P‐selectin directs T lymphocyte‐mediated injury in delayed‐type hypersensitivity responses: studies in glomerulonephritis and cutaneous delayed‐type hypersensitivity

Abstract

The role of P-selectin in T-lymphocyte accumulation and injury was studied in delayed-type hypersensitivity (DTH) responses in the skin and glomeruli of rats. Sprague Dawley rats were sensitized to sheep globulin and challenged 5 days later in the skin by subcutaneous injection and simultaneously in glomeruli by intravenous injection of a subnephritogenic dose of sheep anti-rat glomerular basement membrane globulin. This resulted in cutaneous and glomerular T lymphocyte-dependent macrophage influx and injury characteristic of DTH. Up-regulation of P-selectin expression on endothelial cells was observed in both inflammatory lesions. Treatment of rats with anti-CD5 antibody immediately prior to antigen challenge prevented the development of injury as assessed by measurement of proteinuria and skin swelling, as well as local T cell and macrophage accumulation in the glomerulus and in the skin, but did not block up-regulation endothelial cell P-selectin. Treatment with anti-CD4 antibody produced similar results. Blocking P-selectin in vivo with a functionally inhibitory antibody prevented development of proteinuria and skin swelling following antigen challenge. Local accumulation of T cells and macrophages was markedly attenuated in glomeruli and the skin and up-regulation of endothelial cell P-selectin was prevented. These data demonstrate that P-selectin is locally up-regulated on endothelial cells in T cell-dependent glomerular and cutaneous inflammation and suggests a pivotal functional role for P-selectin in local T cell recruitment and subsequent injury in DTH.

Leukocyte Recruitment to the Inflamed Glomerulus: A Critical Role for Platelet-Derived P-Selectin in the Absence of Rolling

“…Evidence from histological studies has demonstrated a role for adhesion molecule-mediated leukocyte recruitment to glomeruli (17)(18)(19)(20)(21)37). Moreover, findings such as the inhibitory effect of P-selectin blockade on leukocyte recruitment have suggested that the conventional sequence of rolling preceding adhesion applies in glomerular vessels (20,22). However, this has never been demonstrated directly.…”

“…P-selectin inhibition has been shown to reduce glomerular leukocyte recruitment and renal injury, suggesting that P-selectin-mediated rolling interactions contribute to efficient glomerular leukocyte recruitment (20,22). In contrast, other work has shown that P-selectin-deficient (P-selectin Ϫ/Ϫ ) mice have increased levels of glomerular recruitment and renal damage, suggesting that not only is P-selectin not required, it may actually inhibit glomerular leukocyte recruitment (23,24).…”

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

“…P-selectin is an adhesion molecule that is expressed on platelets and several other cell types, and the level of P-selectin has been reported to be elevated in other autoinflammatory diseases, in which it has also been recognized as a circulating disease marker (11)(12)(13). The prominence of P-selectin in experimentally induced immune nephritis has also been quite extensively studied (34)(35)(36)(37). Interestingly, a protective role for endothelial P-selectin in immune nephritis has been suggested (37).…”

IL-18 Has IL-12-Independent Effects in Delayed-Type Hypersensitivity: Studies in Cell-Mediated Crescentic Glomerulonephritis

“…Tissue sections (6 m) were stained to demonstrate CD4 ϩ cells, CD8 ϩ cells, and macrophages using a three-layer immunoperoxidase technique, as previously described (33)(34)(35). The primary mAb were GK1.5 (anti-mouse CD4, American Type Culture Collection, Manassas, VA), 53-6.7 (anti-mouse CD8, American Type Culture Collection), and M1/70 (antimouse Mac-1, American Type Culture Collection).…”