Istvan Berczi

Immunomodulation by bromocriptine

Treatment of rats with the dopaminergic ergot alkaloid bromocriptine (BRC) inhibited the following immune reactions: contact sensitivity skin reaction to dinitrochlorobenzene (DNCB); antibody formation to sheep red blood cells and to bacterial lipopolysaccharide; adjuvant arthritis; and experimental allergic encephalitis. Immunosuppressive doses of BRC (5 mg/kg) decreased the serum prolactin (PRL) levels from 84.8 +/- 15.9 ng/ml to 4.9 +/- 1.6 ng/ml. Further studies on DNCB contact sensitivity and on antibody formation revealed that the immunocompetence of BRC-suppressed animals could be restored by additional treatment with either prolactin (PRL) or growth hormone (GH). Treatment with adrenocorticotropic hormone antagonized the restoring effect of PRL and GH. These results suggest that BRC suppressed immunity by its inhibition of PRL, and possibly also by inhibition of GH secretion.

The immune effects of neuropeptides

Current evidence indicates that the neuroendocrine system is the highest regulator of immune/inflammatory reactions. Prolactin and growth hormone stimulate the production of leukocytes, including lymphocytes, and maintain immunocompetence. The hypothalamus-pituitary-adrenal axis constitutes the most powerful circuit regulating the immune system. The neuropeptides constituting this axis, namely corticotrophin releasing factor, adrenocorticotrophic hormone, alpha-melanocyte stimulating hormone, and beta-endorphin are powerful immunoregulators, which have a direct regulatory effect on lymphoid cells, regulating immune reactions by the stimulation of immunoregulatory hormones (glucocorticoids) and also by acting on the central nervous system which in turn generates immunoregulatory nerve impulses. Peptidergic nerves are major regulators of the inflammatory response. Substance P and calcitonin gene-related peptide are pro-inflammatory mediators and somatostatin is anti-inflammatory. The neuroendocrine regulation of the inflammatory response is of major significance from the point of view of immune homeostasis. Malfunction of this circuit leads to disease and often is life-threatening. The immune system emits signals towards the neuroendocrine system by cytokine mediators which reach significant blood levels (cytokine-hormones) during systemic immune/inflammatory reactions. Interleukin-1, -6, and TNF-alpha are the major cytokine hormones mediating the acute phase response. These cytokines induce profound neuroendocrine and metabolic changes by interacting with the central nervous system and with many other organs and tissues in the body. Corticotrophin releasing factor functions under these conditions as a major co-ordinator of the response and is responsible for activating the ACTH-adrenal axis for regulating fever and for other CNS effects leading to a sympathetic outflow. Increased ACTH secretion leads to glucocorticoid production. alpha-melanocyte stimulating hormone functions under these conditions as a cytokine antagonist and an anti-pyretic hormone. The sympathetic outflow, in conjunction with increased adrenal activity. leads to the elevation of catecholamines in the bloodstream and in tissues. Current evidence suggests that neuroimmune mechanisms are essential in normal physiology, such as tissue turnover, involution, atrophy, intestinal function, and reproduction. Host defence against infection, trauma and shock relies heavily on the neuroimmunoregulatory network. Moreover, abnormalities of neuroimmunoregulation contribute to the aetiology of autoimmune disease, chronic inflammatory disease, immunodeficiency, allergy, and asthma. Finally, neuroimmune mechanisms play an important role in regeneration and healing.

Pituitary dependence of bone marrow function

Summary. The anaemia, leucopenia, thrombocytopenia and impaired DNA and RNA synthesis in the bone marrow of hypophysectomized rats could be restored by syngeneic pituitary grafts placed under the kidney capsule, or by treatments with ovine or bovine prolactin or growth hormone. Treatment with ACTH, FSH, LH and TSH had no effect in this respect. These results indicate that bone marrow function is regulated by the pituitary gland.

The Submandibular Gland: A Key Organ in the Neuro-Immuno-Regulatory Network?

The evidence for the integration of the submandibular gland (SMG) into the neuroimmunoregulatory network has been reviewed. In laboratory rodents, factors extracted from the SMG were shown to stimulate lymphocyte proliferation, to affect the weight of the thymus, spleen and lymph nodes and to induce immunosuppression in several in vivo animal models. The SMG produces significant quantities of nerve growth factor (NGF), epidermal growth factor (EGF), transforming growth factor-beta and kallikreins, which are secreted into the saliva and affect immune and mucosal tissues and nerve endings in the gastrointestinal tract. These factors play a role in regulating mucosal immuno/inflammatory response and in regeneration and healing. The major salivary glands also produce antimicrobial proteins and secretory IgA antibodies which are essential factors in mucosal host defense. SMG-derived NGF, EGF and glandular kallikrein are delivered into the bloodstream where they may act as important systemic immunoregulators and also have major regulatory influences on the central neuroendocrine system. There is evidence to indicate that EGF is involved in the regulation of gonadal function. Growth hormone, prolactin, androgens, thyroid hormone and corticosteroids regulate protein synthesis in the SMG, whereas secretory activity is regulated by sympathetic (alpha- and beta-adrenergic) parasympathetic (muscarinic) and peptidergic (substance P and vasoactive intestinal peptide) nerve fibers. Fluid and electrolyte secretion is promoted by parasympathetic, whereas protein secretion is stimulated by sympathetic nerve impulses. Steroid hormones and cytokines (interleukin-1 alpha, -beta, tumor necrosis factor, interferon-gamma) have a major regulatory influence on protein secretion, including the secretion of immunoglobulin into the saliva. The SMG interacts with the mucosal and systemic compartments of the immune system, with the central and peripheral nervous systems, with the pituitary gland, and with peripheral endocrine organs. These interactions enable the SMG to exert regulatory influences on immune/inflammatory reactions in the gastrointestinal tract, in the lungs, and possibly elsewhere. It is suggested that these functions make this gland a key regulatory organ in the neuroimmunoregulatory network. Evidence is increasing that the major salivary glands fulfill similar functions in other species, including humans.

Neuroimmune Regulation in Immunocompetence, Acute Illness, and Healing

Adaptive immunocompetence is maintained by growth hormone (GH), prolactin (PRL), and vasopressin (VP). Innate or natural immunocompetence depends on cytokines, hormones (especially of the hypothalamus–pituitary–adrenal axis), and catecholamines. The acute phase response (APR, or acute febrile illness) is an emergency defense reaction whereby the adaptive, T cell–dependent, immune reactions are suppressed and the innate immune function is dramatically amplified. Infection and various forms of injury induce APR. Cytokines [interleukin (IL)‐1β, tumor necrosis factor‐α, and IL‐6] stimulate corticotropin‐releasing hormone (CRH) and VP secretion and cause a “sympathetic outflow.” Colony‐stimulating factors activate leukocytes. CRH is a powerful activator of the pituitary adrenocortical axis and elevates glucocorticoid (GC) levels. Cytokines, GCs, and catecholamines play fundamental roles in the amplification of natural immune defense mechanisms. VP supports the APR at this stage. However, VP remains active and is elevated for a longer period than is CRH. VP, but not CRH, is elevated during chronic inflammatory diseases. VP controls adaptive immune function and stimulates adrenocorticotropic hormone (ACTH) and PRL secretion. PRL maintains the function of the thymus and of the T cell–dependent adaptive immune system. The ACTH–adrenal axis stimulates natural immunity and of suppressor/regulatory T cells, which suppress the adaptive immune system. VP also has a direct effect on lymphoid cells, the significance of which remains to be elucidated. It is suggested that VP regulates the process of recovery from acute illness.

Neuro-hormonal host defence in endotoxin shock

The sensitivity (LD100) of mice to lipopolysaccharide (LPS) endotoxin and to its toxic moiety, lipid A (LA), increased 500-fold after adrenalectomy (ADX). Inhibition of glucocorticoid synthesis in intact mice by metyrapone had a similar, though less dramatic, sensitizing effect to LPS. In ADX mice, the serum level of tumor necrosis factor-alpha (TNF) was 40-60 times higher than that in controls at 2 h after LPS/LA treatment. In intact mice the serum corticosterone level fell 1 h after lipid A injection to below detectable levels, which was followed by a brisk increase reaching the peak level of 48-50 micrograms/100 ml at 2 h. Both TNF production and the lethal effect of PLS/LA could be inhibited in ADX mice by glucocorticoid treatment. Plasma prolactin was increased significantly 1 h after endotoxin administration in both intact and ADX animals.

Pituitary Hormones and Contact Sensitivity in Rats

Hypophysectomized (Hypo‐X) rats do not develop contact sensitivity to dinitrochlorobenzene (DNCB). Daily treatment with prolactin or growth hormone completely restores the DNCB‐reactivity of Hypo‐X animals. Treatment of such animals with ACTH, FSH, LH, TSH or HCG has no restoring potential. Treatment with ACTH in addition to prolactin or growth hormone antagonizes restoration of Hypo‐X rats. These experiments indicate that the pituitary gland has the potential of regulating contact sensitivity.

Modulation of natural killer cell-mediated cytotoxicity by tamoxifen and estradiol.

Background. The nonsteroidal antiestrogenic drug, tamoxifen, inhibits the growth of estrogen receptor‐positive tumors by interfering with the growth‐stimulatory effect of estradiol. However, there is compelling evidence that tamoxifen treatment also is beneficial for patients with estrogen receptor‐negative tumors. The hypothesis that tamoxifen is capable of enhancing the immunologic defense of tumor‐bearing hosts was been investigated as a possible method for targeting receptor‐negative neoplasms.

The Stress Concept and Neuroimmunoregulation in Modern Biology

Sixty years ago Hans Selye discovered that the neuroendocrine and immune systems interact during stress. The pathophysiological significance of neuroendocrine-immune interaction during injury has only been recognized recently. Today it is rapidly emerging that, in addition to defense against exogenous pathogenic agents, the immune system plays a key role in host defense against injury. During acute-phase reactions to infection/injury, when there is no time to mount a specific immune response, the neuroimmunoregulatory network suppresses specific immunity while rapidly elevating the production of acute-phase proteins (APP) in the liver. APP recognize microbes and abnormal cells/tissues and activates the immune system nonspecifically to fight infection or injury. There is a remarkable similarity between the stress syndrome as outlined by Selye in 1946 and the acute-phase response as we know it today. Moreover, it is becoming clear that the immune system participates in the normal physiological regulation of the body, which was also recognized by Selye in his later years. Although with much delay, the scientific community is beginning to fully appreciate Selyes ingenious discoveries which were far ahead of his time.

Natural Immunity and Neuroimmune Host Defense

Abstract: Innate resistance is mediated by non‐immune defense and by natural immunity. Non‐immune defense includes diverse mechanisms (e.g., physico‐chemical defense by bile acids). Natural killer (NK) cells, γδ T lymphocytes and CD5+ B lymphocytes are key mediators of natural immunity. These cells utilize germ‐line coded receptors that recognize highly conserved, homologous epitopes (homotopes). Typically, it is not the antigen, but cytokines and hormones that regulate the level of NK‐mediated cytotoxicity. These include interleukin‐2, interferons, prolactin and growth hormone. Less is known about γδ T lymphocytes. CD5+ B lymphocytes produce germ‐line coded antibodies (predominantly IgM) that are polyspecific, and able to recognize a great variety of microorganisms, cancer cells and self‐components. Antigen is not an effective stimulus for natural antibody (NAb), but bacterial lipopolysaccharide (LPS) is. During the acute phase response (febrile illness) the T‐cell‐regulated adaptive immune response is switched off and natural immune mechanisms are amplified several hundred to a thousand times within 24‐48 hours (immunoconversion). This immunoconversion is initiated by immune‐derived cytokines, and involves profound neuroendocrine and metabolic changes, all in the interest of host defense. Immune recognition is assured by natural antibodies and by some liver‐derived acute phase proteins, such as C‐reactive protein or endotoxin‐binding protein, the level of which is elevated in the serum. Thus, natural immunity is essential for a first and last line of defense and the neuroendocrine system is an important promoter of this activity.