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. 2020 Apr 30;11:745. doi: 10.3389/fimmu.2020.00745

FIGURE 1.

FIGURE 1

MALT1 protease inhibition by MLT-943 reduces Tregs in rat and mouse. (A–C) SRBC immunized rats were treated with MLT-943 at various doses and regimens as indicated in (A). Numbers below the bars indicate 3 and 12 h serum exposure levels of MLT-943 at the given dosing regimen (graph depicts mean ± SEM). (B) Graph depicts percent of inhibition of rat anti-SRBC IgM, compared to vehicle group (pooled data of two experiments, n = 5 each). The relationship between MLT-943 blood levels at the 12 h trough time point in individual animals with the extent of inhibition of anti-SRBC IgM. (C) The relationship between MLT-943 blood levels in individual animals with the extent of inhibition of IL-2 production induced ex vivo by stimulation of whole blood with PMA/anti-CD28 antibody. Red lines depict 50% inhibition of anti-SRBC IgM and corresponding MLT-943 concentration. (D) Naive rats were treated with MLT-943 for 10 consecutive days. Frequency Foxp3+CD25+ Tregs in blood during treatment (gray shaded) and after cessation of MLT-943 treatment in blood. (E,F) C57BL/6 WT mice were treated with mepazine or MLT-943 for 12 days. Peak (1 h) and trough (15 h) blood compound concentrations are indicated below the legend. BQL: below quantification limit. (E) Treg frequency as well as (F) functional markers on Tregs in peripheral blood were followed by FACS on day 5 of treatment. Lines depict mean ± SEM. Statistical difference was determined using t-tests (one per time point, MLT-943 5 mg/kg QD vs. vehicle: (D) and MLT-943 40 mg/kg BID vs. vehicle 1 (E)), *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.