Treatment of lupus patients with a tolerogenic peptide, hCDR1 (Edratide): immunomodulation of gene expression.
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by dysregulation of cytokines, apoptosis, and B- and T-cell functions. The tolerogenic peptide, hCDR1 (Edratide), ameliorated the clinical manifestations of murine lupus via down-regulation of pro-inflammatory cytokines and apoptosis, up-regulation of the immunosuppressive cytokine TGF-beta, and the induction of regulatory T-cells. In the present study, gene expression was determined in peripheral blood mononuclear cells of 9 lupus patients that were treated for 26 weeks with either hCDR1 (five patients), or placebo (four patients). Disease activity was assessed by SLEDAI-2K and the BILAG scores. Treatment with hCDR1 significantly down-regulated the mRNA expression of the pathogenic cytokines IL-1beta, TNF-alpha, IFN-gamma, and IL-10, of BLyS (B-lymphocyte stimulator) and of the pro-apoptotic molecules caspase-3 and caspase-8. In contrast, the treatment up-regulated in vivo gene expression of both TGF-beta and FoxP3. Furthermore, hCDR1 treatment resulted in a significant decrease in SLEDAI-2K (from 8.0+/-2.45 to 4.4+/-1.67; P=0.02) and BILAG (from 8.2+/-2.7 to 3.6+/-2.9; P=0.03) scores. Thus, the tolerogenic peptide hCDR1, immunomodulates, in vivo, the expression of genes that play a role in SLE, consequently restoring the global immune dysregulation of lupus patients. Hence, hCDR1 has a potential role as a novel disease-specific treatment for lupus patients.
The Weizmann Institute of Science, Rehovot, Israel.
Zev M
ZM
Sthoeger
Amir
A
Sharabi
Yair
Y
Molad
Ilan
I
Asher
Heidy
H
Zinger
Molly
M
Dayan
Edna
E
Mozes
D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D022801:Complementarity Determining Regions / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000008:administration & dosage*; D017634:Self Tolerance / Q000276:immunology; D012720:Severity of Illness Index; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D022801:Complementarity Determining Regions; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; C516151:edratide; D020169:Caspases