A monoclonal antibody against kininogen reduces inflammation in the HLA-B27 transgenic rat.
The human leukocyte antigen B27 (HLA-B27) transgenic rat is a model of human inflammatory bowel disease, rheumatoid arthritis and psoriasis. Studies of chronic inflammation in other rat models have demonstrated activation of the kallikrein-kinin system as well as modulation by a plasma kallikrein inhibitor initiated before the onset of clinicopathologic changes or a deficiency in high-molecular-mass kininogen. Here we study the effects of monoclonal antibody C11C1, an antibody against high-molecular-mass kininogen that inhibits the binding of high-molecular-mass kininogen to leukocytes and endothelial cells in the HLA-B27 rat, which was administered after the onset of the inflammatory changes. Thrice-weekly intraperitoneal injections of monoclonal antibody C11C1 or isotype IgG1 were given to male 23-week-old rats for 16 days. Stool character as a measure of intestinal inflammation, and the rear limbs for clinical signs of arthritis (tarsal joint swelling and erythema) were scored daily. The animals were killed and the histology sections were assigned a numerical score for colonic inflammation, synovitis, and cartilage damage. Administration of monoclonal C11C1 rapidly decreased the clinical scores of pre-existing inflammatory bowel disease (P < 0.005) and arthritis (P < 0.001). Histological analyses confirmed significant reductions in colonic lesions (P = 0.004) and synovitis (P = 0.009). Decreased concentrations of plasma prekallikrein and high-molecular-mass kininogen were found, providing evidence of activation of the kallikrein-kinin system. The levels of these biomarkers were reversed by monoclonal antibody C11C1, which may have therapeutic potential in human inflammatory bowel disease and arthritis.
Department of Cardiovascular and Metabolic Diseases Research, Wyeth Research, Cambridge, Massachusetts, USA. jkeith@wyeth.com
James C
JC
Keith
Irma M
IM
Sainz
Irma
I
Isordia-Salas
Robin A
RA
Pixley
Yelena
Y
Leathurby
Leo M
LM
Albert
Robert W
RW
Colman
D000818:Animals; D030801:Animals, Genetically Modified; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001168:Arthritis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015796:HLA-B27 Antigen / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007704:Kininogens / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D000911:Antibodies, Monoclonal; D015796:HLA-B27 Antigen; D007704:Kininogens