P-selectin directs T lymphocyte-mediated injury in delayed-type hypersensitivity responses: studies in glomerulonephritis and cutaneous delayed-type hypersensitivity.
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.
Tipping
P G
PG
Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia.
Huang
X R
XR
Berndt
M C
MC
Holdsworth
S R
SR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001485:Basement Membrane / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D018956:CD5 Antigens / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D006968:Hypersensitivity, Delayed / Q000209:etiology / Q000276:immunology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D019007:P-Selectin / Q000276:immunology / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D018956:CD5 Antigens; D019007:P-Selectin