Macrophages act as effectors of tissue damage in acute renal allograft rejection

Background. Macrophages constitute 38% to 60% of infiltrating cells during acute renal allograft rejection. Their contribution to tissue damage during acute rejection was; examined by depleting macrophages in a rat model. Methods. Lewis rats underwent bilateral nephrectomy and then received a Dark Agouti renal allograft and liposomal-clodronate, control phosphate-buffered saline liposomes, or saline intravenously (n=7 per group) on days 1 and 3 postsurgery. Grafts were harvested on day 5. Results. Liposomal-clodronate treatment resulted in a 70% reduction in blood ED1(+) monocytes and 60% reduction in intragraft ED1(+) macrophages (both P<0.01). Half of all remaining interstitial ED1(+) cells were undergoing apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling(+)/ED1(+)), and thus functional depletion of more than 75% of macrophages was achieved. Histologic and functional parameters of acute rejection were attenuated: interstitial infiltrate, tubulitis, and glomerulitis (P<0.01); tubular cell apoptosis (P<0.001); tubular cell proliferation (P<0.01); and serum creatinine (P<0.01). Production of inducible nitric oxide synthase by infiltrating cells and urinary nitric oxide excretion was reduced by 90% (P<0.001). In contrast, no reduction in the number of other leukocytes was seen (CD3(+), CD4(+), CD8(+), and natural killer cells). Activation of lymphocytes (CD25(+)) and production of lymphocyte effector molecules (granzyme B) were unaltered. Conclusion. This study demonstrates that macrophages contribute to tissue damage during acute rejection.