Target silencing of disease-associated B-lymphocytes by chimeric molecules in SCID model of pristane-induced autoimmunity.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the generation of autoantibodies against a diverse array of self-antigens. The B cells producing immunoglobulin G (IgG) antibodies to double-stranded DNA appear to play a main role in the disease progression. Their specific elimination is a reasonable mechanism for effective therapy of SLE. The presently used approaches for silencing autoreactive disease-associated B cells are nonspecific and more precise therapies are needed. We have previously constructed a chimeric protein molecule consisting of several DNA-mimotope peptides coupled to a rat monoclonal anti-mouse CD32 (FcγRIIb) antibody. The mineral oil pristane induces a lupus-like syndrome in non-autoimmune mice leading to the development of glomerulonephritis and lupus-associated autoantibodies. In the present paper, using a pristane-induced autoimmune model in SCID mice, we analyzed the ability of the chimeric antibody to suppress selectively the autoreactive B lymphocytes by cross-linking B-cell surface immunoglobulin receptors with the inhibitory IgG FcγRIIb receptors. Treatment with DNA-like chimeric molecules inhibited B- and T-cell proliferation, restricted the number of anti-DNA antibody-producing cells and suppressed the generation of IgG anti-DNA antibodies. In contrast, phosphate buffered saline (PBS)-injected control mice experienced an increase of disease-associated antibody levels and developed glomerulonephritis similar to pristane-treated donor Balb/c mice.
Department of Immunology, Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
I
I
Dimitrova
V
V
Gesheva
K
K
Nikolova
N
N
Mihaylova
T
T
Todorov
M
M
Nikolova
A
A
Tchorbanov
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002460:Cell Line; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004247:DNA / Q000276:immunology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D051381:Rats; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013729:Terpenes / Q000494:pharmacology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D013729:Terpenes; C009042:pristane; D004247:DNA