PMID- 10666482
OWN - NLM
STAT- MEDLINE
DCOM- 20000301
LR  - 20181113
IS  - 1076-1551 (Print)
IS  - 1528-3658 (Electronic)
IS  - 1076-1551 (Linking)
VI  - 5
IP  - 12
DP  - 1999 Dec
TI  - RDP1258, a new rationally designed immunosuppressive peptide, prolongs allograft 
      survival in rats: analysis of its mechanism of action.
PG  - 820-32
AB  - Peptides derived from the HLA class I heavy chain (a.a. 75-84) have been shown to 
      modulate immune responses in vitro and in vivo in a non-allele-restricted 
      fashion. In vivo studies in rodents have demonstrated prolonged allograft 
      survival following peptide therapy. The immunomodulatory effect of these peptides 
      has been correlated with peptide-mediated modulation of heme oxygenase 1 activity 
      (HO-1). Recently, we used a rational approach for designing novel peptides with 
      enhanced immunosuppressant activity. These peptides were also more potent 
      inhibitors of HO-1 activity in vitro. Here we evaluated one of these peptides, 
      RDP1258, for its ability to prolong heterotopic heart graft survival in rats. The 
      peptide mediated effect on HO-1 was analyzed in vitro and in vivo. Peptide 
      RDP1258 was shown to inhibit rat HO-1 in vitro in a dose-dependent fashion. 
      However, RDP1258, like other HO-inhibitors, when administered to rats, 
      secondarily resulted in an up-regulation of splenic HO-1 activity. Up-regulation 
      of HO-1 was associated with prolonged heart allograft survival (6.6 +/- 0.6 vs. 
      2/14 > 100 days and 12/14 16.2 +/- 1.7 days; p < 0.001). The analysis of graft 
      infiltrating cells on day 5 after transplantation showed a significant decrease 
      in the number of graft infiltrating cells in RDP1258-treated recipients compared 
      to untreated ones (14.8 vs. 32.7%; p < 0.01). In addition, grafts from 
      peptide-treated animals showed significantly decreased expression of TNF-alpha 
      mRNA and increased levels of iNOS mRNA. Our results are consistent with the 
      recent observation that up-regulation of HO-1 results in the inhibition of 
      several immune effector functions. Modulation of HO-1 activity may enable the 
      development of novel immunomodulatory strategies in humans.
FAU - Cuturi, M C
AU  - Cuturi MC
AD  - ITERT/INSERM U437, Nantes, France. ccuturi@nantes.inserm.fr
FAU - Christoph, F
AU  - Christoph F
FAU - Woo, J
AU  - Woo J
FAU - Iyer, S
AU  - Iyer S
FAU - Brouard, S
AU  - Brouard S
FAU - Heslan, J M
AU  - Heslan JM
FAU - Pignon, P
AU  - Pignon P
FAU - Soulillou, J P
AU  - Soulillou JP
FAU - Buelow, R
AU  - Buelow R
LA  - eng
PT  - Journal Article
PL  - England
TA  - Mol Med
JT  - Molecular medicine (Cambridge, Mass.)
JID - 9501023
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Isoantibodies)
RN  - 0 (Oligopeptides)
RN  - 0 (Protoporphyrins)
RN  - 0 (RDP 1258)
RN  - 0 (RNA, Messenger)
RN  - 63AAN3JDZE (cobaltiprotoporphyrin)
RN  - EC 1.14.14.18 (Heme Oxygenase (Decyclizing))
SB  - IM
MH  - Adjuvants, Immunologic/chemical synthesis/*pharmacology
MH  - Animals
MH  - Cell Movement/drug effects/immunology
MH  - Cytotoxicity, Immunologic/drug effects
MH  - Enzyme Inhibitors/immunology/pharmacology
MH  - Graft Survival/*drug effects
MH  - Heart Transplantation/immunology/pathology
MH  - Heme Oxygenase (Decyclizing)/antagonists & inhibitors/metabolism
MH  - Immunosuppressive Agents/chemical synthesis/*pharmacology
MH  - Isoantibodies/biosynthesis
MH  - Male
MH  - Oligopeptides/chemical synthesis/*pharmacology
MH  - Protoporphyrins/immunology/pharmacology
MH  - RNA, Messenger/biosynthesis
MH  - Rats
MH  - Rats, Inbred Lew
PMC - PMC2230490
EDAT- 2000/02/10 09:00
MHDA- 2000/03/04 09:00
PMCR- 1999/12/01
CRDT- 2000/02/10 09:00
PHST- 2000/02/10 09:00 [pubmed]
PHST- 2000/03/04 09:00 [medline]
PHST- 2000/02/10 09:00 [entrez]
PHST- 1999/12/01 00:00 [pmc-release]
AID - 0215 [pii]
PST - ppublish
SO  - Mol Med. 1999 Dec;5(12):820-32.