Selective depletion of splenic CD4 dendritic cells in mice treated with immunomodulatory quinoline-3-carboxamide ABR-215757.
The quinoline-3-carboxamide ABR-215757 (5757) is in clinical development for the treatment of human SLE and has shown efficacy in several mouse models of T cell-mediated inflammatory autoimmune disease. The goal of this study was to determine the impact of 5757 on steady state immune cells. We show that the number of splenic CD4 dendritic cells (DCs) was reduced in 5757-treated mice, while there was no effect on other splenic DC populations, on DCs in lymph nodes or on lymphocytes. This reduction was fully reversible and the kinetics of CD4 DC loss during exposure and recovery after withdrawal of treatment was identical. The loss of CD4 DCs was neither caused by reduced proliferation nor by increased apoptosis. CD4 DCs reside in the splenic marginal zone, but the loss of these cells did not influence other cell populations at this site. The similar kinetics of the decay and repopulation of the splenic CD4 DC compartment suggests that the reduced number of CD4 DC in 5757 treated mice may be a result of blockade of CD4 DC precursor development in the spleen and not of toxicity. Alternatively, induced emigration of CD4 DC to the periphery, or an interference with adherence of these cells in the spleen marginal zone, may also explain our data.
Stenström
Martin
M
Immunology Group, Department of Experimental Medical Science, Immunology Group, BMC D14, Lund University, SE 22184, Lund, Sweden.
Anderson
Per
P
Eroukhmanoff
Lena
L
Leanderson
Tomas
T
Ivars
Fredrik
F
D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D056747:Immunomodulation; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects
D015704:CD4 Antigens; D011804:Quinolines; C541322:quinoline-3-carboxamide