A complement-dependent model of thrombotic thrombocytopenic purpura induced by antibodies reactive with endothelial cells.
Thrombotic thrombocytopenic purpura (TTP) is an immunologically mediated disease characterized by thrombocytopenia, hemolytic anemia, and pathologic changes in various organs, including the kidney, which are secondary to widespread thromboses. Central to TTP is platelet activation, which may occur from a variety of mechanisms, including endothelial cell activation or injury. In this study, injection of K6/1, a monoclonal antibody with widespread reactivity toward endothelia, led to dose-dependent thrombocytopenia in rats. This was magnified if animals were preimmunized with mouse IgG, thereby resulting in an accelerated autologous phase of injury. In this setting, significant anemia also resulted. Rats injected with K6/1 developed renal injury, consisting of tubular damage and glomerular thrombi. Thrombocytopenia and renal morphological abnormalities were eliminated if animals were complement depleted with cobra venom factor prior to K6/1 injection and worsened when the activity of the ubiquitous complement regulator Crry was inhibited with function-neutralizing antibodies. Therefore, we have developed a complement-dependent model of TTP in rats by injecting monoclonal antibodies reactive with endothelial cells. Antibody-directed complement activation leads to stimulation of platelets, through direct interactions with complement fragments and/or indirectly through endothelial cell activation or injury, with the subsequent development of TTP.
Ren
Guohui
G
Section of Nephrology, The University of Chicago, Chicago, Illinois 60637, USA.
Hack
Bradley K
BK
Minto
Andrew W
AW
Cunningham
Patrick N
PN
Alexander
Jessy J
JJ
Haas
Mark
M
Quigg
Richard J
RJ
D000743:Anemia, Hemolytic / Q000209:etiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D003165:Complement System Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology*; D006463:Hemolytic-Uremic Syndrome / Q000209:etiology; D007074:Immunoglobulin G / Q000276:immunology; D007674:Kidney Diseases / Q000209:etiology; D007678:Kidney Glomerulus / Q000276:immunology; D008297:Male; D051379:Mice; D011697:Purpura, Thrombotic Thrombocytopenic / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D003165:Complement System Proteins