A novel immunomodulator KRP-203 combined with cyclosporine prolonged graft survival and abrogated transplant vasculopathy in rat heart allografts.
To find more effective and less toxic immunosuppressive strategies in long-term treatment for organ transplantation patients, we examined the effects on rat heart allograft survival of a novel sphigosine-1-phosphate receptor agonist, KRP-203, combined with a subtherapeutic dose of cyclosporine (CsA). Rat heart transplantation was performed across a major histocompatibility complex-incompatible (DA to LEW) rat combination. KRP-203 alone showed little or no effect on heart allograft survival. In contrast, KRP-203 combined with a subtherapeutic dose of CsA led to prolonged allograft survival. Histologic analyses showed that the combination completely suppressed acute rejection, as characterized by allograft vasculopathy, mononuclear cell infiltration, and myocardial necrosis in the heart allografts. RT-PCR analysis showed that the allografts treated with CsA or KRP-203 alone showed no suppression of IL-10, IFN-gamma, and TNF-alpha mRNA expression, but when combined with a subtherapeutic dose of CsA it completely suppressed their mRNA expressions. Furthermore, the combination treatment reduced donor-specific antibody production. KRP-203 combined with a subtherapeutic dose of CsA synergistically prolonged rat heart allograft survival. The combination of CsA with KRP-203 may provide an option to prevent allograft rejection and reduce adverse effects.
Takahashi
M
M
Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan. masafumi@jichi.ac.jp
Shimizu
H
H
Murakami
T
T
Enosawa
S
S
Suzuki
C
C
Takeno
Y
Y
Hakamata
Y
Y
Kudou
S
S
Izawa
S
S
Yasue
T
T
Kobayashi
E
E
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006650:Histocompatibility Testing; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008285:Major Histocompatibility Complex; D008297:Male; D011183:Postoperative Complications / Q000473:pathology* / Q000517:prevention & control; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*; D014184:Transplantation, Homologous / Q000276:immunology
D016207:Cytokines; D007166:Immunosuppressive Agents; C501899:KRP-203; D013438:Sulfhydryl Compounds; D016572:Cyclosporine