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1.
Figure 6

Figure 6. Monocytes pretreated with the combination of suboptimal doses of atorvastatin and GA promote Th2 differentiation.. From: Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity.

Bone marrow–derived monocytes/macrophages isolated from (PL/J × SJL/J)F1 mice were treated with optimal and suboptimal doses of atorvastatin (10 and 0.1 μM, respectively) or GA (50 and 6.25 μM, respectively) alone or in combination. Pretreated monocytes were washed and cocultured with naive myelin-specific T cells from B10.PL MBP TCR Tg mice in the presence of MBP Ac1-11. Th1 and Th2 differentiation was evaluated by measurement of IFN-γ and IL-4, respectively. Treatment groups were compared with the control group using 1-way ANOVA. Data are representative of 2 separate experiments. #P < 0.001; *P < 0.001; *P < 0.05.

Olaf Stüve, et al. J Clin Invest. 2006 April 3;116(4):1037-1044.
2.
Figure 4

Figure 4. The combination of atorvastatin and GA promotes secretion of antiinflammatory Th2 cytokines.. From: Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity.

On day 0, (PL/J × SJL/J)F1 mice were immunized with MBP Ac1-11. GA (50 μg) was administered s.c. on day –7. Daily atorvastatin (0.05 mg/kg/d) was begun 2 days prior to GA injection (day –9). Control mice received daily oral PBS (vehicle) and a s.c. injection of IFA only. Spleen cells were obtained on day 10 and cultured (5 × 105/well) in the presence of MBP Ac1-11 at the doses indicated. Supernatants were examined for Th1 (IFN-γ, TNF-α, and IL-12) and Th2 (IL-4 and IL-10) cytokines by ELISA as described in Methods. Mean ± SEM are shown. Data are representative of 3 separate experiments.

Olaf Stüve, et al. J Clin Invest. 2006 April 3;116(4):1037-1044.
3.
Figure 5

Figure 5. Combination therapy of atorvastatin and GA reduces secretion of proinflammatory cytokines and promotes secretion of IL-10 by monocytes.. From: Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity.

Bone marrow–derived monocytes/macrophages were isolated from (PL/J × SJL/J)F1 mice as described in Methods. Treatment of monocytes with optimal doses of atorvastatin (10 μM) or GA (50 μM) suppressed secretion of proinflammatory cytokines IL-12 and TNF-α and promoted secretion of the antiinflammatory cytokine IL-10. Suboptimal doses of atorvastatin (0.1 μM) or GA alone (6.25 μM) did not alter cytokine secretion, whereas treatment using the combination of these suboptimal doses suppressed secretion of TNF-α and IL-12 and promoted IL-10 secretion. Monocytes in each group were pretreated with IFN-γ for 24 hours. Cytokine secretion by unstimulated monocytes was measured and recorded: IL-12, 112 (± 2); TNF-α, 153 (± 2); and IL-10, 141 (± 3) pg/ml. Treatment groups were compared to the control group (untreated) using 1-way ANOVA. Data are representative of 3 separate experiments. *P < 0.05.

Olaf Stüve, et al. J Clin Invest. 2006 April 3;116(4):1037-1044.
4.
Figure 1

Figure 1. Atorvastatin and GA in combination do not antagonize each other.. From: Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity.

(A) Therapeutic doses of oral atorvastatin (AT; 10 mg/kg/d) and GA (250 μg in IFA) were administered in combination to (PL/J × SJL/J)F1 mice (10 per group) immunized with MBP Ac1-11 (100 μg) in CFA. GA was administered once (s.c. in IFA) 7 days prior to immunization (day –7). Daily atorvastatin (0.05 mg/kg/d) treatment began 2 days prior to GA injection (day –9). Control mice received daily oral PBS (vehicle) and 1 s.c. injection of IFA. (B) Dose titration to identify a suboptimal GA dose in prevention of EAE. GA (50, 100, or 250 μg in IFA) was administered s.c. on day –7 (5 mice per group). Control mice received a single s.c. injection of IFA. (C) Dose titration to identify a suboptimal atorvastatin dose in prevention of EAE. Atorvastatin (0.05, 0.1, 1, or 10 mg/kg/d) was administered daily by oral gavage to mice (5 per group) starting 9 days prior to immunization with MBP Ac1-11. Control mice received daily oral PBS. Data are representative of 3 separate experiments.

Olaf Stüve, et al. J Clin Invest. 2006 April 3;116(4):1037-1044.
5.
Figure 2

Figure 2. Combination therapy using suboptimal doses of atorvastatin and GA prevents clinical and histologic EAE.. From: Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity.

(A) On day 0, (PL/J × SJL/J)F1 mice (10 per group) were immunized with MBP Ac1-11 (100 μg). GA (50 μg in IFA) was administered once on day –7. Daily atorvastatin (0.05 mg/kg/d) was begun 2 days prior to GA injection (day –9). Control mice received daily oral PBS (vehicle) starting 2 days prior to a s.c. injection of IFA on day –7. Shown are group scores ± SEM. Data are representative of 4 separate experiments. Comparisons were made between the group treated with combination therapy and the groups that received either atorvastatin treatment alone, GA treatment alone, or no treatment. *P < 0.005 by ANOVA, which was considered significant. (BG) Combination of atorvastatin and GA suppresses histologic EAE in brain tissue. (B) No infiltrates were detected in unimmunized (PL/J × SJL/J)F1 mice. (CE) EAE lesions with infiltrates of mononuclear cells were detected in vehicle-treated MBP Ac1-11–immunized mice (C) and mice treated with suboptimal doses of oral atorvastatin (0.05 mg/kg/d; D) or GA (50 μg; E). (F and G) Reduced CNS infiltration was observed in mice treated with the combination of suboptimal doses of atorvastatin and GA. CNS tissue was harvested, fixed, and stained with H&E (magnification, ×40) as described in Methods.

Olaf Stüve, et al. J Clin Invest. 2006 April 3;116(4):1037-1044.
6.
Figure 3

Figure 3. Combination therapy using suboptimal doses of atorvastatin and GA reverses clinical and histologic EAE.. From: Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity.

(A) On day 0, (PL/J × SJL/J)F1 mice were immunized with MBP Ac1-11 (100 μg). Mice were randomized (10 per group) to start treatment when they developed a clinical disease score ≥ 2 (dashed line; solid line indicates continued treatment after all mice were randomized). Treatment groups included suboptimal doses of GA (50 μg/d s.c. and PBS orally), atorvastatin (0.05 mg/kg/d orally and PBS s.c.) and combination of these 2 medications. Control mice received PBS (vehicle) s.c. and orally. Shown are group scores ± SEM. Data shown are representative of 2 separate experiments. Comparisons were made between the group treated with combination therapy and the groups that received either atorvastatin treatment alone, GA treatment alone, or no treatment. #P < 0.001 by Mann-Whitney U test, which was considered significant. (BD) Histologic analysis revealed a reduced number of parenchymal (B), meningeal (C), and total (D) inflammatory foci in mice treated with the combination of suboptimal doses of atorvastatin and GA. *P < 0.008 by 1-way, multiple-range ANOVA for multiple comparisons. (E) Mice treated with the combination of suboptimal doses of atorvastatin and GA showed reduced inflammatory cell infiltration (upper panels, H&E), demyelination (lower panels, Luxol fast blue–hematoxylin [LFB]), and axonal injury (arrows indicate swollen axons). Original magnification, ×160. Scale bar: 5μm.

Olaf Stüve, et al. J Clin Invest. 2006 April 3;116(4):1037-1044.

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