In vitro and in vivo immunomodulatory effects of cobalt protoporphyrin administered in combination with immunosuppressive drugs.
BACKGROUND
Immunosuppressive strategies are designed to take advantage of potential synergies between drugs to possibly decrease the risk of side-effects. In the present study, the ability of Cobalt protoporphyrin (CoPP) to potentiate the effect of the immunosuppressive drugs mycophenolate sodium (MPS) or cyclosporin A (CsA) was explored in vitro and in vivo.


METHODS
In vitro analyses of proliferation and apoptosis were performed on primate T cell cultures, following incubation with the immunosuppressive drugs MPS or CsA, alone or in combination with CoPP. In vivo the effect of CoPP and CsA combination therapy was assessed in a rat heterotopic cardiac allotransplantation model.


RESULTS
In vitro results suggest that co-administration of CoPP with CsA or MPS increases immunosuppressive effects of these drugs when combined with CoPP. In particular, the co-administration of CoPP with CsA resulted in the synergistic induction of lymphocyte apoptosis. In vivo, animals immunosuppressed with CsA (1.5 mg/kg) or CoPP (20 mg/kg) alone, had a median survival of 7 or 8 days, respectively. In contrast, animals immunosuppressed with CsA (1.5 mg/kg) combined with CoPP (20 mg/kg) had significantly prolonged median survival (12 days), compared to recipients treated with CsA or CoPP alone (p<0.05).


CONCLUSIONS
Our in vitro and in vivo studies demonstrate that CoPP can potentiate the immunomodulatory effects of CsA, ultimately extending allograft survival.
Besenzon
Federica
F
Department of Surgical and Gastroenterological Sciences, University of Padua, Ospedale Giustinianeo, Padua, Italy. federica.besenzon@unipd.it
Dedja
Arben
A
Vadori
Marta
M
Bosio
Erika
E
Seveso
Michela
M
Tognato
Elena
E
Polito
Luigino
L
Calabrese
Fiorella
F
Valente
Marialuisa
M
Rigotti
Paolo
P
Ancona
Ermanno
E
Cozzi
Emanuele
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000008:administration & dosage; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D056747:Immunomodulation; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D011524:Protoporphyrins / Q000008:administration & dosage*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D007166:Immunosuppressive Agents; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D016572:Cyclosporine; D009173:Mycophenolic Acid