Syk Inhibition Induces Platelet Dependent Peri-islet Hemorrhage in the Rat Pancreas.
Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that is an important signaling enzyme downstream of immunoreceptors containing an intracellular immunoreceptor tyrosine activating motif (ITAM). These receptors encompass a wide variety of biological functions involved in autoimmune disease pathogenesis. There has been considerable interest in the development of inhibitors of the Syk pathway for the treatment of rheumatoid arthritis and systemic lupus erythematosus. We report that Syk inhibition mechanistically caused peri-islet hemorrhages and fibrin deposition in the rat pancreas and that this finding is due to a homeostatic functional defect in platelets. In more limited studies, similar lesions could not be induced in mice, dogs, and cynomolgus monkeys at similar or higher plasma drug concentrations. Irradiation-induced thrombocytopenia caused a phenotypically similar peri-islet pancreas lesion and the formation of this lesion could be prevented by platelet transfusion. In addition, Syk inhibitor-induced lesions were prevented by the coadministration of prednisone. A relatively greater sensitivity of rat platelets to Syk inhibition was supported by functional analyses demonstrating rat-specific differences in response to convulxin, a glycoprotein VI agonist that signals through Syk. These data demonstrate that the Syk pathway is critical in platelet-endothelial cell homeostasis in the peri-islet pancreatic microvasculature in rats.
AbbVie Bioresearch Center, Worcester, Massachusetts, USA andrew.long@abbvie.com.
Andrew J
AJ
Long
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Erik
E
Sampson
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Richard W
RW
McCarthy
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Christopher M
CM
Harris
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Marc
M
Barnard
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Dan
D
Shi
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Donna
D
Conlon
AbbVie, North Chicago, Illinois, USA.
Robert
R
Caldwell
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
David
D
Honor
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Neil
N
Wishart
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Michael
M
Hoemann
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Lori
L
Duggan
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Douglas
D
Fritz
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Christopher
C
Stedman
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Elizabeth
E
O'Connor
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Igor
I
Mikaelian
AbbVie Bioresearch Center, Worcester, Massachusetts, USA.
Annette
A
Schwartz
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006470:Hemorrhage / Q000139:chemically induced*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000473:pathology; D008252:Macaca fascicularis; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D000072377:Syk Kinase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D000072377:Syk Kinase; C000606898:Syk protein, rat
Syk; hemorrhage; islet; pancreas; platelet; rat; toxicity