Antibody against interleukin-6 reduces inflammation and numbers of cysts in brains of mice with toxoplasmic encephalitis

Suzuki, Yasuhiro; Yang, Qiyuan; Conley, Frances K.; Abrams, John S.; Remington, Jack S.

doi:10.1128/iai.62.7.2773-2778.1994

Cited by 53 publications

(33 citation statements)

References 10 publications

(5 reference statements)

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“…Suzuki et al (1997) using gene deficient mice have also recently demonstrated a protective effect for IL-6 in resistance against toxoplasmic encephalitis. Paradoxically using anti-IL-6 monoclonal antibodies in this disease model this group had previously postulated a disease enhancing role for IL-6 (Suzuki et al 1994). However, in this earlier study by Suzuki et al (1994) as well as other studies on endotoxic shock (Heremans et al 1992) and Staphlycoccus aureus infection (Nakane et al 1995) such treatment increased circulating IL-6 levels suggesting a possible 'chaperoning' effect by neutralizing antibodies.…”

Section: Discussionmentioning

confidence: 65%

“…Thus in vitro studies suggest on the one hand that IL-6 may play an exacerbating role by inhibiting IFN-g mediated parasite killing (Beaman et al 1994), but on the other hand, further studies suggest IL-6 may play a protective role by inducing encystment (Weiss et al 1995). In vivo studies have suggested an exacerbative role for IL-6 as anti-IL-6 treatment reduces serum IFN-g levels, cyst burdens and brain inflammation (Suzuki et al 1994). However, the administration of antibodies against IL-6 has been shown in this and other studies (Hereman et al 1992) to increase serum IL-6 levels probably as a result of 'chaperoning' effects.…”

Section: Introductionmentioning

confidence: 99%

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A protective role for IL‐6 during early infection with Toxoplasma gondii

Jebbari

Ferguson

Bluethmann

et al. 1998

Parasite Immunology

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IL-6 deficient mice were found to be significantly more susceptible to peroral infection with Toxoplasma gondii than their wild-type counterparts as measured by survival, brain cyst burdens and brain pathology at 28 days post infection. The physical manifestations of disease, such as weight loss, were not observed in IL-6 deficient animals until at least seven days later than such changes occurred in wildtype mice. During this early stage of infection IL-6+/+ but not IL-6-/- mice mounted a peripheral blood neutrophilia. Furthermore, between 6-8 days post-infection there was a significant increase in plasma IFN-gamma levels in wild-type but not IL-6 deficient mice. Not until days 18-23 post-infection, concurrent with the majority of deaths in IL-6-/- mice, were plasma IFN-gamma levels substantially and significantly raised in IL-6-/- mice. At this time not only were these plasma IFN-gamma levels 20-fold higher than background but eight-fold greater than peak (6-8 days post-infection) IFN-gamma levels in IL-6+/+ mice. IFN-gamma dependent parasite specific IgG2a levels were also significantly higher in IL-6-/- mice over this period and thereafter. Overall the evidence suggests that in the absence of IL-6 mice are unable to initiate a rapid proinflammatory response against T. gondii, which allows increased parasite growth. Increased mortality in IL-6-/- mice may be directly due to this increased parasite burden and the excessive inflammatory response this induces three weeks post-infection.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

A protective role for IL‐6 during early infection with Toxoplasma gondii

Jebbari

Ferguson

Bluethmann

et al. 1998

Parasite Immunology

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“…Cysts of the ME49 strain were obtained from brains of Swiss-Webster mice (Simonson, Gilroy, CA, USA) that had been infected intraperitoneally (i.p.) with 10 cysts for 2-3 months, as previously described (Suzuki et al 1994a). For peroral infection, mice were infected with 100 cysts by gavage (Liesenfeld et al 1996).…”

Section: Infection With T Gondiimentioning

confidence: 99%

TNF‐α, nitric oxide and IFN‐γ are all critical for development of necrosis in the small intestine and early mortality in genetically susceptible mice infected perorally with Toxoplasma gondii

Liesenfeld

Kang

Park

et al. 1999

Parasite Immunology

144

114

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We previously reported that genetic susceptibility of mice to peroral infection with T. gondii is associated with CD4+ T cell-dependent, interferon (IFN)-gamma-mediated necrosis of their small intestine. We examined the role of tumour necrosis factor (TNF)-alpha and nitric oxide (NO), in addition to IFN-gamma. At 7 days after infection, a marked increase in CD4+ T cells was observed in lamina propria mononuclear cells (LPC) of the small intestine as compared with normal mice, and significantly greater amounts of mRNA for IFN-gamma, TNF-alpha, and inducible NO synthase (iNOS) were detected in LPC of the small intestine of infected than uninfected animals. Treatment of infected mice with anti-TNF-alpha monoclonal antibody (mAb) or the iNOS inhibitor, aminoguanidine, prevented necrosis and prolonged time to death. Infected iNOS-targeted mutant mice did not develop the disease whereas infected, control mice did. Treatment with anti-TNF-alpha mAb did not affect the expression of IFN-gamma in the LPC but inhibited expression of iNOS in the infected mice, indicating the role of TNF-alpha in the induction of iNOS. These results suggest that NO induced by a combination of IFN-gamma and TNF-alpha through activation of iNOS is a critical mediator of intestinal pathology and contributes to early mortality in genetically susceptible mice.

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“…More recently, IL-6-deficient mice (gene targeted IL-6 −/− ) were shown to lose resistance to encephalitis caused by Toxoplasma with a significant increase in cysts and areas of inflammation [18]. Interestingly, previous studies on this model using monoclonal antibodies to murine IL-6 had indicated a reduction in inflammatory response, but this was due to a paradoxical increase in IL-6 serum levels produced by the antibodies [19]. In autoimmune EAE, administration of antibodies to IL-6 reduced the degree of disease but again with elevated levels of IL-6 in blood and CNS, making it unclear whether IL-6 is protective or contributes to the development of EAE [20].…”

Section: Introductionmentioning

confidence: 99%

Interleukin‐6 functions in autoimmune encephalomyelitis: a study in gene‐targeted mice

et al. 1998

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The encephalitogenic peptide pMOG 35-55 from the myelin oligodendrocyte glycoprotein was used to induce experimental autoimmune encephalomyelitis (EAE) in H-2b mice with the interleukin-6 (IL-6) gene intact or disrupted. The IL-6+/+ mice developed a chronic form of EAE ascending paralysis, whereas the IL-6-/- mice were resistant to the disease. Injections of recombinant IL-6 following pMOG immunization induced severe disease in the IL-6-/- mice. Histological examination of brain and spinal cord sections showed that the perivascular infiltration of inflammatory cells evident in IL-6+/+ mice was absent in the IL-6-/- animals and could be restored by exogenous IL-6 administration. Anti-MOG antibody levels were much lower in the IL-6-/- mice, but were not restored to high levels by IL-6 injections which elicited the development of pMOG 35-55-induced EAE. T lymphocytes reactive to the pMOG antigen were recovered from lymph nodes of both types of mice and Tcell lines could be established from both. Adoptive transfer of Tcell lines from IL-6+/+ mice induced EAE in the mice with the intact IL-6 gene but less in the IL-6-deficient mice, indicating that the resistant phenotype cannot be explained solely by lack of encephalitogenic Tcells. The absence of cell infiltrates in the brain and spinal cords of IL-6-/- mice upon adoptive transfer of the pathogenic Tcells from IL-6+/+ mice is consistent with a function of IL-6 in the local perivascular inflammatory process.

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Antibody against interleukin-6 reduces inflammation and numbers of cysts in brains of mice with toxoplasmic encephalitis

Cited by 53 publications

References 10 publications

A protective role for IL‐6 during early infection with Toxoplasma gondii

A protective role for IL‐6 during early infection with Toxoplasma gondii

TNF‐α, nitric oxide and IFN‐γ are all critical for development of necrosis in the small intestine and early mortality in genetically susceptible mice infected perorally with Toxoplasma gondii

Interleukin‐6 functions in autoimmune encephalomyelitis: a study in gene‐targeted mice

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