Amelioration of SLE-like manifestations in (NZBxNZW)F1 mice following treatment with a peptide based on the complementarity determining region 1 of an autoantibody is associated with a down-regulation of apoptosis and of the pro-apoptotic factor JNK kinase.
Treatment with peptides based on the complementarity determining regions (CDR) of murine and human monoclonal anti-DNA antibodies that bear the common idiotype, 16/6 Id, ameliorates disease manifestations of mice with either induced or spontaneous SLE. Aberrant expression and function of the p21Ras/MAP kinase pathway are associated with active SLE. Therefore, we examined the effect of treatment with a CDR1-based peptide of a human autoantibody (hCDR1) on the p21Ras pathway and SLE manifestations of SLE-prone (NZBxNZW)F1 mice. Untreated SLE-afflicted mice demonstrated increased expression of p21Ras and the phosphorylated active form of its down-stream element JNK kinase in conjunction with reduced hSOS and unchanged p120GAP, as compared to healthy controls. Amelioration of SLE manifestations following treatment with hCDR1 was associated with a diminished expression of phosphorylated JNK kinase, mainly in the T cell population that also exhibited reduced rates of apoptosis. Thus, hCDR1 therapy ameliorates SLE, at least in part, via down-regulation of the activity of the pro-apoptotic JNK kinase.
Rapoport
Micha J
MJ
Department C of Internal Medicine, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
Sharabi
Amir
A
Aharoni
Dorit
D
Bloch
Olga
O
Zinger
Heidy
H
Dayan
Molly
M
Mozes
Edna
E
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000187:drug effects* / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D022801:Complementarity Determining Regions / Q000627:therapeutic use*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D007114:Immunization; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D008814:Mice, Inbred NZB; D010446:Peptide Fragments / Q000627:therapeutic use*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
D001323:Autoantibodies; D022801:Complementarity Determining Regions; D010446:Peptide Fragments; D048670:MAP Kinase Kinase 4; D016283:Proto-Oncogene Proteins p21(ras)