Anti‐interleukin‐6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus

Liang, Bailin; Gardner, Daniel S.; Griswold, Don E.; Bugelski, Peter J.; Song, Xiao Yu

doi:10.1111/j.1365-2567.2006.02433.x

Cited by 173 publications

(105 citation statements)

References 28 publications

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“…Overproduction of IL-6 has been associated with SLE (58) and IL-6 administration exacerbated the lupus disease in NZB/W F 1 mice (59). Conversely, anti-IL-6 mAb inhibited autoimmune responses in this lupus strain (60) and had a beneficial effect on the renal disease by inducing a diminution of anti-dsDNA autoantibody production and a significant reduction of the number of CD21 ϩ CD23 Ϫ MZ B cells, all features that were also present in TLR4-deficient B6 lpr/lpr mice. Similarly, IFN-␥ is involved in the pathogenesis of mouse lupus (61)(62)(63).…”

Section: Discussionmentioning

confidence: 94%

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

Lartigue

Colliou²,

Calbo³

et al. 2009

The Journal of Immunology

133

100

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies directed against nuclear Ags and immune complex deposits in damaged organs. Environmental factors have been thought to play a role in the onset of the disease. The recognition of these factors is mediated by TLRs, in particular TLR2 and TLR4 which bind pathogen-associated molecular patterns of Gram+ and Gram− bacteria, respectively. We attempted to determine the role of these TLRs in SLE by creating TLR2- or TLR4-deficient C57BL/6lpr/lpr mice. These mice developed a less severe disease and fewer immunological alterations. Indeed, in C57BL/6lpr/lpr-TLR2 or -TLR4-deficient mice, glomerular IgG deposits and mesangial cell proliferation were dramatically decreased and antinuclear, anti-dsDNA, and anti-cardiolipin autoantibody titers were significantly reduced. However, the response against nucleosome remained unaffected, indicating a role of TLR2 and TLR4 in the production of Abs directed against only certain categories of SLE-related autoantigens. Analysis of B cell phenotype showed a significant reduction of marginal zone B cells, particularly in C57BL/6lpr/lpr-TLR4-deficient mice, suggesting an important role of TLR4 in the sustained activation of these cells likely involved in autoantibody production. Interestingly, the lack of TLR4 also affected the production of cytokines involved in the development of lupus disease.

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Section: Discussionmentioning

confidence: 94%

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

Lartigue

Colliou²,

Calbo³

et al. 2009

The Journal of Immunology

133

100

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“…These studies emphasize the importance of steady-state levels of IL-6 for responses to infection, as well as the ability of IL-6 to cause severe immunopathology when expressed at high levels. Given the long association between IL-6 and SLE (36,37,(46)(47)(48)(49), it is surprising that there are very few studies that have targeted the IL-6 axis in SLE, and no significant clinical trials using anti-IL-6 (tocilizumab), even though targeting of IL-6 has been shown to be successful in the treatment of autoimmune-prone animals (50)(51)(52). This is particularly surprising given that therapies targeting IL-6 have been shown to be very effective in the treatment of other autoimmune diseases such as rheumatoid arthritis (53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

Autoimmune Disease in Lyn-Deficient Mice Is Dependent on an Inflammatory Environment Established by IL-6

Tsantikos

Oracki

Quilici

et al. 2009

The Journal of Immunology

122

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Lyn-deficient mice develop Ab-mediated autoimmune disease resembling systemic lupus erythematosus where hyperactive B cells are major contributors to pathology. In this study, we show that an inflammatory environment is established in Lyn−/− mice that perturbs several immune cell compartments and drives autoimmune disease. Lyn−/− leukocytes, notably B cells, are able to produce IL-6, which facilitates hyperactivation of B and T cells, enhanced myelopoiesis, splenomegaly, and, ultimately, generation of pathogenic autoreactive Abs. Lyn−/− dendritic cells show increased maturation, but this phenotype is independent of autoimmunity as it is reiterated in B cell-deficient Lyn−/− mice. Genetic deletion of IL-6 on a Lyn-deficient background does not alter B cell development, plasma cell accumulation, or dendritic cell hypermaturation, suggesting that these characteristics are intrinsic to the loss of Lyn. However, hyperactivation of B and T cell compartments, extramedullary hematopoiesis, expansion of the myeloid lineage and autoimmune disease are all ameliorated in Lyn−/−IL-6−/− mice. Importantly, our studies show that although Lyn−/− B cells may be autoreactive, it is the IL-6–dependent inflammatory environment they engender that dictates their disease-causing potential. These findings improve our understanding of the mode of action of anti–IL-6 and B cell-directed therapies in autoimmune and inflammatory disease treatment.

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“…32 Application of anti-IL-6R as well as anti-IL-6 antibodies were subsequently shown to ameliorate disease by two independent groups. 33,34 Mechanistically, the deleterious effects of IL-6 were largely ascribed to production of pathogenic antibodies. Some authors also suspected IL-6 effects on T-cell activation; however, this was not addressed any further and effects on Th17 responses have not yet been studied.…”

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confidence: 99%

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

Luig¹,

Kluger²,

Goerke³

et al. 2015

Journal of the American Society of Nephrology

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IL-6 can mediate proinflammatory effects, and IL-6 receptor (IL-6R) blockade as a treatment for inflammatory diseases has entered clinical practice. However, opposing effects of IL-6 have been observed in models of GN. Although IL-6 is proinflammatory in murine lupus nephritis, protective effects have been observed for IL-6 in the nephrotoxic nephritis (NTN) model of acute crescentic GN. In light of the potential dangers of IL-6-directed treatment, we studied the mechanisms underlying the contradictory findings in GN. IL-6 can signal through the membrane-bound IL-6R, which is expressed only on hepatocytes and certain leukocytes (classic), or through the soluble IL-6R, which binds the ubiquitously expressed gp130 (alternative). Preemptive treatment of mice with anti-IL-6R or anti-IL-6 worsened NTN, whereas selective blockade of alternative IL-6 signaling by the fusion protein sgp130Fc did not. FACS analysis of mouse spleen cells revealed proinflammatory macrophages express the highest levels of IL-6Ra, and in vitro treatment with IL-6 blocked macrophage proliferation. Furthermore, proinflammatory macrophages were expanded during inflammation in IL-6 2/2 mice. Late application of anti-IL-6 after establishment of adaptive nephritogenic immunity was sufficient to aggravate NTN within 2.5 days, a period when macrophages are active. Finally, NTN was aggravated in mice with macrophage-specific impairment of IL-6 classic signaling, coincident with enhanced macrophage proliferation and accumulation in the kidney. Our data thus reveal a novel mechanism in which IL-6-mediated dampening of macrophage activation protects tissues from overshooting immune responses. This finding has important implications for potential IL-6-directed therapies and supports the careful choice of recipient patients and timing.

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Anti‐interleukin‐6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus

Cited by 173 publications

References 28 publications

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus

Autoimmune Disease in Lyn-Deficient Mice Is Dependent on an Inflammatory Environment Established by IL-6

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

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