Modulation of autoreactive responses of peripheral blood lymphocytes of patients with systemic lupus erythematosus by peptides based on human and murine anti-DNA autoantibodies

Abstract

SUMMARYTwo peptides, based on the sequences of the complementarity-determining regions (CDR) 1 and 3 of a pathogenic murine monoclonal anti-DNA autoatibody that bears the 16/6 idiotype (Id), were shown to either prevent or treat an already established systemic lupus erythematosus (SLE) in two murine models of lupus. Two additional peptides based on the human monoclonal anti-DNA, 16/6 Id were synthesized. This study was undertaken in order to investigate the ability of the CDR-based peptides to immunomodulate SLE-associated responses of peripheral blood lymphocytes (PBL) of SLE patients. PBL of 24 of the 62 SLE patients tested proliferated in vitro following stimulation with the human 16/ 6 Id. Peptides based on the CDRs of both the human and murine anti-DNA autoantibodies inhibited efficiently and specifically the 16/6 Id-induced proliferation and IL-2 production. The latter inhibitions correlated with an up-regulated production (by 2·5-3·5-fold) of the immunosuppressive cytokine, TGFb . Overall, the results of our study demonstrate that the CDR-based peptides are capable of down-regulating in vitro autoreactive T cell responses of PBL of SLE patients. Thus, these peptides are potential candidates for a novel specific treatment of SLE patients.

Cerebrospinal fluid T cell clones from patients with multiple sclerosis: recognition of idiotopes on monoclonal IgG secreted by autologous cerebrospinal fluid B cells

“…The cytokine profile of CSF mAb-specific TCC was not clear-cut, as the TCC also produced the Th2 and regulatory cytokines IL-5 and IL-10. Interestingly, CDR-derived peptides from anti-DNA mAb have been reported to inhibit T cell responses to complete CDR-bearing mAb in SLE patients [50]. A potentially dichotomous effect of immune responses to Id has been indicated in BALB/c mice, where an Id was immunogenic when born by IgM, but tolerogenic when born by IgG [51].…”

A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4+CD25+cells and TGF-β

“…A peptide, GYYWSWIRQPPGKGEEWIG, designated hCDR1, based on the CDR1 of the human anti-DNA mAb that bears a major idiotype, 16͞6Id (7,38), was synthesized (solid-phase synthesis by F-moc chemistry) by Polypeptide Laboratories (Torrance, CA) and used in this study. A peptide containing the same amino acids as hCDR1, with a scrambled order (scrambled peptide), SKGIPQYGGWPWEGWRYEI, was used as a control.…”

Down-Regulation of Stromal Cell-Derived Factor-1α-Induced T Cell Chemotaxis by a Peptide Based on the Complementarity-Determining Region 1 of an Anti-DNA Autoantibody via Up-Regulation of TGF-β Secretion

“…The beneficial effects of this treatment were associated with a down-regulated secretion of IFN-␥, IL-10, and TNF-␣ and an up-regulation of TGF-␤ (9, 10). As a potential candidate for the treatment of SLE patients, a peptide based on the sequence of CDR1 of the human 16/6Id mAb, designated human CDR1 (hCDR1), was synthesized (12) and shown to ameliorate lupus manifestations in experimental models (13) and to specifically inhibit the 16/6Id-triggered in vitro proliferation and IL-2 production of PBL derived from SLE patients. The latter was correlated with up-regulated production of TGF-␤ (12) Stromal cell-derived factor-1␣ (SDF-1␣; CXCL12) is a pleiotropic CXC chemokine that affects the function of various cell types, including T cells, via its interactions with the CXCR4 receptor (14).…”