TIRC7 is induced in rejected human kidneys and anti-TIRC7 mAb with FK506 prolongs survival of kidney allografts in rats.
TIRC7 delivers essential signals during immune activation as antibodies targeting TIRC7 inhibit lymphocyte proliferation and Th1 cytokine expression in vitro and prolonged kidney and heart allograft survival in vivo. Immunohistochemical analysis of biopsy specimens from human renal allografts undergoing rejection despite treatment with Calcineurin inhibitors (CI) showed elevated TIRC7 expression. Accordingly, with a view to clinical application, we evaluated the therapeutic effect of a chimerized anti-TIRC7 mAb in combination with Tacrolimus (FK506) using a rat kidney transplantation model (DA to Lewis). The combination of sub-therapeutic doses of both compounds significantly (p<0.05) prolonged the median graft survival to 19.5 days compared to monotherapy with FK506 (median survival, 7d) or mAb against TIRC7 (7d). These results suggest a potential synergism of anti-TIRC7 mAb and FK506 action, which could be developed into a novel combination therapy in the clinic by lowering side effects of present CI treatment. Moreover, the identification of TIRC7 in graft infiltrating lymphocytes might serve as a diagnostic marker to detect allograft rejection.
Kumamoto
Yusuke
Y
School of Medicine, Keio University, Tokyo, Japan.
Tamura
Akihiko
A
Volk
Hans-Dieter
HD
Reinke
Petra
P
Löhler
Jürgen
J
Tullius
Stefan G
SG
Utku
Nalân
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015153:Blotting, Western; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology*; D008297:Male; D018613:Microscopy, Confocal; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000627:therapeutic use*; D014184:Transplantation, Homologous; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000276:immunology*
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D025262:Vacuolar Proton-Translocating ATPases; D016559:Tacrolimus