Serrate1-induced notch signalling regulates the decision between immunity and tolerance made by peripheral CD4(+) T cells.

Signals derived from antigen-presenting cells (APC) influence the functional differentiation of CD4(+) T cells. We report here that Serrate1 (Jagged1), a ligand for the Notch1 receptor, may contribute to the differentiation of peripheral CD4(+) T cells into either helper or regulatory cells. Our findings demonstrate that antigen presented by murine APC overexpressing human Serrate1 induces naive peripheral CD4(+) T cells to become regulatory cells. These cells can inhibit primary and secondary immune responses, and transfer antigen-specific tolerance to recipient mice. Our results show that Notch signalling may help explain 'linked' suppression in peripheral tolerance, whereby tolerance induced to one epitope encompasses all epitopes on that antigen during the course of an immune response.

Tissue damage in cattle infected with Theileria annulata accompanied by metastasis of cytokine-producing, schizont-infected mononuclear phagocytes.

The distribution of schizont-infected cells in six calves undergoing acute, lethal sporozoite-induced infections with Theileria annulata was examined, the calves being killed in the early, middle or late stages of disease. A combination of histological and immunocytochemical techniques showed that schizont-infected cells became disseminated rapidly through the lymphoid tissues from the prescapular lymph node draining the site of inoculation to distant lymph nodes (e.g., precrural, mesenteric and mediastinal) and to the spleen and thymus. The parasitized cells also spread rapidly into non-lymphoid organs, being found in the liver, kidney, lung, abomasum, adrenal glands and pituitary gland by day 7, in the brain by day 12 and in the heart by day 14 after infection. As infection progressed, the schizonts differentiated into merozoites. By the late stages of disease, the cells containing merozoites greatly out-numbered schizont-infected cells. The parasitized mononuclear cells were labelled by antibodies to bovine interferon-alpha1 and tumour necrosis factor-alpha and, during the later stages of the disease, contained erythrocytes parasitized by piroplasms. The results suggested that the parasitized mononuclear cells themselves played a role in the development of clinical disease and in tissue damage. These findings provide new evidence that tropical theileriosis can no longer be viewed as a lymphoproliferative disease resulting from the uncontrolled multiplication and metastasis of lymphoid cells infected with T. annulata schizonts, but is caused by a parasite that lives in, and is disseminated by, cytokine-secreting, proliferating mononuclear phagocytes.

Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome.

BACKGROUND: Chronic fatigue syndrome (CFS) is a disorder of unknown etiology, consisting of prolonged, debilitating fatigue, and a multitude of symptoms including neurocognitive dysfunction, flu-like symptoms, myalgia, weakness, arthralgia, low-grade fever, sore throat, headache, sleep disturbances, and swelling and tenderness of lymph nodes. No effective treatment for CFS is known. OBJECTIVE: The purpose of the study was to evaluate the efficacy of the reduced form of nicotinamide adenine dinucleotide (NADH) i.e., ENADA the stabilized oral absorbable form, in a randomized, double-blind, placebo-controlled crossover study in patients with CFS. Nicotinamide adenine dinucleotide is known to trigger energy production through ATP generation which may form the basis of its potential effects. METHODS: Twenty-six eligible patients who fulfilled the Center for Disease Control and Prevention criteria for CFS completed the study. Medical history, physical examination, laboratory studies, and questionnaire were obtained at baseline, 4, 8, and 12 weeks. Subjects were randomly assigned to receive either 10 mg of NADH or placebo for a 4-week period. Following a 4-week washout period, subjects were crossed to the alternate regimen for a final 4-week period. RESULTS: No severe adverse effects were observed related to the study drug. Within this cohort of 26 patients, 8 of 26 (31%) responded favorably to NADH in contrast to 2 of 26 (8%) to placebo. Based upon these encouraging results we have decided to conduct an open-label study in a larger cohort of patients. CONCLUSION: Collectively, the results of this pilot study indicate that NADH may be a valuable adjunctive therapy in the management of the chronic fatigue syndrome and suggest that further clinical trials be performed to establish its efficacy in this clinically perplexing disorder.

Induction of tolerance via the respiratory mucosa.

Immunological tolerance is defined as a state of specific non-responsiveness to a particular antigen induced by previous exposure to that same antigen. The mucosal surfaces comprise the upper and lower respiratory tracts, the gastrointestinal tract and the urogenitary tract, and are a major site of antigenic challenge. The immune system associated with the mucosa has the extraordinary potential to discriminate between antigens that are harmless (e.g. inhaled and dietary antigens) and those that are associated with pathogens. Normally soluble proteins delivered through the mucosal surfaces do not elicit a strong systemic immune response but instead induce a transient local immune response that is replaced by long-term peripheral unresponsiveness this is termed mucosal tolerance. The phenomenon of oral tolerance is well established and considerable attention has focussed on defining the underlying mechanisms. However, only comparatively recently was the induction of tolerance via the respiratory mucosa described, and it is this form of mucosal tolerance which forms the basis of this review.

Nitric oxide causes the macroschizonts of Theileria annulata to disappear and host cells to become apoptotic.

The proliferation of Theileria annulata macroschizont-infected cell lines in vitro was significantly inhibited by nitric oxide (NO) generated by S-nitroso-N-acetyl-DL-penicillamine (SNAP). Incubation with SNAP caused the macroschizonts to disappear and host cells to become apoptotic. SNAP-derived NO also significantly inhibited the incorporation of tritiated thymidine by cultures of cells in which the schizonts had been induced to differentiate into merozoites by maintenance at 41 degrees C instead of 37 degrees C, the temperature used for culturing macroschizont-infected cells. These results point to NO as the mediator of macrophage anti-T. annulata activity and provide new evidence that the protective immune mechanisms which allow cattle to recover from primary infection and resist challenge may be attributed principally to the products of activated macrophages. These findings indicate that effective inactivated vaccines against T. annulata should include antigens able to stimulate the type of CD4+ T cell response which elicits macrophage activation and NO synthesis.

Bovine cells infected in vivo with Theileria annulata express CD11b, the C3bi complement receptor.

Bovine cells from cattle infected with Theileria annulata were phenotyped with monoclonal antibodies recognizing bovine leukocyte antigens. Macroschizont-infected, transformed cell lines prepared from peripheral blood mononuclear cells of cattle, infected with sporozoites, were assessed by flow cytometry; parasitized cells in tissues from infected cattle were examined by immunocytochemical techniques. Co-expression of markers for different cell lineages by the cell lines precluded a definite conclusion as to their phenotypic origins. For, while the pattern of leukocyte antigens expressed by these in vivo-derived schizont-infected cells, which included CD11b, was indicative of a myeloid origin, the possibility that they were NK cells could not be excluded. The monoclonal antibody (MAb) IL-A15, which recognizes CD11b, reacted with a high proportion of parasitized cells in sections of tissues from infected cattle at all stages of acute disease. Mononuclear cells infected with parasites at all stages of differentiation, from macroschizont to microschizont, expressed CD11b. Such parasitized cells occurred throughout the lymphoid tissues, being found in the thymus, spleen and lymph nodes, particularly the prescapular node draining the site of infection, the hepatic, mesenteric and precrural nodes, as well as in the reticulo-endothelial tissue of the liver, kidney, lung, abomasum, adrenal and pituitary glands. These observations provided the first evidence for a myeloid origin for the parasitized T. annulata cells found in infected bovine tissues and blood and suggested a mechanism whereby schizonts could transfer from cell to cell during mechanical infection with schizont-infected cells.

Bactericidal activity in the pig roundworm Ascaris suum.

A potent, humoral, bactericidal activity against Micrococcus luteus was discovered in pseudocoelomic fluid of the pig roundworm, Ascaris suum. The activity, which was not bacteriolytic, was not due to lysozyme or to a dietary antibiotic. It was not inactivated by exposure to 100 degrees C, to low or high pH, or to ethanol. Dialysis, electrophoresis and agar-diffusion experiments suggested that the main antibacterial activity in the fluid was associated with a basic substance of molecular weight somewhat less than 14,000 Da. Two other Gram-positive organisms, Bacillus megaterium and Staphylococcus aureus, were also killed by the Ascaris fluid, but the Gram-negative Escherichia coli, Proteus vulgaris and Bordetella bronchiseptica were insensitive.