A peptide based on the complementarity determining region 1 of a human monoclonal autoantibody ameliorates spontaneous and induced lupus manifestations in correlation with cytokine immunomodulation.
A peptide based on the sequence of the complementarity determining region (CDR) 1 of a human monoclonal anti-DNA autoantibody that bears the 16/6 idiotype (16/6Id) was synthesized as a potential candidate for the treatment of SLE patients. The peptide, designated hCDR1, did not induce experimental SLE upon active immunization of mice. The ability of the peptide to treat an already established lupus that was either induced in BALB/c mice or developed spontaneously in (NZB x NZW)F1 mice was tested. Ten weekly injections of hCDR1 (200, 50 microg/mouse) given subcutaneously mitigated disease manifestations (e.g., leukopenia, proteinuria and kidney damage) and resulted in a prominent reduction in the dsDNA specific antibody titers. Furthermore, treatment with hCDR1 resulted in reduced secretion and expression of the "pathogenic" cytokines [i.e., INFgamma, IL-1beta, TNFalpha (in the induced model) and IL-10], whereas the immunosuppressive cytokine TGFbeta was up-regulated. Thus, the significant ameliorating effects of hCDR1 are manifested at least partially via the immunomodulation of the cytokine profile. These results suggest that hCDR1 is a potential candidate for a novel treatment of SLE patients.
Luger
Dror
D
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Dayan
Molly
M
Zinger
Heidy
H
Liu
Jian-Ping
JP
Mozes
Edna
E
D000818:Animals; D000974:Antibodies, Antinuclear / Q000187:drug effects; D000911:Antibodies, Monoclonal / Q000187:drug effects; D001323:Autoantibodies / Q000187:drug effects*; D022801:Complementarity Determining Regions / Q000627:therapeutic use*; D016207:Cytokines / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007114:Immunization; D007155:Immunologic Factors / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D022801:Complementarity Determining Regions; D016207:Cytokines; D007155:Immunologic Factors; D010446:Peptide Fragments