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Protein-engineered molecules carrying GAD65 epitopes and targeting CD35 selectively down-modulate disease-associated human B lymphocytes.
- Source :
-
Clinical and experimental immunology [Clin Exp Immunol] 2019 Sep; Vol. 197 (3), pp. 329-340. Date of Electronic Publication: 2019 May 09. - Publication Year :
- 2019
-
Abstract
- Type 1 diabetes mellitus is an autoimmune metabolic disorder characterized by chronic hyperglycemia, the presence of autoreactive T and B cells and autoantibodies against self-antigens. A membrane-bound enzyme on the pancreatic beta-cells, glutamic acid decarboxylase 65 (GAD65), is one of the main autoantigens in type 1 diabetes. Autoantibodies against GAD65 are potentially involved in beta-cell destruction and decline of pancreatic functions. The human complement receptor type 1 (CD35) on B and T lymphocytes has a suppressive activity on these cells. We hypothesized that it may be possible to eliminate GAD65-specific B cells from type 1 diabetes patients by using chimeric molecules, containing an anti-CD35 antibody, coupled to peptides resembling GAD65 B/T epitopes. These molecules are expected to selectively bind the anti-GAD65 specific B cells by the co-cross-linking of the immunoglobulin receptor and CD35 and to deliver a suppressive signal. Two synthetic peptides derived from GAD65 protein (GAD65 epitopes) and anti-CD35 monoclonal antibody were used for the construction of two chimeras. The immunomodulatory activity of the engineered antibodies was tested in vitro using peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients. A reduction in the number of anti-GAD65 IgG antibody-secreting plasma cells and increased percentage of apoptotic B lymphocytes was observed after treatment of these PBMCs with the engineered antibodies. The constructed chimeric molecules are able to selectively modulate the activity of GAD65-specific B lymphocytes and the production of anti-GAD65 IgG autoantibodies by co-cross-linking of the inhibitory CD35 and the B cell antigen receptor (BCR). This treatment presents a possible way to alter the autoimmune nature of these cells.<br /> (© 2019 British Society for Immunology.)
- Subjects :
- Adult
Autoantibodies genetics
Autoantibodies immunology
Diabetes Mellitus, Type 1 drug therapy
Diabetes Mellitus, Type 1 genetics
Diabetes Mellitus, Type 1 immunology
Diabetes Mellitus, Type 1 pathology
Female
Humans
Male
Receptors, Antigen, B-Cell genetics
Receptors, Antigen, B-Cell immunology
Recombinant Fusion Proteins chemistry
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins pharmacology
Antibodies, Monoclonal chemistry
Antibodies, Monoclonal genetics
Antibodies, Monoclonal pharmacology
Epitopes, B-Lymphocyte chemistry
Epitopes, B-Lymphocyte genetics
Epitopes, B-Lymphocyte pharmacology
Glutamate Decarboxylase chemistry
Glutamate Decarboxylase genetics
Glutamate Decarboxylase pharmacology
Peptides chemistry
Peptides genetics
Peptides pharmacology
Protein Engineering
Receptors, Complement 3b antagonists & inhibitors
Receptors, Complement 3b genetics
Receptors, Complement 3b immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2249
- Volume :
- 197
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Clinical and experimental immunology
- Publication Type :
- Academic Journal
- Accession number :
- 31009057
- Full Text :
- https://doi.org/10.1111/cei.13305