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Antibody formation to sheep red blood cells and the development of contact dermatitis in response to dinitrochlorobenzene are impaired in hypophysectomized (Hypo-X) rats. Rat prolactin, rat growth hormone, bovine prolactin, bovine growth hormone, human placental lactogen and human growth hormone all restored the immunological competence of Hypo-X animals. The possible mechanism of action of these hormones on immune reactions is discussed.

Lipopolysaccharide (LPS) of gram-negative bacteria is capable of activating the immune system of higher animals, which may lead to cytokine-induced lethal shock and death. LPS has little toxicity for the frog and fish, but it kills the horseshoe crab instantly by causing intravascular blood coagulation. The response to LPS evolved from simple reactions in lower animals into an intense reaction in mammals that involves a massive immune activation leading to a profound neuroendocrine and metabolic response. This is now known as the acute-phase response (APR). During APR, LPS-binding proteins (LBP) are produced by the liver in rapidly increasing quantities under the influence of interleukin-6, glucocorticoids, and catecholamines. After combination with LPS, LPB is capable of activating monocyte-macrophages and granulocytes via the CD14 surface receptor. Other receptors (CD18, 80-kDa receptor) allow for direct action by LPS of phagocytes, B and T lymphocytes, and other cells. Numerous other acute-phase proteins are produced in the liver, including C-reactive protein, complement components, fibrinogen, enzyme inhibitors, and anti-inflammatory proteins. Similar responses may be stimulated by subtoxic doses of LPS or by detoxified LPS, which manifest in endotoxin tolerance. Tolerant animals and man show increased resistance to LPS, to infections, and to various noxious insults. Infection and various forms of tissue injury are also capable of causing APR. There is much evidence to indicate that APR, which manifests in febrile illness, is an efficient host defense reaction. It is an emergency response in cases where specific immunity fails to protect the host. Therefore, the neuroimmunoregulatory network converts the immune system to a less specific, but rapid and more efficient response, APR. The hypothesis is presented that intestinal LPS serves to amplify the APR in response to various insults, which contribute to host defense, regeneration, and healing.

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Abstract. Hypophysectomized female Fischer 344 and Wistar-Furth rats had severely impaired primary and secondary antibody responses to sheep red blood cells (SRBC). Mercaptoethanol-sensitive (IgM) and mercaptoethanol-resistant (IgG) antibodies were similarly affected. Titers to E. Coli 055:B5 lipopolysaccharide were also significantly decreased in such animals. The antibody response of hypophysectomized rats could be restored by syngeneic pituitary grafts when placed under the kidney capsule or by prolactin treatment. Growth hormone was less effective in this respect than prolactin. Treatment of normal rats with ACTH suppressed their antibody formation to SRBC. These results indicate that the pituitary gland has the potential to regulate humoral immune responses.

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-β 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 (α- and β-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-1α, -β, tumor necrosis factor, interferon-γ) 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.

The response of hypophysectomized, sham-operated and non-operated female Fischer 344 and Wistar-Furth rats was compared to various antigenic stimuli. Antibody production against sheep red blood cells, skin response to dinitrochlorobenzene and the development of adjuvant arthritis after treatment with Freund's complete adjuvant were all markedly suppressed in hypophysectomized animals. Sham-operated rats responded as well as did non-operated controls. Skin graft survival was also prolonged in hypophysectomized rats when compared to controls. These results indicate that the pituitary gland plays an important role in immune reactions.

Hypophysectomized (Hypox) female Fischer 344 rats had 10-20% lactogenic activity in their serum when compared to controls by the Nb2 lymphoma proliferation assay. If such animals were treated daily with a rabbit antirat PRL serum, their serum lactogenic activity diminished further; severe anemia and immunological anergy developed; and death occurred within 8 weeks. In contrast, untreated Hypox animals increased gradually their serum lactogenic activity, starting on the 7th week after pituitary removal, which rose up to 50% of control levels by week 9. Hypox animals showed normochromic normocytic anemia, a grossly reduced immunocompetence, decreased body, thymus, spleen, adrenal, and ovary weights, and decreased DNA and RNA synthesis in the thymus, spleen, and bone marrow. However, the condition of Hypox animals did not deteriorate further over the 9-week experimental period. All the hematological deficiencies and decrease in organ weights observed in Hypox rats were normalized after grafting with syngeneic pituitaries (SPG). These effects of SPG could be inhibited by additional treatment with antirat PRL serum. Treatment of Hypox animals with ovine PRL had a restoring effect similar to SPG, which was not inhibited by additional antirat PRL serum treatment. Rat and ovine PRL and GH and human placental lactogen all stimulated the incorporation of 3H-thymidine by rat bone marrow cells in vitro. These results indicate that PRL has a multiple trophic effect and is capable of maintaining vital bodily functions for long periods of time.