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Suppression of Disease-Associated B Lymphocytes by GAD65 Epitope-Carrying Protein-Engineered Molecules in a Streptozotocin-Induced Mouse Model of Diabetes

Suppression of Disease-Associated B Lymphocytes by GAD65 Epitope-Carrying Protein-Engineered Molecules in a Streptozotocin-Induced Mouse Model of Diabetes

Iliyan Konstantinov Manoylov, Gabriela Valentinova Boneva, Irini Atanas Doytchinova, Nikolina Mihaylova Mihaylova, Andrey Ivanov Tchorbanov

Monoclon Antib Immunodiagn Immunother. 2019 Oct;38(5):201-208.

PMID: 31603741

Abstract:

Type 1 diabetes mellitus is an autoimmune syndrome defined by the presence of autoreactive T and B cells, which results in destruction of insulin-producing beta cells. Autoantibodies against GAD65 (glutamic acid decarboxylase 65)-a membrane-bound enzyme on pancreatic beta cells, contribute to beta cells' destruction and the loss of pancreatic functions. Mouse FcγRIIb on B lymphocytes possesses an inhibitory effect on the activity of these cells. We hypothesized that it may be possible to suppress GAD65-specific B cells in mice with diabetes using chimeric molecules, containing an anti-FcγRIIb antibody, coupled to peptide B/T epitopes derived from the GAD65 protein. With these engineered chimeras, we expect to selectively co-cross-link the anti-GAD65-specific B cell receptor (BCR) and FcγRIIb, thus delivering a suppressive signal to the targeted B cells. An anti-FcγRIIb monoclonal antibody and two synthetic peptide epitopes derived from the GAD65 molecule were used for chimeras' construction. The suppressive activity of the engineered molecules was tested in vivo in mice with streptozotocin (STZ)-induced type 1 diabetes. These chimeric molecules exclusively bind disease-associated B cells by recognizing their GAD65-specific BCR and selectively deliver a strong inhibitory signal through their surface FcγRIIb receptors. A reduction in the number of anti-GAD65 IgG antibody-secreting plasmocytes and an increased percentage of apoptotic B lymphocytes were observed after treatment with protein-engineered antibodies of mice with STZ-induced type 1 diabetes.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4247653	Monoclonal Anti-GAD65 antibody produced in mouse			Price

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