Again, the way to a 'physiological therapy' is deceptively simple, to the point of being naive.
Possible nim intervention in neurohormonal derangements and autoimmune processes in neuropathology
It is now firmly established that bi-directional connections and signals link the neuroendocrine and immune systems. This reciprocal relationship has been demonstrated by a large variety of models in developing and mature organisms (Jankovic et al. 1981, Pierpaoli 1981, Pierpaoli & Besedovsky 1975, Pierpaoli et al. 1970, Pierpaoli et al. 1977). It is especially noteworthy that such bidirectional links are established very early in ontogeny and constitute a basic aspect of the final brain programming for neuroendocrine and immune functions in the adult (Pierpaoli 1981). Mature cells of the immune system, carrying on their surface antigenic determinants which are different to those of the host allotype (alloantigens), when injected into immunologically and endocrinologically immature recipients produce an irreversible change (tolerance) to the immune-recognition apparatus of the recipient (allotolerance to tissues and cells of the donor) and, at the same time, permanent changes of neuroendocrine regulation as expressed by hormone levels in blood (Pierpaoli et al. 1977). Thus the two-way circuit seems to be established very early in ontogeny and to constitute an integral part of the system by which the organism distinguishes 'self' from 'non-self'. Construction of immune responsiveness is thus a part of the early brain programming for immune responsiveness and endocrine regulation (Pierpaoli et al. 1977).On the other hand, at the anatomical, morphological and ultrastructural levels also, an intimate connection exists between central and peripheral nervous tissues and the cells of the lymphohaemopoietic organs like the thymus, the spleen, the bone marrow and lymph nodes (Bulloch 1985, Zetterstroem et al. 1973). Immunological signals are detected immediately by the neuroendocrine system, in particular by the gonadal adrenal system (Maestroni & Pierpaoli 1981). This suggests strongly a close link between those cells, tissues and hormones involved in reproduction physiology and in maintenance of self (immunity, resistance to infectious agents or an 'intruder'). We have proposed, however, that maintenance of 'self' by immune resistance became subordinate to maintenance of self by reproduction on an evolutionary scale (Pierpaoli 1981).

There is an extraordinary variety of neurological, behavioural and endocrine alterations and disorders in animal models, or in humans, before the onset or during the course of autoimmune diseases, including those of the central and peripheral nervous system in which an immune or autoimmune component is recognized. As mentioned in the previous sections, however, the main attention has been devoted to the presence, expression, detection, measurements and cure of the immunological symptoms. Most typically, the use of corticosteroids is generally accepted as a means of curing symptoms in many autoimmune diseases. Unfortunately, until recent discoveries in neuro-endocrinology and pharmacology and the development of new psychomimetic drugs, an NIM approach to the cure of autoimmune diseases affecting the neural system, and based on possible elimination or diminution of persisting neuroendocrine derangements rather than relief of immune symptoms, was not feasible. Nowadays, one can aim at early detection of possible endocrine derangements in the initial phase of neurological diseases, by systematic measurements of basal levels of hormones in blood, analysis of the function of endocrine glands and detection of specific deficiencies or increases in production of hormones. These findings would indicate the necessity for intervention with replacement therapy, the use of promoters or inhibitors of hormone synthesis or release, the use of antagonists to hormone receptors, or of some of the increasing variety of drugs acting on the CNS and affecting the production or function of neurotransmitters or hormones.It may be that one cannot cure an immune deficiency or an autoimmune disease once it is established, or reverse its course. We may succeed in diminishing the intensity of the symptoms however, by affecting immunological (lymphomonokines, interferons, etc.) or humoral factors (neurotransmitters, hormone-releasing and inhibitory agents, polypeptide hormones, and so on), rather than controlling their targets, namely the immune celIs whose secretory products, in the last analysis, produce the morphological alterations in neurological diseases. Nowadays, the distinction between the celIs and factors of the immune and neural systems is becoming more and more artificial: cells of the immune system are apparently able to produce hormones which were formerly considered to be produced only by certain endocrine glands (Smith et al. 1982) while celIs of the neural system can all produce those factors, like interleukins, which are secreted by ìymphocytes (Fontana et al., 1982).
To summarize, an approach to the cure of neurological discases via neuroimmunomodulation, aims at specific intervention on those primary neuroendocrine derangements which undoubtedly promote and/or affect the onset and maintenance of immune disorders linked to a number of neurological diseases, such as MS, myasthenia gravis, idiopathic polymyositis, polyneuritis and other immune-related neuropathies.
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