In contrast, inactive derivatives of 2702.75-84 had no effect on HO activity. Therefore, the immunosuppressive effects of the described immunomodulatory peptides are similar to those of cobaltprotoporphyrin, a known up-regulator of HO-1. Our results suggest that HO-1 modulation may be a novel mechanism of immunomodulation.Peptides derived from various regions of the HLA class I heavy chain have been shown to exert immunomodulatory effects by influencing T cell responses (1-4). Clayberger and co-workers (5, 6) studied the less polymorphic region of the HLA class I ␣ 1 -helix (residues 75-84). Peptides corresponding to this region of the HLA-B7 (07.75-84) or HLA-B2702 (2702.75-84) molecule blocked the differentiation of human CTL precursors in vitro in a non-allele-restricted manner (5).The 2702.75-84 peptide inhibited not only differentiation, but also T and NK 1 cell-mediated lysis of target cells in a nonallele-restricted manner. Woo et al. (7) subsequently demonstrated a more powerful effect when the peptides were used in a dimeric form (2702.84 -75-75-84). These peptides have also been studied in vivo in transplantation models. In rats, 07.75-84 induced permanent acceptance of LEW heart allografts in ACI recipients when combined with subtherapeutic doses of cyclosporine A (6). In congeneic LEW.1W donors and LEW.1A recipients, 07.75-84 induced long term graft survival without additional cyclosporine A treatment (8). In a mouse heart transplant model, where C57Bl/6 mice were used as donors and CBA mice as recipients, treatment with both 2702.75-84 and 2702.84 -75-75-84 prolonged graft survival significantly, with B2702.84 -75-75-84 showing a more powerful effect (7, 9, 10). Administration of 2702.75-84 has been shown to prolong the survival of skin allografts significantly when the tail skin of C57Bl/6 mice was grafted on CBA mice (9).Despite the peptide's effectiveness, its mechanism of action is not fully understood. For reasons discussed elsewhere (7, 9, 10) a direct interaction with T cell receptors or NK cell inhibitory receptors can be excluded. The recent observation that both L-and D-enantiomers of peptide 2702.75-84 prolong heart allograft survival in vivo indicated that the peptides' immunomodulatory activity is probably not based on indirect presentation by major histocompatibility class molecules (10). Similarly, the recent hypothesis that peptide 2702.75-84 modulates immune responses by binding to HSP/HSC70 can be excluded because the D-isomer of 2702.75-84 did not bind such proteins (11,12).Based on these observations, we looked for additional proteins that may interact with these immunomodulatory peptides. For these studies, we used a 2702.75-84-derived peptide (D2702.75-84(E 3 V)) with two modifications: (i) synthesis with D-amino acids and (ii) substitution of glutamic acid residue at position 76 in 2702.75-84 with valine. Compared with peptide 2702.75-84, this peptide displayed enhanced immunomodulatory activity in vitro and in vivo (12). Affinity purification using this peptide resulted in th...
Assuming that both D- and L-isomers modulate immune responses by similar mechanisms, these results suggest that the peptides' effect is independent of binding to hsc70.
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