Eva Nagy

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.

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.

Immunomodulation by tamoxifen and pergolide

Treatment of rats with tamoxifen citrate or pergolide mesylate was as effective in inhibiting antibody formation and contact sensitivity skin reactions as was hypophysectomy. The immunocompetence of tamoxifen citrate- and pergolide mesylate-suppressed animals could be fully restored by additional treatment with prolactin or growth hormone.

Growth inhibition of murine mammary carcinoma by monoclonal IgE antibodies specific for the mammary tumor virus.

SummaryTwo IgE-producing hybridomas were established from spleen cells of Balb/c mice, which had been immunized with mouse mammary tumor virus (MMTV). These IgE monoclonal antibodies (mAbs) reacted specifically with the major envelope glycoprotein (gp36) of MMTV, as established by the immunoblot assay and by passive cutaneous anaphylaxis. The effect of the IgE mAbs (produced by clone A8) on the growth of the MMTV-secreting mammary adenocarcinoma H2712 was investigated in syngeneic C3H/HeJ mice. The mice were inoculated s.c. with either 105 (≈100 × LD50) or 106 (≈1000 × LD50) tumor cells and received repeated i.p. injections of 25 µg anti-gp36 IgE mAbs at 4-day intervals for 8 weeks. This treatment prevented the development of subcutaneous tumors in 50% of the animals. Similar protection was observed when the tumor cells (105/animal) were injected i.p. 4 days prior to the beginning of the i.p. treatment consisting of injections of 25 µg mAbs at 4-day intervals for 6 weeks. However, these mAbs did not protect C3H/HeJ mice against the MMTV-negative MA16/c carcinoma cells. Hence, these results support the view that IgE-mediated cytotoxic mechanisms may play an immunologically specific antitumor surveillance role and that laboratory-induced antitumor IgE mAbs have the potential of specific therapeutic agents for in vivo destruction of tumor cells.

Prolactin and Contact Sensitivity

Hypophysectomized (Hypo‐X) rats did not develop contact dermatitis in response to dinitrochlorobenzene (DNCB). Syngeneic pituitary grafts placed under the kidney capsule or daily treatment with prolactin restored the DNCB‐reactivity of Hypo‐X animals. Combined treatment with other pituitary hormones was ineffective. Treatment of normal rats with a potent prolactin antagonist drug, bromocriptine, was as effective in inhibiting contact sensitivity as was hypophysectomy. These results indicate that contact sensitivity is a prolactin dependent reaction.

Effects of Hypophysectomy on Immune Function

This chapter discusses the effects of hypophysectomy on immune function. The complete removal of the hypophysis leads to decreased cellularity of the bone marrow, atrophy of lymphoid organs, and arrest of nucleic acid synthesis in bone marrow, thymus, and spleen. These changes are associated with a progressive deterioration of hemopoiesis and a general immunodeficiency. Partial or complete absence of these symptoms occurs if hypophysectomy is incomplete. Both hemopoiesis and immunocompetence can be restored in hypophysectomized animals by syngeneic pituitary grafts or with proper doses of GH, prolactin, or placental lactogen. The role of the pituitary gland in immunoregulation is emphasized further by the demonstration in several laboratories that the leukocyte derived mediator interleukin-1 (IL-1) is capable of effecting pituitary hormone release. Interleukin-1 is very efficient in stimulating the release of ACTH through the activation of CRF secretion by the hypothalamus. If the immune system is activated beyond a certain level, which occurs frequently during infections, body temperature will also rise, owing to the action of IL-1 on heat regulatory centers of the brain. Furthermore, IL-1 has been demonstrated to induce acute-phase proteins in the liver, to influence glucose metabolism, to trigger protein degradation in muscle, and to affect bone metabolism, all of which may be viewed as important changes for successfully combating infection.

Placental lactogen is a haemopoietic hormone

The anaemia and thrombocytopenia of hypophysectomized (Hypox) rats could be corrected readily by daily treatment with human placental lactogen. Spontaneous DNA synthesis in the bone marrow of Hypox rats was grossly impaired, which was also normalized by placental lactogen. Human placental lactogen exerted a direct mitogenic effect on rat bone marrow cells in vitro. These results indicate that placental lactogen is a potent haemopoietic hormone.