Defective T-cell response in beige mutant mice

Saxena, Rajiv K.; Saxena, Queen B.; Adler, William H.

doi:10.1038/295240a0

Cited by 83 publications

(45 citation statements)

References 13 publications

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“…Others (9) have likewise observed that antibody-mediated in vivo depletion of NK cells has little impact on LVS infection, with the caveat that the available antisera may effect only partial NK cell depletion. It should be noted that although beige mice are typically considered to be NK cell deficient, they do also demonstrate decreased T-cell cytolytic activity (22), which could account for the slight loss of IL-12-mediated protection that was observed after infection of these animals. Large numbers of IFN-␥-positive NK cells and concomitant decreases in the numbers of IFN-␥-positive T cells are observed in the lungs of mice within 72 h after i.n.…”

Section: Discussionmentioning

confidence: 99%

Intranasal Interleukin-12 Treatment for Protection against Respiratory Infection with theFrancisella tularensisLive Vaccine Strain

et al. 2005

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Francisella tularensis is a gram-negative intracellular bacterium that can induce lethal respiratory infection in humans and rodents. However, little is known about the role of innate or adaptive immunity in protection from respiratory tularemia. In the present study, the role of interleukin-12 (IL-12) in inducing protective immunity in the lungs against intranasal infection of mice with the live vaccine strain (LVS) of F. tularensis was investigated. It was found that gamma interferon (IFN-␥) and IL-12 were strictly required for protection, since mice deficient in IFN-␥, IL-12 p35, or IL-12 p40 all succumbed to LVS doses that were sublethal for wild-type mice. Furthermore, exogenous IL-12 treatment 24 h before intranasal infection with a lethal dose of LVS (10,000 CFU) significantly decreased bacterial loads in the lungs, livers, and spleens of wild-type BALB/c and C57BL/6 mice and allowed the animals to survive infection; such protection was not observed in IFN-␥-deficient mice. The resistance induced by IL-12 to LVS infection was still observed in NK cell-deficient beige mice but not in CD8 ؊/؊ mice. These results demonstrate that exogenous IL-12 delivered intranasally can prevent respiratory tularemia through a mechanism that is at least partially dependent upon the expression of IFN-␥ and CD8 T cells.

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Section: Discussionmentioning

confidence: 99%

Intranasal Interleukin-12 Treatment for Protection against Respiratory Infection with theFrancisella tularensisLive Vaccine Strain

et al. 2005

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“…These groups included beige C57BL/6J-bg' mice deficient in NK cells (12)(13)(14) (group VIa), and NK cell normal C57BL/6J mice that served as control (group VIb). Both groups were injected with 50,000 U of IL-2 and IFN-a following the schedule used in group II, and with 10 mg RbABM IgG.…”

Section: Experimental Designmentioning

confidence: 99%

Pathogenesis of an experimental model of Goodpasture's hemorrhagic pneumonitis.

Queluz

Pawlowski²,

Brunda³

et al. 1990

J. Clin. Invest.

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The mechanisms that allow circulating basement membrane antibodies (Ab) to interact with the alveolar basement membrane (ABM) inducing Goodpasture's hemorrhagic pneumonitis are unknown. In laboratory animals the ABM is inaccessible to phlogogenic amounts of ABM Ab unless the permeability of the unfenestrated alveolar endothelium is increased. This study was designed to test the hypothesis that in the mouse polypeptide mediators, generated by activated lymphoid cells or cells infected by viruses, contribute to the pathogenesis of passive Goodpasture's hemorrhagic pneumonitis. In naive mice that received rabbit ABM Ab, these bound to the glomerular basement membrane but not to the ABM and their lungs were normal. In the lungs of mice injected with human recombinant IL-2 and IFN-a specific binding of ABM IgG, C3, and fibrinogen to the ABM, diffuse and severe erythrocyte extravasation, and accumulation of mononuclear and polymorphonuclear leukocytes were constantly observed. ABM Ab and IL-2 or ABM Ab and IFN-a did not produce comparable effects. Mice injected only with IL-2 and IFN-a had enlarged, edematous lungs without pulmonary hemorrhages. The results show that the synergism of IL-2 and IFN-a convert the lung into a preferential target for AMB Ab, suggesting that cytokines may have a role in the pathogenesis of human Goodpasture's pneumonitis. (J. Clin. Invest. 1990Invest. . 85:1507Invest. -1515 Goodpasture's pneumonitis * basement membrane antibodies.

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“…In relation to this, it is noteworthy that beige mice have an impaired cytotoxic T-cell activity in addition to NK-cell deficiency (2,33). Therefore, it is also possible that KRM may need intact-cell functions of CD8+ T cells to efficiently express its in vivo activity against M. intracellulare infection.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapeutic efficacy of a newly synthesized benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex infection induced in mice

Tomioka

Saito

Sato

et al. 1992

Antimicrob Agents Chemother

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Newly synthesized benzoxazinorifamycin, KRM-1648, was studied for its in vivo anti-Mycobacterium avium complex (MAC) activities. When the MICs were determined by the agar dilution method with Middlebrook 7H11 agar medium, KRM-1648 exhibited similarly potent in vitro antimicrobial activities against the MAC isolated from AIDS and non-AIDS patients, indicating possible usefulness of KRM-1648 against AIDSassociated MAC infections. KRM-1648 exhibited potent therapeutic activity against experimental murine infections induced by M. intracellulare N-260 (virulent strain) and N-478, which has much weaker virulence. Similarly, KRM-1648 exhibited an excellent therapeutic efficacy against M. intracelulare infection induced in NK-cell-deficient beige mice (as a plausible model for AIDS-associated MAC infection), in which a much more progressed state of gross lesions and bacterial loads at the sites of infection were observed. When the infected beige mice were killed at weeks 4 and 8, obvious therapeutic efficacy was seen on the basis of reduction in the incidence and degree of lung lesions and bacterial loads in the lungs and spleen with infections due to M. intracelulare N-241, N-256, and N-260. In this case, the efficacy was the highest in N-260 infection, followed by strain N-241. When mice were observed until infection-induced death, survival time of the infected beige mice was found to be prolonged by KRM treatment. However, KRM-1648 was not efficacious in suppressing the progression of pulmonary lesions and the increase in bacterial loads at the sites of infection, including lungs and spleen, at the late phase of infection. This may imply some difficulty with chemotherapy for AIDSassociated MAC infection, even with KRM-1648 treatment, which has excellent in vitro and in vivo anti-MAC activities, as shown in the present study.Rifampin (RMP) and other rifarmycins, including rifabutin (RBT), rifapentine, and so on, are highly active against slowly growing mycobacteria, particularly Mycobacterium tuberculosis and some nontuberculous mycobacteria (1,3,5,7,14,18,24,28,29,36). However, they are not so excellent in their in vitro activity against M. avium complex (MAC) (5,19,28), supposedly because of the permeability barrier of the organisms (11,25). Moreover, it is not known whether RMP and other rifamycins are really efficacious in the treatment of patients with MAC infections. Some investigators have reported that multidrug chemotherapy, including treatment with RMP, has been used in many cases of clinical management of AIDS-or non-AIDS-associated MAC patients with success (4, 6). In contrast, others have reported unavoidable difficulty in clinical control of MAC, even by using RMP combined with other drugs (36). For instance, Rosenzweig (27) reported that sustained conversion of sputum with such chemotherapy alone was achieved in only 41% of patients and, after a 6-month trial of drugs including RMP, 33% of the patients experienced relapse.Because rifamycin with a high in vitro anti-MAC activity and superior pharmacokin...

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Defective T-cell response in beige mutant mice

Cited by 83 publications

References 13 publications

Intranasal Interleukin-12 Treatment for Protection against Respiratory Infection with theFrancisella tularensisLive Vaccine Strain

Intranasal Interleukin-12 Treatment for Protection against Respiratory Infection with theFrancisella tularensisLive Vaccine Strain

Pathogenesis of an experimental model of Goodpasture's hemorrhagic pneumonitis.

Chemotherapeutic efficacy of a newly synthesized benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex infection induced in mice

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