Tuberculosis, a major health problem in developing countries, has reemerged in recent years in many industrialized countries. The increased susceptibility of immunocompromised individuals to tuberculosis, and many experimental studies indicate that T cell-mediated immunity plays an important role in resistance. The lymphokine interferon gamma (IFN-gamma) is thought to be a principal mediator of macrophage activation and resistance to intracellular pathogens. Mice have been developed which fail to produce IFN-gamma (gko), because of a targeted disruption of the gene for IFN-gamma. Upon infection with Mycobacterium tuberculosis, although they develop granulomas, gko mice fail to produce reactive nitrogen intermediates and are unable to restrict the growth of the bacilli. In contrast to control mice, gko mice exhibit heightened tissue necrosis and succumb to a rapid and fatal course of tuberculosis that could be delayed, but not prevented, by treatment with exogenous recombinant IFN-gamma.

SummaryThe expression of protective immunity to Mycobacterium tuberculosis in mice is mediated by T lymphocytes that secrete cytokines . These molecules then mediate a variety of roles, including the activation ofparasitized host macrophages, and the recruitment of other mononuclear phagocytes to the site of the infection in order to initiate granuloma formation . Among these cytokines, interferon y (IFN-y) is believed to play a key role is these events. In confirmation ofthis hypothesis, we show in this study that mice in which the IFN-y gene has been disrupted were unable to contain or control a normally sublethal dose of M. tuberculosis, delivered either intravenously or aerogenically. In such mice, a progressive and widespread tissue destruction and necrosis, associated with very high numbers ofacid-fast bacilli, was observed. In contrast, despite the lack of protective immunity, some DTH-like reactivity could still be elicited. These data, therefore, indicate that although IFN-y may not be needed for DTH expression, it plays a pivotal and essential role in protective cellular immunity to tuberculosis infection .C urrent murine models of experimental Mycobacterium tuberculosis infection indicate that the emergence of acquired immunity to this organism is mediated by populations of both class I and II MHC-restricted T lymphocytes, which secrete cytokines that result in the activation of parasitized macrophages and promotion of the granulomatous response (1-4) . The cytokine IFN-y, which is an effective inducer of antimicrobial mechanisms in several systems (5, 6) has been shown to inhibit the growth of mycobacteria in vitro (7-9), but its role in vivo has yet to be precisely defined. In this regard, we report here that mice in which the IFN-y gene has been disrupted (IFN-y gene knockout mice [GKO mice]), develop a fatal, disseminated form of disease when inoculated with a normally sublethal inoculum of M. tuberculosis . These results indicate, therefore, that IFN-'Y plays a pivotal role in the expression ofprotective immunity to this infection in the mouse. Moreover, this new immunodeficient mouse model may prove highly useful in the evaluation of therapeutic intervention strategies in the severely immunocompromised host.Mice. GKO mice were generated as described previously (10). Briefly, a normal IFN-y allele in mouse embryonic stem cells was replaced with a defective gene using a targeted vector which introduced a termination codon after the first 30 amino acids of the mature IFN-y protein . The altered stem cells were injected into C57BL/6J blastocysts and transmitted via the germline. Heterozygous offspring ofthe chimeras were intercrossed to generate mice homozygous for the altered (GKO) and wild type (WT) allele . The GKO mice were previously characterized as normal in terms of spleen and thymus cell number and expression of CD3, B220, CD4, and CD8 surface markers, and were shown to be incapable of IFN-y secretion (10).Experimental Infections. The Erdman strain ofM. tuberculosis was grown in Proskauer B...

Interferon-gamma (IFN-gamma) is a pleiotrophic cytokine with immunomodulatory effects on a variety of immune cells. Mice with a targeted disruption of the IFN-gamma gene were generated. These mice developed normally and were healthy in the absence of pathogens. However, mice deficient in IFN-gamma had impaired production of macrophage antimicrobial products and reduced expression of macrophage major histocompatibility complex class II antigens. IFN-gamma-deficient mice were killed by a sublethal dose of the intracellular pathogen Mycobacterium bovis. Splenocytes exhibited uncontrolled proliferation in response to mitogen and alloantigen. After a mixed lymphocyte reaction, T cell cytolytic activity was enhanced against allogeneic target cells. Resting splenic natural killer cell activity was reduced in IFN-gamma-deficient mice. Thus, IFN-gamma is essential for the function of several cell types of the murine immune system.

Hormonal control of metabolic rate can be important in regulating the imbalance between energy intake and expenditure that underlies the development of obesity. In mice fed a high-fat diet, human fibroblast growth factor 19 (FGF19) increased metabolic rate [1.53 +/- 0.06 liters O(2)/h.kg(0.75) (vehicle) vs. 1.93 +/- 0.05 liters O(2)/h.kg(0.75) (FGF19); P < 0.001] and decreased respiratory quotient [0.82 +/- 0.01 (vehicle) vs. 0.80 +/- 0.01 (FGF19); P < 0.05]. In contrast to the vehicle-treated mice that gained weight (0.14 +/- 0.05 g/mouse.d), FGF19-treated mice lost weight (-0.13 +/- 0.03 g/mouse.d; P < 0.001) without a significant change in food intake. Furthermore, in addition to a reduction in weight gain, treatment with FGF19 prevented or reversed the diabetes that develops in mice made obese by genetic ablation of brown adipose tissue or genetic absence of leptin. To explore the mechanisms underlying the FGF19-mediated increase in metabolic rate, we profiled the FGF19-induced gene expression changes in the liver and brown fat. In brown adipose tissue, chronic exposure to FGF19 led to a gene expression profile that is consistent with activation of this tissue. We also found that FGF19 acutely increased liver expression of the leptin receptor (1.8-fold; P < 0.05) and decreased the expression of acetyl coenzyme A carboxylase 2 (0.6-fold; P < 0.05). The gene expression changes were consistent with the experimentally determined increase in fat oxidation and decrease in liver triglycerides. Thus, FGF19 is able to increase metabolic rate concurrently with an increase in fatty acid oxidation.