In vitro and in vivo immunomodulatory effects of RDP1258, a novel synthetic peptide.
Peptides derived from certain regions of human class I MHC molecules are known to have immunomodulatory effects. In particular, amino acid residues 75-84 of the HLA-B7 and HLA-B2702 molecules have demonstrated allele nonspecific immunosuppression in several animal transplant models. There is evidence that these effects are mediated by binding to intracellular heat shock proteins, including heme oxygenase-1. A new derivative of these peptides, RDP1258, was developed using a novel computer-assisted rational design technique. In vitro, RDP1258 peptide inhibited rat heme oxygenase activity in a dose-dependent manner. Similar to observations made with other in vitro heme oxygenase inhibitors, in vivo administration of RDP1258 peptide to naive rats resulted in upregulation of splenic heme oxygenase activity. The effects of the peptide on alloimmune responses were then tested. Addition of RDP1258 to rat and human mixed leukocyte reactions inhibited proliferation in a dose-dependent manner. In a rat renal transplantation model, peptide therapy combined with a sub-therapeutic dose of cyclosporin A significantly prolonged allograft survival. These data provide further evidence that modulation of the heat shock protein heme oxygenase by rationally designed peptides affects immune effector functions and may allow the development of novel immunomodulatory strategies in organ transplantation.
Magee
C C
CC
Laboratory of Immunogenetics and Transplantation, Brigham & Women's Hospital, Boston, Massachusetts 02115, USA.
Azuma
H
H
Knoflach
A
A
Denton
M D
MD
Chandraker
A
A
Iyer
S
S
Buelow
R
R
Sayegh
M
M
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D017931:DNA Primers / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects; D053804:Granzymes; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D015395:Histocompatibility Antigens Class I / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016030:Kidney Transplantation / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics
D000276:Adjuvants, Immunologic; D016207:Cytokines; D017931:DNA Primers; D004791:Enzyme Inhibitors; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D052899:Pore Forming Cytotoxic Proteins; C122045:RDP 1258; D054353:Perforin; D007371:Interferon-gamma; D016572:Cyclosporine; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C509213:GZMB protein, human; D053804:Granzymes; C509215:Gzmb protein, rat; D012697:Serine Endopeptidases