Allograft dysfunction resulting from ischemic reperfusion injury (IRI) leads to increased peri-transplant costs, morbidity, and inferior long-term survival. Leukocyte/endothelial adhesion is an important pathway contributing to IRI pathogenesis. We evaluated a novel ligand-mimetic monoclonal antibody (mAb 107) that blocks proinflammatory functions of leukocyte integrin CD11b/CD18, acting as a “pure“ inhibitor i.e. it lacks the detrimental partial agonism of other integrin inhibitors.

Methods: Unilateral renal ischemia was induced in eight Cynomolgus monkeys by 2 hour hilar cross clamping. The contralateral ureter was ligated. Four animals were treated with mAb 107 (4-12 mg/Kg) and four with saline or irrelevant mAb. Integrin activation state, renal function studies, and renal biopsies at 2 days, 1 month and terminally (6-9 months) were assessed.

Results: All animals required release of the contralateral ureteral ligature at 2 days because of the severity of ATN in the ischemic kidney. Subsequent biopsies of the IRI kidney in the controls revealed progressive tubulointerstitial fibrosis (fig 1A). Re-ligation of the contralateral (normal kidney) ureter 2 days prior to planned study termination resulted in a rapid rise in serum creatinine confirming loss of life-sustaining function by the IRI kidney. In contrast, renal biopsies in the mAb 107-treated animals showed reversal of the ATN histopathology (fig 1B), and pre-terminal ligation of the contralateral ureter resulted in minimal serum creatinine rise.

Conclusion: Inhibition of CD11b/CD18-mediated leukocyte adhesion at the onset of severe kidney IRI by mAb 107 prevented progressive tubulointerstitial renal fibrosis and salvaged kidney function in primates. Ongoing studies are underway to confirm the efficacy of this approach in a renal transplant model and to profile the profibrotic cytokines and growth factors that drive this fibroinflammatory process H & E stain of control (A) and mAb107-treated kidneys (B)

(10x magnification)

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