Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice.
OBJECTIVE
Spleen tyrosine kinase (Syk) is involved in membrane-mediated signaling in various cells, including immune cells. It is overexpressed in T cells from patients with systemic lupus erythematosus (SLE), and its inhibition has been shown to improve T cell function as well as to improve disease manifestations in (NZB x NZW)F(1) lupus-prone mice and in patients with rheumatoid arthritis. While clinical trials examining Syk inhibition in patients with SLE are being considered, the aim of our experiments was to determine whether the therapeutic effects of Syk inhibition extend to other strains of lupus-prone mice and whether they result in improvement in skin disease and modification of established disease.


METHODS
Female MRL/lpr or BAK/BAX mice were studied. Starting either at age 4 weeks (before disease) or at age 16 weeks (after established disease) and continuing for up to 16 weeks, mice were fed chow containing the Syk inhibitor R788 or control chow.


RESULTS
We found that inhibition of Syk in MRL/lpr and BAK/BAX mice prevented the development of skin disease and significantly reduced established skin disease. Similarly, Syk inhibition reduced the size of the spleen and lymph nodes, suppressed the development of renal disease, and suppressed established renal disease. Discontinuation of treatment resulted in extended suppression of skin disease for at least 8 weeks and suppression of renal disease for 4 weeks.


CONCLUSIONS
Syk inhibition suppresses the development of lupus skin and kidney disease in lupus-prone mice, suppresses established disease in lupus-prone mice, and may represent a valuable treatment for patients with SLE.
Deng
Guo-Min
GM
Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. gdeng@bidmc.harvard.edu
Liu
Lena
L
Bahjat
Frances Rena
FR
Pine
Polly R
PR
Tsokos
George C
GC
D000631:Aminopyridines; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008181:Lupus Nephritis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009025:Morpholines; D010078:Oxazines / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012871:Skin Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
D000631:Aminopyridines; D004791:Enzyme Inhibitors; D009025:Morpholines; D010078:Oxazines; D011355:Prodrugs; D011725:Pyridines; D011743:Pyrimidines; D020794:Receptor Protein-Tyrosine Kinases; C084944:TYRO3 protein, human; C523665:fostamatinib