Abstract
BackgroundIntravenous immunoglobulin (IVIG) proved to be an efficient anti-inflammatory treatment for a growing number of neuroinflammatory diseases and protects against the development of experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS).MethodsThe clinical efficacy of IVIG and IVIG-derived F(ab’)2 fragments, generated using the streptococcal cysteine proteinase Ide-S, was evaluated in EAE induced by active immunization and by adoptive transfer of myelin-specific T cells. Frequency, phenotype, and functional characteristics of T cell subsets and myeloid cells were determined by flow cytometry. Antibody binding to microbial antigen and cytokine production by innate immune cells was assessed by ELISA.ResultsWe report that the protective effect of IVIG is lost in the adoptive transfer model of EAE and requires prophylactic administration during disease induction. IVIG-derived Fc fragments are not required for protection against EAE, since administration of F(ab’)2 fragments fully recapitulated the clinical efficacy of IVIG. F(ab’)2-treated mice showed a substantial decrease in splenic effector T cell expansion and cytokine production (GM-CSF, IFN-γ, IL-17A) 9 days after immunization. Inhibition of effector T cell responses was not associated with an increase in total numbers of Tregs but with decreased activation of innate myeloid cells such as neutrophils, monocytes, and dendritic cells. Therapeutically effective IVIG-derived F(ab’)2 fragments inhibited adjuvant-induced innate immune cell activation as determined by IL-12/23 p40 production and recognized mycobacterial antigens contained in Freund’s complete adjuvant which is required for induction of active EAE.ConclusionsOur data indicate that F(ab’)2-mediated neutralization of adjuvant contributes to the therapeutic efficacy of anti-inflammatory IgG. These findings might partly explain the discrepancy of IVIG efficacy in EAE and MS.
Highlights
Intravenous immunoglobulin (IVIG) proved to be an efficient anti-inflammatory treatment for a growing number of neuroinflammatory diseases and protects against the development of experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS)
Continuous administration of IVIG prevented EAE development, termination of treatment at day 6 led to a delayed disease onset and reduced severity and treatment from day 7 on exacerbated EAE symptoms (Fig. 1b) indicating that IVIG is required at high dose and continuously for its protective effect and active during T cell priming in response to active vaccination
In order to investigate the therapeutic potential of IVIG independent of adjuvant administration and T cell priming, we determined its clinical efficacy in the adoptive transfer model of EAE, in which disease is induced by peripheral introduction of pre-activated myelin-specific effector T cells
Summary
Intravenous immunoglobulin (IVIG) proved to be an efficient anti-inflammatory treatment for a growing number of neuroinflammatory diseases and protects against the development of experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS). High-dose therapy with intravenous immunoglobulin (IVIG), obtained from the plasma of several thousand individuals, is an efficient anti-inflammatory and immunomodulatory treatment for a growing number of autoimmune neuroinflammatory diseases. In autoantibody-mediated animal models of autoimmune diseases such as idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, and nephrotoxic nephritis, the IgG Fc domain appears to be essential in mediating the protective effects of IVIG [15,16,17,18,19]. We show that the protective effect of IVIG is dose-dependent, requires prophylactic administration during priming, and is lost upon adoptive transfer of encephalitogenic T cells to induce EAE. IVIG-derived F(ab’) fragments inhibit immunostimulatory adjuvant activity necessary for disease induction and are sufficient to mediate protection from EAE development
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