Genetic requirements for acceleration of diabetes in non-obese diabetic mice expressing interleukin-2 in islet beta cells.

Allison, Janette, McClive, Peter, Oxbrow, Leonie, Baxter, Alan, Morahan, Grant, and Miller, Jacques F.A.P. (1994) Genetic requirements for acceleration of diabetes in non-obese diabetic mice expressing interleukin-2 in islet beta cells. European Journal of Immunology, 24 (10). pp. 2535-2541.

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Abstract

In this report we describe the construction of anti-5-iodo-4-hydroxy-3-nitrophen-acetyl (NIP) mouse/human immunoglobulin (Ig)G4 chimeric molecules with altered amino acid residues in the CH2 domain. Three mutants are described: Gln-268 is substituted by His in γ4 Q268H, Ser-331 is substituted by Pro in γ4 S331P, and in γ4 Q268H/S331P both residues are substituted. The ability of the mutant molecules to induce complement-mediated cell lysis (CML) and phagocytosis by FcγRII- and FcγRIII-bearing polymorphonuclear leukocytes (PMN) were measured. In CML, γ4 Q268H was inactive, but both γ4 S331P and γ4 Q268H/S331P were active provided that the antigenic density on the target cells was high. In phagocytosis mediated by PMN, the mutants γ4 S331P and γ4 Q268H/S331P were both active only when complement was introduced. γ4 Q268H was not active in phagocytosis under any conditions. We conclude that His-268 in human IgG molecules does not modulate CML activity or phagocytosis mediated by FcγRII and/or FcγRIII. Pro-331 rescues CML activity in IgG4 molecules when the epitope density on the target cells is high, but does not affect FcγRII/FcγRIII-mediated phagocytosis. In this manner the mutants γ4 S331P and γ4 Q268H/S331P mimic human IgG2. This could indicate a structural similarity between IgG2 and these mutant molecules that distinguish them from both IgG1 and IgG3.

Item ID: 8433
Item Type: Article (Refereed Research - C1)
Keywords: interleukin-2 transgenic mice, non-obese diabetic mice, autoimmunity, diabetes susceptibility genes, cytokines
ISSN: 1524-4141
Date Deposited: 14 Oct 2010 00:52
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110703 Autoimmunity @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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