Tolerization of NZBW mice to monthly intravenous injections of 1 mg pCons significantly delayed the appearance of multiple Abs and nephritis, and dramatically prolonged survival of treated mice. Tolerization with pCons, which contains MHC class I and II T cell determinants, was shown recently to activate different subsets of inhibitorycytotoxic CD8 T cells that regulate both CD4CD25 effector T cells and B cells. The tolerogenic 19 mer human CDR1 peptide designed by Mozes and colleagues was found to interfere with murine lupus disease via the induction of CD4CD25 regulatory T cells, and suppression involves CD8CD28 regulatory T cells. As mentioned above, however, this peptide did not give expected results when evaluated in lupus patients.
Regarding peptides from nuclear autoantigens, Datta and colleagues showed that repeated intravenous or intra peritoneal administration selleck AGI-5198 into F1 lupus mice with established glomerulonephritis of a single peptide of histone H4, which behaves as a promiscuous T cell epitope, prolonged survival of treated animals and halted progression of renal disease. The protective properties of another peptide of histone H4, accompanied by an increased level of IL 10 and suppression of IFN secreted by lymph node cells, were described in SNF1 mice administrated by the intranasal route. Following intranasal adminis tration of H4 peptide 71 to 93, the number of CD4CD25 regulatory T cells, which is low in NZBW and SNF1 mice as compared with normal mice, was restored in both strains.
Very low dose therapy of SNF1 mice with H4 peptide 71 to 94 was also found to induce CD8 and CD4CD25 regulatory T cells, to decrease IFN levels secreted by pathogenic T cells, and to decrease the Ab levels by 90 to 100%. The histone H3 peptide 111 to 130 encompassing selleckchem Paclitaxel a T cell epitope in NZBW mice was used with success when administrated intradermally in Freunds adjuvant into these mice. Treatment of MRL lprlpr mice with a 21 mer peptide of the laminin chain targeted by lupus Abs also prevented Ab deposition in the kidneys, ameliorated renal disease, decreased the weight gain caused by accumulating ascitic fluid and markedly improved the longevity of treated mice. Prospectives Recent publications describing the successful use of new therapeutic agents in murine models support their further evaluation as therapies for SLE.
In lupus, therefore, the therapeutic potential of targeting Toll like receptors is supported by recent studies involving TLR7 and TLR9. Nonstimulatory DNA sequences, able to inhibit TLR7 and TLR9 activation and referred to as immunoregulatory DNA sequences, have been identified. Interestingly, the adminis tration of one of these immunoregulatory DNA sequences to NZBW mice significantly reduced autoAbs production and proteinuria, and increased survival.