Migration Inhibitory Factor and Interferon in the Circulation of Mice with Delayed Hypersensitivity

Abstract

When mice infected with Mycobacterium tuberculosis strain BCG were inoculated intravenously with old tuberculin (OT) or living BCG cells, both migration inhibitory factor (MIF) and interferon appeared in the circulation within a few hours. In such animals, which showed delayed hypersensitivity by footpad tests, as little as 1.5 mg of OT or as few as 1.7 x 106 bacteria per mouse were capable of eliciting circulating MIF and interferon. Uninfected animals inoculated with large doses of OT or living BCG cells did not produce MIF or interferon. When nonspecific stimuli such as bacterial lipopolysaccharide (LPS; from Salmonella typhimurium strain LT-2), heat-killed Brucella abortus, Newcastle disease virus (NDV), and polyinosinic acid: polycytidilic acid (poly I: C) were inoculated intravenously into BCG-infected mice, MIF was produced in the circulation of animals challenged with LPS or Brucella but not in those challenged with NDV or poly I: C, although all the stimuli were capable of eliciting an interferon response. The interferon elicited in BCG-infected mice by specific antigen differed in at least one important property from the viral inhibitor produced by the nonspecific stimuli. The interferon which appeared after injection of OT or living BCG cells was destroyed by treatment at pH 2 for 24 hr at 4C, whereas the interferons produced after injection of the nonspecific stimuli were stable under the same conditions. The MIF activity in plasma from sensitized mice inoculated with specific antigen was also destroyed by treatment at pH 2. When mouse plasma containing both MIF and interferon activity was filtered through Sephadex G-100, both mediators were excluded in the same peak fractions. Sensitization of mice with complete Freund adjuvant instead of infection with BCG cells produces a different pattern of response. Although hypersensitive to specific antigen by footpad swelling tests, mice sensitized with complete Freund adjuvant failed to produce MIF or interferon when they were inoculated intravenously with OT or living BCG cells.

Interferon‐gamma and resistance to bacterial infections

“…When the interferon that is now known as IFN-y was originally described as being induced by a mitogen in 1965 (1 15), it was thought that only a new technique for induction of interferon had been discovered. As time progressed and further characterization of the interferons occurred, it became clear that IFN-y was a unique class of interferon with special antigenic and physical-chemical properties and was produced by T lymphocytes and natural killer cells as part of an immune response (94,95,105,120).…”

Mice that lack the interferon-gamma receptor have profoundly altered responses to infection with Bacillus Calmette-Guérin and subsequent challenge with lipopolysaccharide.

“…E xperimental infection of mice with the avirulent Bacillus Calmette-Gu~rin (BCG) vaccine strain of Mycobacteriurn bovis represents a well-established model for the study of cellular immune responses. Among the alterations in immune responses seen in mice with BCG infection are increased resistance to homologous and heterologous intracellular infectious agents (1,2), enhanced resistance to transplantable tumors (3), increased production of a number of cytokines including TNF-ot (4), IFN-c~/~ (5), and IFN-7 (6), and greatly increased sensitivity to the lethal action of LPS (7). Although mouse strains differ in the degree of resistance to BCG infection (8,9), even genetically susceptible mice that develop extensive granulomatous inflammatory lesions in their livers, spleens, and lungs survive infection with high doses of BCG.…”

Some Physicochemical Characteristics of an Immune Lymphocyte Product Which Inhibits the Multiplication of Toxoplasma within Mouse Macrophages

“…Several workers reported that Toxoplasma-immune macrophages showed a prolonged lag phase and increased generation time compared to nonimmune macrophages (2,11,23). Our unpublished observations indicated that by incubation with Toxo-GIF, glycogen-induced nonimmune macrophages showed prolonged lag phases (18)(19)(20)(21)(22) hr) compared to those of control macrophages (10-1 1 hr). Consequently, the growth inhibition of Toxoplasma estimated in this study, after the relatively short periods of infection (24-30 hr postinfection), may not only be due to the increased generation time but also to the prolonged lag phase.…”

“…Interferon has been shown to increase the phagocytic activity of macrophages and to inhibit intracellular multiplication of nonviral agents in mouse macrophages (9,15). Murine type II interferon differs in many respects from type I interferon, but it resembles MIF in many aspects and these two have been difficult to differentiate until now (21,30). Since Toxo-GIF also has MIF activity, it is of interest to ascertain whether Toxo-GIF has interferon activity or not.…”