Therapeutic Effect of IVIG on Inflammatory Arthritis in Mice Is Dependent on the Fc Portion and Independent of Sialylation or Basophils

Campbell, Ian K.; Miescher, Sylvia; Branch, Donald R.; Mott, Patrick J.; Lazarus, Alan H.; Han, Dingpei; Maraskovsky, Eugene; Zuercher, Adrian W.; Neschadim, Anton; Leontyev, Danila; McKenzie, Brent; Käsermann, Fabian

doi:10.4049/jimmunol.1301611

Cited by 119 publications

(116 citation statements)

References 56 publications

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“…Despite this convincing evidence, some studies using different or identical in vivo model systems showed sialic acid-independent pathways of IVIg activity (28,29). However, none of these studies can be compared directly because of the use of different protocols and experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

“…However, none of these studies can be compared directly because of the use of different protocols and experimental conditions. For example, the use of desialylated IVIg generated with unqualified desialylation processes (potentially leading to IVIg preparations with residual sialylation content) or alteration to the composition of the IVIg mixture during desialylation or purification could potentially explain the lack of requirement of sialylation in the model of inflammatory arthritis (28,29). Additionally, some studies comparing the biological activity of IVIg and desialylated IVIg used fairly high doses outside the linear range of dose-response, which complicates interpretation of the results because of the complex and multiple mechanisms of IVIg (29).…”

Section: Discussionmentioning

confidence: 99%

“…For example, studies using desialylated IVIg in immune thrombocytopenic purpura (ITP) models (28) and Sambucus nigra agglutinin (SNA) -enriched IVIg in arthritis models (29) have shown that sialylation does not enhance IVIg activity or that it may even be dispensable for its therapeutic effects. On the contrary, more comprehensive studies performed by several independent laboratories testing desialylated or hypersialylated IVIg across different animal models under preventive and therapeutic treatment modalities have shown that sialylation is critical for the anti-inflammatory activity of IVIg (24)(25)(26)(27)30).…”

Section: Significancementioning

confidence: 99%

“…In the first model (K/BxN), IVIg activity was reported to be sialylation-dependent (23,24). The second model (CAIA) was recently reported to be sialylation-independent (29). For these and all in vivo studies, the s4-IVIg product was compared with the same lot of IVIg used as starting material across different models (Figs.…”

Section: Optimization Of Sialylation Process: Minimizing Undesired Momentioning

confidence: 99%

“…Optimal doses within the linear range of the response were used to compare IVIg and s4-IVIg. This dose optimization is an important element of these studies, because in some previous reports, IVIg has been compared with SNA-enriched or desialylated IVIg outside the linear range of the response; therefore, any effect of IVIg sialylation would be difficult to conclude (29). As shown in Fig.…”

Section: Optimization Of Sialylation Process: Minimizing Undesired Momentioning

confidence: 99%

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Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Washburn

Schwab

Ortiz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

204

161

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Despite the beneficial therapeutic effects of intravenous immunoglobulin (IVIg) in inflammatory diseases, consistent therapeutic efficacy and potency remain major limitations for patients and physicians using IVIg. These limitations have stimulated a desire to generate therapeutic alternatives that could leverage the broad mechanisms of action of IVIg while improving therapeutic consistency and potency. The identification of the important anti-inflammatory role of fragment crystallizable domain (Fc) sialylation has presented an opportunity to develop more potent Ig therapies. However, translating this concept to potent anti-inflammatory therapeutics has been hampered by the difficulty of generating suitable sialylated products for clinical use. Therefore, we set out to develop the first, to our knowledge, robust and scalable process for generating a well-qualified sialylated IVIg drug candidate with maximum Fc sialylation devoid of unwanted alterations to the IVIg mixture. Here, we describe a controlled enzymatic, scalable process to produce a tetra-Fc-sialylated (s4-IVIg) IVIg drug candidate and its qualification across a wide panel of analytic assays, including physicochemical, pharmacokinetic, biodistribution, and in vivo animal models of inflammation. Our in vivo characterization of this drug candidate revealed consistent, enhanced anti-inflammatory activity up to 10-fold higher than IVIg across different animal models. To our knowledge, this candidate represents the first s4-IVIg suitable for clinical use; it is also a valuable therapeutic alternative with more consistent and potent anti-inflammatory activity.IVIg | sialylation | antibody | inflammation | autoimmune disease

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Optimization Of Sialylation Process: Minimizing Undesired Momentioning

confidence: 99%

Section: Optimization Of Sialylation Process: Minimizing Undesired Momentioning

confidence: 99%

See 3 more Smart Citations

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Washburn

Schwab

Ortiz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

204

161

View full text Add to dashboard Cite

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Dose‐dependent inhibition of demyelination and microglia activation by IVIG

Winter

Baksmeier

Steckel

et al. 2016

Ann Clin Transl Neurol

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ObjectiveIntravenous immunoglobulin (IVIG) is an established treatment for numerous autoimmune conditions. Clinical trials of IVIG for multiple sclerosis, using diverse dose regimens, yielded controversial results. The aim of this study is to dissect IVIG effector mechanisms on demyelination in an ex vivo model of the central nervous system (CNS)‐immune interface.MethodsUsing organotypic cerebellar slice cultures (OSC) from transgenic mice expressing green fluorescent protein (GFP) in oligodendrocytes/myelin, we induced extensive immune‐mediated demyelination and oligodendrocyte loss with an antibody specific for myelin oligodendrocyte glycoprotein (MOG) and complement. Protective IVIG effects were assessed by live imaging of GFP expression, confocal microscopy, immunohistochemistry, gene expression analysis and flow cytometry.Results IVIG protected OSC from demyelination in a dose‐dependent manner, which was at least partly attributed to interference with complement‐mediated oligodendroglia damage, while binding of the anti‐MOG antibody was not prevented. Staining with anti‐CD68 antibodies and flow cytometry confirmed that IVIG prevented microglia activation and oligodendrocyte death, respectively. Equimolar IVIG‐derived Fab fragments or monoclonal IgG did not protect OSC, while Fc fragments derived from a polyclonal mixture of human IgG were at least as potent as intact IVIG.InterpretationBoth intact IVIG and Fc fragments exert a dose‐dependent protective effect on antibody‐mediated CNS demyelination and microglia activation by interfering with the complement cascade and, presumably, interacting with local immune cells. Although this experimental model lacks blood–brain barrier and peripheral immune components, our findings warrant further studies on optimal dose finding and alternative modes of application to enhance local IVIG concentrations at the site of tissue damage.

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IgE and IL‐33−mediated triggering of human basophils inhibits TLR4−induced monocyte activation

et al. 2014

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Basophils are circulating granulocytes, best known as effector cells in allergic reactions.Recent studies in mice suggest that they might also participate in the suppression of chronic inflammation. The aim of this study was to assess the ability of purified human basophils to modulate monocyte responses upon IL-33 and IgE triggering. Activation of human basophils with IL-33 induced the production of IL-4 and the release of histamine, and enhanced their IgE-mediated activation. In addition, basophils triggered with IL-33 and anti-IgE significantly suppressed the LPS-induced production of the proinflammatory cytokine TNF-α and the upregulation of the costimulatory molecule CD80 by monocytes. These effects were mainly explained by the release of histamine, as they could be inhibited by the histamine receptor 2 antagonist ranitidine, with a smaller contribution of IL-4. In contrast, basophil-derived IL-4 and histamine had opposing effects on the expression of the inhibitory Fc γ receptor IIb and the production of IL-10 by monocytes. Our data show that basophils can influence monocyte activation and suggest a previously unrecognized role for human basophils in the modulation of monocyte-mediated immune responses, through the balanced secretion of histamine and IL-4.Keywords: Basophils r Cellular activation r Histamine r Immune regulation r Monocytes Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionBasophils are circulating granulocytes, representing less than 1% of peripheral blood leukocytes. They are classically known for their involvement as effector cells in allergic reactions [1][2][3]. Because of their paucity and the difficulty in isolating them, there is still relatively little information available on their functions and potential immunomodulatory effects [4]. Studies in mice suggest a possible role for basophils in the induction of adaptive immunity in the context of Th2 responses, where they have been shown to be the major producers of , although their function as Correspondence: Dr. Felice Rivellese e-mail: rivelles@gmail.com antigen presenting cells and their dispensability in the induction of Th2 responses are still under debate [6,7]. In addition, recent experimental data showed how these rare leukocytes might also exert anti-inflammatory effects in the context of autoimmune and allergic inflammation. In a mouse model of arthritis, basophils have been implicated in the immunosuppressive response mounted upon injection of intravenous immunoglobulin (IVIG) [8]. Briefly, the authors proposed the following scenario to elucidate IVIG-mediated immune suppression: myeloid-derived cells, in response to the sialylated fraction of IVIG, release IL-33, which, in turn, activates basophils to produce IL-4. Finally, basophil-derived IL-4 induces the upregulation of the inhibitory Fc γ Receptor (FcγRIIb) on inflammatory macrophages, leading to the suppression of antibody-dependent inflammation. Thus, IL-33www.eji-journal.eu 3046 Felice R...

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Therapeutic Effect of IVIG on Inflammatory Arthritis in Mice Is Dependent on the Fc Portion and Independent of Sialylation or Basophils

Cited by 119 publications

References 56 publications

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Dose‐dependent inhibition of demyelination and microglia activation by IVIG

IgE and IL‐33−mediated triggering of human basophils inhibits TLR4−induced monocyte activation

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