Prolongation of heart xenograft survival in a hamster-to-rat model after therapy with a rationally designed immunosuppressive peptide.
BACKGROUND
Modification of the aminoacid sequence of peptides derived from the HLA class I heavy chain in combination with computer rational design resulted in the development of a peptide, RDP1258, with enhanced immunosuppressive activity.


METHODS
We evaluated the activity of this peptide, analyzing infiltrate by immunohistology and cytokine transcripts by reverse transcriptase-polymerase chain reaction method, in a hamster-to-rat xenograft model where recipients were treated with cobra venom factor (CVF) and peptide.


RESULTS
Although CVF or peptide alone had no effect, a combination of CVF/peptide RDP1258 resulted in a significant prolongation of graft survival (7.9+/-1 vs. 4.5+/-0 and 3.5+/-0 days, P<0.001). This effect was associated with an increased expression of heme oxygenase 1 (HO-1) in spleen, a significant reduced graft infiltrate, and a decrease of tumor necrosis factor-alpha mRNA transcripts (P<0.05) compared with CVF-treated recipients (1.6+/-0.07 vs. 3.3+/-0.3%, P=0.001) on day 3 after transplantation.


CONCLUSIONS
These observations are consistent with the observation that up-regulation of HO-1 results in inhibition of immune effector functions and suggest that the peptide acts, at least partially, through HO-1 regulation.
Institut National de la Santé Et de la Recherche Médicale, Unité 437, Nantes, France. sbrouard@nantes.inserm.fr
S
S
Brouard
M C
MC
Cuturi
P
P
Pignon
R
R
Buelow
P
P
Loth
A
A
Moreau
J P
JP
Soulillou
D000818:Animals; D000906:Antibodies; D003169:Complement Inactivator Proteins / Q000494:pharmacology; D003165:Complement System Proteins / Q000378:metabolism; D006224:Cricetinae; D004546:Elapid Venoms / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000276:immunology; D051547:Heme Oxygenase-1; D007136:Immunoglobulins / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D010455:Peptides / Q000494:pharmacology / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000378:metabolism; D014183:Transplantation, Heterologous / Q000276:immunology*; D015854:Up-Regulation
D000906:Antibodies; D003169:Complement Inactivator Proteins; D004546:Elapid Venoms; D007136:Immunoglobulins; D010455:Peptides; C016310:cobra venom factor; D003165:Complement System Proteins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1