Generation of gene-engineered chimeric DNA molecules for specific therapy of autoimmune diseases.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the development of self-reactive B and T cells and autoantibody production. In particular, double-stranded DNA-specific B cells play an important role in lupus progression, and their selective elimination is a reasonable approach for effective therapy of SLE. DNA-based vaccines aim at the induction of immune response against the vector-encoded antigen. Here, we are exploring, as a new DNA-based therapy of SLE, a chimeric DNA molecule encoding a DNA-mimotope peptide, and the Fv but not the immunogenic Fc fragment of an FcγRIIb-specific monoclonal antibody. This DNA construct was inserted in the expression vector pNut and used as a naked DNA vaccine in a mouse model of lupus. The chimeric DNA molecule can be expressed in eukaryotic cells and cross-links cell surface receptors on DNA-specific B cells, delivering an inhibitory intracellular signal. Intramuscular administration of the recombinant DNA molecule to lupus-prone MRL/lpr mice prevented increase in IgG anti-DNA antibodies and was associated with a low degree of proteinuria, modulation of cytokine profile, and suppression of lupus nephritis.
Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.
Vera
V
Gesheva
Zsuzsanna
Z
Szekeres
Nikolina
N
Mihaylova
Iliyana
I
Dimitrova
Maria
M
Nikolova
Anna
A
Erdei
Jozsef
J
Prechl
Andrey
A
Tchorbanov
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005818:Genetic Engineering; D007074:Immunoglobulin G / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010455:Peptides / Q000737:chemistry / Q000235:genetics*; D010957:Plasmids / Q000235:genetics / Q000627:therapeutic use*; D057127:Single-Chain Antibodies / Q000235:genetics* / Q000378:metabolism
D000974:Antibodies, Antinuclear; D016207:Cytokines; D007074:Immunoglobulin G; D010455:Peptides; D057127:Single-Chain Antibodies