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IVIG Intravenous Immunoglobulin. Gabriela M a Claudia Tiago. IVIG ou IVIg Intravenous Immunoglobulin. IVIG is a blood product administered intravenously It contains the pooled Ig G extracted from the plasma of over one thousand blood donors - PowerPoint PPT Presentation

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  • Gabriela Ma ClaudiaTiago

  • IVIG is a blood product administered intravenouslyIt contains the pooled IgG extracted from the plasma of over one thousand blood donorsImmunoglobulin products from human plasma were first used in 1952 to treat immune deficiency. It was initially shown to be effective in ITP in 1981.Treatment for: Immune deficiencies (plasma protein replacement therapy)Autoimmune Diseases (anti-inflammatory at a high dose 1-2 g/Kg) Acute InfectionsIVIG cost is climbing and well over $50/g. ($8,000 for a 80 kg person at 2g/kg)IVIG's effects last between 2 weeks and 3 months

    primary immune dysfunction: 100 to 400 mg/kg of body weight every 3 to 4 weeks.autoimmune diseases: 2 grams per kilogram of body weight for three to six months over a five day course once a month. Then maintenance therapy of 100 to 400 mg/kg of body weight every 3 to 4 weeks follows.

  • Rational basisIVIG: pool of IgGImmunoglobulins: effector molecules of immune defense

    Igs properties:

    Variable domainsConstant domainFcDiversitySpecificityCellular effector pathwaysFcimmune complex

  • IVIG mechanism of actionNeutralization ???

    Target: harmful antibodies

    Idiotypic Network TheoryABCA e B = IDIOTYPEA e C = ISOTYPEOK

  • Antibody Feedback: Cross-linking between BCR and FcIIR B cell blockedFc mechanism of IVIG action

  • IVIG mechanism of actionThe precise mechanism by which IVIG suppresses harmful inflammation has not been definitively establishedBUT.is believed to involve the Fc receptor

    How? Which one(s)?

    FcRFcRFcRFcRIFcRIIAFcRIIB1FcRIIB2FcRIIIAFcRIIIBFcRIFcRII FcRIFc/RFcRn

  • IVIG mechanism actionFc Receptors (FcyR)a protein found on the surface of NK cells, macrophages, neutrophils, mast cells and othersFcRs are the most important Fc receptors for inducing phagocytosis of opsonized microbes

  • Glycoforms of IgG (Asn297)Carbohydrate whit terminal sugar residues such as galactose, sialic acid, N-acetylglucosamine, and fucosemore than 30 different antibody glycovariants have been detected in human serum, with about 25%30% of them in the IgG glycoform.

    Thus, these variants, multiplied by the four different IgG subclasses, result in more than 120 different glycoproteins in the IVIG preparation that could contain the active anti-inammatory component

  • IVIG has anti-inflammatory effect at a high dose 1-2 g/Kg

    120 different glycoproteins in the IVIG preparation terminal sugar residues of sialic acid confers anti-inflammatory property

    1-3% of IgGs in IVIG have sFc (sialylation)

    recombinant sFc: enhanced 35 fold of action in vivoCarbohydrateCarbohydrate-Binding ProteinsC-Type LectinsSiglecsGalectinsCD1

  • DC-SIGN is a C-type lectin receptor

    binds to mannose type carbohydrates.

    Phagocytosis

    Cell rolling interactions (ICAM) and activation of CD4+ T cells

    Binds sFc anti-inflammatory responses

    Population of regulatory macrophageSplenic Marginal Zone

  • Maria ClaudiaTiago

  • Objective: To define the mechanism by which the 2,6-sialylated Fc mediates an anti- inflammatory response To identify the properties of the regulatory macrophage population To identify the receptor required for initiating this pathway in response to 2,6-sialylated Fc.

  • ResultsAre the splenic marginal zone macrophage necessary for IVIG-mediated immune suppression?Defined defects in specific immune cell populationsIVIG1 hour afterArthritis inducing sera(K/BxN)Clinical score analysisSpecific macrophage populations in the splenic marginal zone might be required for the anti-inflammatory effect of the 2,6 sialylated Fc found in IVIG

  • ResultsWhich receptor expressed in macrophages is required for IVIG protection?Interacting with glycopeptides:Scavenger receptor (MARCO) bacteriasSialoadhesin receptor (CD169) sialic acidC-type lectin receptor (SIGN-R1) polysaccharide dextranTKO-SIGNR1 - antibody that results in the transient down-regulation of SIGN-R1 expression

  • ResultsWhich receptor expressed in macrophages is required for IVIG protection?The c-type lectin, SIGN-R1, is required for IVIG protectionAnkle bones

  • ResultsDid SIGN-R1 able to bind to the 2,6-sialyted Fc?SIGN-R1 binds 2,6-sialylated Fc.

  • ResultsDid SIGN-R1 able to bind to the 2,6-sialyted Fc and asialylated Fcs?The 2,6-sialylation of the IgG Fc converts the molecule to a species that acquires the ability to engage a mSIGN-R1 and mediate an antiinflammatory response.

  • ResultsCRD - carbohydrate recognition domainsYellow Identical amino acidsGreen Similar amino acidsHuman DC-SIGN expressed on dendritic cells

  • ResultsDid DC-SIGN able to bind to the 2,6-sialyted Fc?CHO cells expressing SIGN-R1, hDC-SIGN or hFcRIIbPulsed with 2,6-FcsMannan = ligand for DC-SIGNFibrinogen = similar to Fc linked glycanHuman DC-SIGN, binds 2,6-sialylated Fc

  • Results2,6-sialylation FcantiinflammatoryresponseFcRIIbFcR bindingmSIGN-R1, hDC-SIGN bindingC57Bl/6SIGN-R1-/-FcRIIb-/-

  • ResultsDid FcRIIb involve in the mechanism by which the 2,6-Fc mediates an anti-inflammatory response?

    The absence of FcRIIb in the recipient prevented the protection afforded by these splenocytes

  • Conclusion

  • Objective: To study hDC-SIGN in the context of IVIG anti-inflammatory activity in expressing-hDC-SIGN mice.

  • Could hDC-SIGN mediate anti-inflammatory protection by IVIG?hDC-SIGN+/SIGN-R1-/-WTSIGN-R1-/-Treated with sFcChallenged with arthritogenic K/BxN serumClinical score assessementhDC-SIGN substitutes for SIGN-R1 in mediating IVIG anti-inflammatory protection

  • BMM Were hDC-SIGN+ macrophages sufficient to induce an anti-inflammatory response?hDC-SIGN+WT30minsFc or asyaloFc+WTTransfered to WT micehDC-SIGN+ Macrophages treated with sFC showed reduced joint inflammation Challenged with K/BxNClinical score assessement

  • Is FcRIIB required to the anti-inflammatory property induced hDC-SIGN+ macrophages? hDC-SIGN+-BMMhDC-SIGN+30minsFc or PBS+SIGN-R1-/-Transfered toFcRIIB-/- The anti-inflammatory property induced by hDC-SIGN+ macrophages depends on FcRIIB Challenged with K/BxNClinical score assessement

  • Was IL-4 responsable for mediating IVIG anti-inflammatory activity?BMMhDC-SIGN+30minsFc or PBS+WTTransfered toIL-4-/- IL-4 is crucial for mediating IVIG anti-inflammatory activity Challenged with K/BxNClinical score assessement

  • Could Th2 cytokines supress K/BxN-induced inflammation?WTFcRIIB-/- Treated with IL-4, IL-13 or IL-3K/BxNClinical score evaluationInflammation was attenuated after Th2 cytokines administration

  • Did sFc administration increase Th2 cytokines production?SIGN-R1-/-WT Treated with sFc (1h)Splenic cells were removedQuantification of IL-4, IL-33 and IL-25 mRNA expression (qPCR)IL-33 mRNA was upregulated in WT mice after sFc administration

  • WTTreated with PBS, IL-33, IL-25 or TSLPK/BxNClinical score evaluation and analyses of IL-4 levels Can IL-33 induce IL-4 production? IL-33 reverts K/BxN-induced inflammation by increasing IL-4 levels

  • hDC-SIGN+/SIGN-R1-/-Treated with sFc or sFc+anti-IL-33RK/BxNClinical score evaluationDoes Anti-IL-33R ablate the sFc protection?The IL-33R blocking increases joint inflammation

  • Did IL-33 and IL-4 increase FcRIIB expression on monocytes?hDC-SIGN+-Monocytes (CD11b+Ly6G+)+PBS or IL-4 or IL-33 or IL-2524hFcRIIB expression by FACSFcRIIB expression on monocytes was increased after IL-33 and IL-4 treatment

  • Are basophils involved with reduced joint inflammation?hDC-SIGN+/SIGN-R1-/-Treated with sFc or sFc+anti-FcRIK/BxNClinical score evaluationBasophils contribute for IVIG anti-inflammatory activity

  • IL-4-GFP miceTreated with PBS or sFcK/BxNClinical score evaluationand quantification of IL-4-producing basophils Are basophils the main source of IL-4 production during sFc treatment?Increased IL-4-producing basophils were induced during sFC treatment

  • Were basophils associated with anti-inflammatory activity induced by sFc? WT or FcRIIB-/-Basophils (DX5+FcRI+c-Kit-)PBS, IVIG or IL-33+Transfered toWT Challenged with K/BxNIL-33-treated basophils also increased anti-inflammatory activity in a FcRIIB-dependent manner

  • CONCLUSION

    autoimmune idiopathic thrombocytopenic purpura (ITP)*Ac secretados inibem a ativao contnua da cl B por meio da formao de complexos Ag-Ac que se ligam simultaneamente aos receptores BCR e Fcy em cels B especficas para o Ag. Fenmeno chamado de Feedback de anticorpos. Assim h o bloqueio da produo adicional de Ac.Se administra IgG preformada (retirada por plasmaferese) cai drasticamente o numero de cels produtoras de AcCasos: camundongo nocauteado para FcyRII: produo descontrolada de Acs. Humano: Polimorfismo no gene FcyRII foi relacionado com suscetibilidade ao LES. Alm disso: o tratamento com IVIG (Ig intravenosa) foi desenvolvido para vrias doenas empiricamente. A IVIG (imunoglobulina intravenosa) derivada de um conjunto de amostras de sangue de centenas de doadores. Introduzida h cerca de 30 anos, ela tem sido usada no tratamento de uma srie de distrbios do sistema imunolgico. It is mainly used as treatment in three major categories:Immune deficiencies such as X-linked agammaglobulinemia, hypogammaglobulinemia (primary immune deficiencies), and acquired compromised immunity conditions (secondary immune deficiencies) featuring low antibody levels; Inflammatory and autoimmune diseases; Acute infections.

    *

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