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< 0.001); 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.

Macrophages are key cells in biologic defenses, participating in both the innate and adaptive immune responses. Their ability to act independently, or in concert with other arms of the immune system, allows them to play a vital role in defense of the host.