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Effect of immunoglobulin G (IgG) interchain disulfide bond cleavage on efficacy of intravenous immunoglobulin for immune thrombocytopenic purpura (ITP). 2010

Y Machino, and H Ohta, and E Suzuki, and S Higurashi, and T Tezuka, and H Nagashima, and J Kohroki, and Y Masuho
Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.

Intravenous immunoglobulin (IVIG) has been used widely to treat immune thrombocytopenic purpura (ITP), but the mechanisms of its action remain unclear. We investigated the affinity for Fcγ receptors (FcγRs) and the thrombocytopenia-ameliorating effect of S-sulfonated gammaglobulin (SGG) and S-alkylated gammaglobulin (AGG), in comparison with unmodified gammaglobulin (GG), in a mouse ITP model. Cleavage of immunoglobulin (Ig)G interchain disulfide bonds by either S-sulfonation or S-alkylation did not decrease the affinity for FcγRIIA (CD32A) and FcγRIIB (CD32B), but did decrease the affinity for FcγRIA (CD64A) and FcγRIIIA (CD16A), presumably because of changes in H-chain configuration. The interchain disulfide bond cleavage decreased the affinity much more for mouse FcγRIV than for mouse FcγRIIB. The ability of AGG to ameliorate ITP was greatly diminished, while SGG, whose disulfide bonds are reconstituted in vivo, was as effective as GG. These results suggest that the interchain disulfide bonds are important for therapeutic effect. It is also suggested that the interaction of IVIG with the inhibitory receptor FcγRIIB is insufficient for effective amelioration of ITP and that, at least in this model, direct binding of IVIG to FcγRIIIA is also required.

UI MeSH Term Description Entries
D007074 Immunoglobulin G The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of IgG, for example, IgG1, IgG2A, and IgG2B. Gamma Globulin, 7S,IgG,IgG Antibody,Allerglobuline,IgG(T),IgG1,IgG2,IgG2A,IgG2B,IgG3,IgG4,Immunoglobulin GT,Polyglobin,7S Gamma Globulin,Antibody, IgG,GT, Immunoglobulin
D007167 Immunotherapy Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. Immunotherapies
D008297 Male Males
D008807 Mice, Inbred BALB C An inbred strain of mouse that is widely used in IMMUNOLOGY studies and cancer research. BALB C Mice, Inbred,BALB C Mouse, Inbred,Inbred BALB C Mice,Inbred BALB C Mouse,Mice, BALB C,Mouse, BALB C,Mouse, Inbred BALB C,BALB C Mice,BALB C Mouse
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000478 Alkylation The covalent bonding of an alkyl group to an organic compound. It can occur by a simple addition reaction or by substitution of another functional group. Alkylations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000915 Antibody Affinity A measure of the binding strength between antibody and a simple hapten or antigen determinant. It depends on the closeness of stereochemical fit between antibody combining sites and antigen determinants, on the size of the area of contact between them, and on the distribution of charged and hydrophobic groups. It includes the concept of "avidity," which refers to the strength of the antigen-antibody bond after formation of reversible complexes. Affinity, Antibody,Antibody Avidity,Avidity, Antibody,Affinities, Antibody,Antibody Affinities,Antibody Avidities,Avidities, Antibody
D016553 Purpura, Thrombocytopenic, Idiopathic Thrombocytopenia occurring in the absence of toxic exposure or a disease associated with decreased platelets. It is mediated by immune mechanisms, in most cases IMMUNOGLOBULIN G autoantibodies which attach to platelets and subsequently undergo destruction by macrophages. The disease is seen in acute (affecting children) and chronic (adult) forms. Autoimmune Thrombocytopenic Purpura,Idiopathic Thrombocytopenic Purpura,Purpura, Thrombocytopenic, Autoimmune,Werlhof's Disease,Autoimmune Thrombocytopenia,Immune Thrombocytopenia,Immune Thrombocytopenic Purpura,Thrombocytopenic Purpura, Autoimmune,Werlhof Disease,Autoimmune Thrombocytopenias,Autoimmune Thrombocytopenic Purpuras,Disease, Werlhof,Disease, Werlhof's,Idiopathic Thrombocytopenic Purpuras,Immune Thrombocytopenias,Immune Thrombocytopenic Purpuras,Purpura, Autoimmune Thrombocytopenic,Purpura, Idiopathic Thrombocytopenic,Purpura, Immune Thrombocytopenic,Purpuras, Autoimmune Thrombocytopenic,Purpuras, Idiopathic Thrombocytopenic,Purpuras, Immune Thrombocytopenic,Thrombocytopenia, Autoimmune,Thrombocytopenia, Immune,Thrombocytopenias, Autoimmune,Thrombocytopenias, Immune,Thrombocytopenic Purpura, Idiopathic,Thrombocytopenic Purpura, Immune,Thrombocytopenic Purpuras, Idiopathic,Thrombocytopenic Purpuras, Immune,Werlhofs Disease

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