Potential of Peptide Therapeutics for Treating Lupus Patients

Relatively recently has emerged the idea of using peptides described as sequences able to modulate the autoimmune response, as these peptides will only target specific autoreactive B and T cells (Singh 2000). Several successful attempts of peptide-based therapy have been described in murine model of lupus (Monneaux and Muller 2004). Some peptides corresponding to antibody idiotypes—for example the pCONS peptide, a consensus peptide derived from the variable heavy chain (VH) region of NZBxNZW (BW) IgG antibodies to DNA and predicted to possess T cell stimulatory activity (Hahn et al. 2001; Hahn et al. 2005), or peptides derived from the sequence of the complementary-determining regions 1 and 3 (pCDR1 and pCDR3) of a human anti-DNA monoclonal antibody that bears the so-called 16/6 Id (Zinger et al. 2003)—have been used with remarkable efficacy in BW lupus mice. An impressive protective effect was also observed in MRL/lpr mice with a peptide identified using combinatorial chemistry approaches and able to interfere with Fcy-receptor recognition (Marino et al. 2000). For therapeutic application, this immunoglobulin-binding peptide (called TG19320) was used as a protease-resistant tetrameric tripeptide containing D-amino acid residues.

Regarding peptides from nuclear autoantigens, Datta and colleagues showed that repeated intravenous (i.v.) or intraperitoneal (i.p.) administration into (SWRxNZB)Fl (SNF1) lupus mice with established glomerulonephritis of a single peptide of histone H4 (sequences 16-39), which behaves as a "promiscuous" T cell epitope, prolonged survival of treated animals and halted progression of renal disease (Kaliyaperumal et al. 1999). The protective properties of another peptide of histone H4 (sequences 71-93) accompanied by an increased level of IL-10 and suppression of IFN-y secreted by lymph node (LN) cells were described by Staines and collaborators who administrated the peptide to SNF1 mice by the intranasal (i.n.) route (Wu et al. 2002). Wu and Staines (2004) showed further that following i.n. (but not intradermal) administration of H4 peptides 71-93, the number of CD4/CD25+ regulatory T cells, which is low in BW and SNF1 mice as compared with normal mice, was restored in both strains. Very low-dose therapy of SNF1 mice with H4 peptides 71-94 was also found to induce CD8+ and CD4/CD25+ regulatory T cells containing autoantigen-specific cells to decrease IFN-y levels secreted by pathogenic T cells and to decrease the antibody levels by 90-100% (Kang et al. 2005). The histone H3 peptides 111-130 encompassing a T cell epitope in BW mice was also used with success when administrated intradermally (4 X 100 ^g in Freund's adjuvant) into BW mice (Suen et al. 2004). Treatment (5 X 80 ^g i.p. in saline weekly for 260 days) of MRL/lpr mice with a 21-mer peptide of laminin a-chain targeted by lupus antibodies also prevented antibody deposition in the kidneys, ameliorated renal disease, decreased the weight gain caused by accumulating ascitic fluid and markedly improved longevity of treated mice (Amital et al. 2005).

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