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Protective effect of an Anti-LFA 1 monoclonal antibody (odulimomab) on renal damage due to ischemia and kidney autotransplantation
Protective Effect of an Anti-LFA 1 Monoclonal Antibody (Odulimomab) on Renal Damage Due to Ischemia and Kidney Autotransplantation X. Martin, M. Da Silva, S.R. Virieux, A. Hadj Aissa, R. Buffet, J. Tiollier, and J.M. Dubernard
I
SCHEMIA-reperfusion injury may influence the initial graft function as well as the development of acute and chronic rejection.1 Ischemia-reperfusion injury involves production of proinflammatory mediators, which regulate the expression of different cell-surface adhesion proteins on endothelial cells and the activation of leukocytes associated with cell-endothelial and cell-cell adhesion.2,3 The purpose of this study is to evaluate the effects of blocking LFA-1 using odulimomab, an anti-LFA-1 monoclonal antibody (MAb) in a primate model. MATERIALS AND METHODS Seventeen monkeys (cynomolgus monkeys weighing between 2.5 and 5.4 kg) were used in the experiments. The animals were under general anesthesia. Surgical procedure consisted of dissection of the left kidney, warm ischemia by cross-clamping the renal pedicle (35 to 45 minutes), section of the pedicle, and a flush of EuroCollins solution with 2 hours of cold ischemia; then autotransplantation and right nephrectomy. The monkeys were divided into two groups: odulimomab-treated group (n ⫽ 9), which received the first dose of odulimomab (1.5 mg/kg IV) after pedicle clamping followed by daily injection of 0.75 mg/kg until sacrifice, and an untreated control group (n ⫽ 8). Serum creatinine, glomerular, and tubular functions were studied before ischemia and at 3 days after ischemia and autotransplantation.
RESULTS
Before the experimental ischemia, the animals of both groups showed a mean glomerular filtration rate (GFR) for the two kidneys of 1.27 ⫾ 0.71 mL 䡠 kg⫺1 䡠 min⫺1. At 3 days, the GFR was 1.24 ⫾ 0.26 mL/min/kg in the odulimomabtreated group vs 0.87 ⫾ 0.39 mL 䡠 kg⫺1 䡠 min⫺1 in the control group (P ⬍ .05). At the same time point, potassium fraction reabsorption was ⫹51.3% in the odulimomabtreated group vs ⫺9.2% in the control group (P ⬍ .05).
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 32, 481 (2000)
Serum creatinine clearance increased about threefold over baseline 24 hours after ischemia and autotransplantation in both groups. Three days after ischemia and autotransplantation, the creatinine level decreased and this evolution was more evident in the odulimomab-treated group. DISCUSSION
The model of ischemia-reperfusion injury with autotransplantation of the kidney in primates has been shown to provide a reproducible model of human cadaveric renal transplantation. In the present study, this model was used to investigate the effects of odulimomab, a MAb against the adhesion molecule LFA-1, which has been developed for kidney transplantation.4 Our results showed that odulimomab offers a significant protection against ischemia and reperfusion injury and reduces the impairment in renal function after transplantation. Further studies are required to investigate its protective mechanism of action. REFERENCES 1. Akinlolu O, Robert A, et al: Transplantation 63:968, 1997 2. Rabb H, Mendiola C, Dietz J, et al: Am Phys Soc F1052, 1994 3. Linas SL, Whittenburg D, Parsons PE, et al: Kidney Int 48:1584, 1995 4. Kelly KJ, Williams WW, Colvin RB, et al: Proc Natl Acad Sci USA 91:812, 1994 From the Service d’Urologie et Chirurgie de la Transplantation (X.M., M.D., S.R.V., A.H.A., J.M.D.), Hoˆpital Edouard Herriot, Lyon, France. Address reprint requests to X. Martin, Service d’Urologie et Chirurgie de la Transplantation, Hoˆpital Edouard Herriot, Lyon, France.
0041-1345/00/$–see front matter PII S0041-1345(00)00849-6 481
I
SCHEMIA-reperfusion injury may influence the initial graft function as well as the development of acute and chronic rejection.1 Ischemia-reperfusion injury involves production of proinflammatory mediators, which regulate the expression of different cell-surface adhesion proteins on endothelial cells and the activation of leukocytes associated with cell-endothelial and cell-cell adhesion.2,3 The purpose of this study is to evaluate the effects of blocking LFA-1 using odulimomab, an anti-LFA-1 monoclonal antibody (MAb) in a primate model. MATERIALS AND METHODS Seventeen monkeys (cynomolgus monkeys weighing between 2.5 and 5.4 kg) were used in the experiments. The animals were under general anesthesia. Surgical procedure consisted of dissection of the left kidney, warm ischemia by cross-clamping the renal pedicle (35 to 45 minutes), section of the pedicle, and a flush of EuroCollins solution with 2 hours of cold ischemia; then autotransplantation and right nephrectomy. The monkeys were divided into two groups: odulimomab-treated group (n ⫽ 9), which received the first dose of odulimomab (1.5 mg/kg IV) after pedicle clamping followed by daily injection of 0.75 mg/kg until sacrifice, and an untreated control group (n ⫽ 8). Serum creatinine, glomerular, and tubular functions were studied before ischemia and at 3 days after ischemia and autotransplantation.
RESULTS
Before the experimental ischemia, the animals of both groups showed a mean glomerular filtration rate (GFR) for the two kidneys of 1.27 ⫾ 0.71 mL 䡠 kg⫺1 䡠 min⫺1. At 3 days, the GFR was 1.24 ⫾ 0.26 mL/min/kg in the odulimomabtreated group vs 0.87 ⫾ 0.39 mL 䡠 kg⫺1 䡠 min⫺1 in the control group (P ⬍ .05). At the same time point, potassium fraction reabsorption was ⫹51.3% in the odulimomabtreated group vs ⫺9.2% in the control group (P ⬍ .05).
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 32, 481 (2000)
Serum creatinine clearance increased about threefold over baseline 24 hours after ischemia and autotransplantation in both groups. Three days after ischemia and autotransplantation, the creatinine level decreased and this evolution was more evident in the odulimomab-treated group. DISCUSSION
The model of ischemia-reperfusion injury with autotransplantation of the kidney in primates has been shown to provide a reproducible model of human cadaveric renal transplantation. In the present study, this model was used to investigate the effects of odulimomab, a MAb against the adhesion molecule LFA-1, which has been developed for kidney transplantation.4 Our results showed that odulimomab offers a significant protection against ischemia and reperfusion injury and reduces the impairment in renal function after transplantation. Further studies are required to investigate its protective mechanism of action. REFERENCES 1. Akinlolu O, Robert A, et al: Transplantation 63:968, 1997 2. Rabb H, Mendiola C, Dietz J, et al: Am Phys Soc F1052, 1994 3. Linas SL, Whittenburg D, Parsons PE, et al: Kidney Int 48:1584, 1995 4. Kelly KJ, Williams WW, Colvin RB, et al: Proc Natl Acad Sci USA 91:812, 1994 From the Service d’Urologie et Chirurgie de la Transplantation (X.M., M.D., S.R.V., A.H.A., J.M.D.), Hoˆpital Edouard Herriot, Lyon, France. Address reprint requests to X. Martin, Service d’Urologie et Chirurgie de la Transplantation, Hoˆpital Edouard Herriot, Lyon, France.
0041-1345/00/$–see front matter PII S0041-1345(00)00849-6 481