Disseminated tuberculosis in interferon gamma gene-disrupted mice.

Abstract

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...

Host Responses and Antigens Involved in Protective Immunity to Mycobacterium tuberculosis

“…Recent studies have furthermore provided strong evidence in favour of a protective role for IFN-g in the mouse model. Mice with a disruption of the gene for IFN-g were unable to control a mycobacterial infection and died very rapidly with widespread dissemination, caseous necroses and large abscesses [58,59]. However some discrepancies exist concerning the efficacy of IFN-g alone in activating human macrophages, and a costimulation with vitamin D3 may be necessary [60].…”

Interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) are necessary in the early stages of induction of CD4 and CD8 cytotoxic T cells byMycobacterium lepraeheat shock protein (hsp) 65 kD

“…Hence, the requirement for IFN-g and TNF-a could be a general feature in response to mycobacterial infections, as has already been proven for M. tuberculosis and M. bovis BCG [37,45], suggesting an interaction between T cells and monocytesmacrophages rather than T cell subsets. An altered balance in the production of cytokines would result in failure of monocyte activation, including the secretion of monokines, antigen presentation and lymphocyte activation.…”

“…IFN-g and TNF-a play an important role in the development of the protective response against M. leprae and M. tuberculosis [36][37][38]. IFN-g enhances the microbicidal activity through the release of TNF-a, IL-1 and IL-6 [39], and it also modulates IL-12 and IL-10 secretion [35,40].…”

Broad heparin‐binding haemagglutinin‐specific cytokine and chemokine response in infants following Mycobacterium bovis BCG vaccination

“…42: 2511-2522 study have implicated in the PPD-specific and now the HBHAspecific response in BCG vaccinees are IL-1α and IL-6. The importance of IFN-γ as a component of anti-TB immune responses has been acknowledged and is supported by studies in patients and mice with disabling mutations in the IFN-γ receptor [25][26][27][28]. For this reason, it has for some years been the cytokine of choice for investigators wishing to demonstrate an immune response with the potential for effective protection against TB [6,29].…”