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Murine experimental autoimmune encephalomyelitis is diminished by treatment with the angiogenesis inhibitors B20-4.1.1 and angiostatin (K1-3).

MacMillan CJ, Doucette CD, Warford J, Furlong SJ, Hoskin DW, Easton AS - PLoS ONE (2014)

Bottom Line: B20-4.1.1 reduced spinal cord vascular permeability while K(1-3) had no effect.B20-4.1.1 reduced peripheral T cell proliferation while K(1-3) had no effect.We conclude that these angiogenesis inhibitors mitigate EAE by both suppressing spinal cord angiogenesis and reducing peripheral T cell activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.

ABSTRACT
Angiogenesis is the formation of new blood vessels form pre-existing vasculature whose contribution to inflammatory conditions of the Central Nervous System is being studied in order to generate novel therapeutic targets. This study is the first to investigate the impact of two particular angiogenesis inhibitors on murine Experimental Autoimmune Encephalomyelitis (EAE), an inflammatory disease that mimics aspects of the human disease Multiple Sclerosis. The inhibitors were chosen to reduce angiogenesis by complimentary means. Extrinsic factors were targeted with B20-4.1.1 through its ability to bind to murine Vascular Endothelial Growth Factor (VEGF). Vascular processes connected to angiogenesis were targeted directly with K(1-3), the first three kringle domains of angiostatin. Mice treated with B20-4.1.1 and K(1-3) from onset of signs had reduced clinical scores 18-21 days after EAE induction. Both agents suppressed spinal cord angiogenesis without effect on local VEGF expression. B20-4.1.1 reduced spinal cord vascular permeability while K(1-3) had no effect. T cell infiltration into the spinal cord at day 21 was unaffected by either treatment. B20-4.1.1 reduced peripheral T cell proliferation while K(1-3) had no effect. Lymphoid cells from treated mice produced reduced levels of the T helper-17 (Th-17) cell cytokine interleukin (IL)-17 with no effect on the Th-1 cytokine interferon (IFN)-γ or Th-2 cytokine IL-4. However, when both drugs were added in vitro to naive T cells or to antigen stimulated T cells from mice with untreated EAE they had no effect on proliferation or levels of IL-17 or IFN-γ. We conclude that these angiogenesis inhibitors mitigate EAE by both suppressing spinal cord angiogenesis and reducing peripheral T cell activation.

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B20-4.1.1 and K(1-3) Reduce Clinical Scores in EAE.A. EAE treated with B20-4.1.1. B. Treatment with K(1-3). C. Treatment with IgG. Arrows indicate treatment days. Data shown are mean ± standard error of the mean (SEM). Indicated significance is either relative to control (*–***; P<0.05–0.001) or else compares untreated EAE with treated EAE (#,###; P<0.05, 0.001). Number of mice (n): B20-4.1.1 group: EAE only, n = 3, treated group, n = 24 up to day 14, 12 after day 14, B20-4.1.1 only, n = 3. K(1-3) group: EAE only: n = 6, treated group, n = 16 up to day 14, 8 after day 14, K(1-3) only, n = 4; IgG group: EAE only: n = 4, IgG treated, n = 12 up to day 14, 6 after day 14, IgG only, n = 2.
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pone-0089770-g001: B20-4.1.1 and K(1-3) Reduce Clinical Scores in EAE.A. EAE treated with B20-4.1.1. B. Treatment with K(1-3). C. Treatment with IgG. Arrows indicate treatment days. Data shown are mean ± standard error of the mean (SEM). Indicated significance is either relative to control (*–***; P<0.05–0.001) or else compares untreated EAE with treated EAE (#,###; P<0.05, 0.001). Number of mice (n): B20-4.1.1 group: EAE only, n = 3, treated group, n = 24 up to day 14, 12 after day 14, B20-4.1.1 only, n = 3. K(1-3) group: EAE only: n = 6, treated group, n = 16 up to day 14, 8 after day 14, K(1-3) only, n = 4; IgG group: EAE only: n = 4, IgG treated, n = 12 up to day 14, 6 after day 14, IgG only, n = 2.

Mentions: Both treatments were given to mice on the day of symptom onset (around day 9) and subsequently administered every 3 days until death. Fig. 1A shows the effect of B20.4.1.1 on clinical score. While treatment was started on day 9, a decline in clinical score only became apparent at day 16, with significant reductions between days 18–21 (P<0.001). K(1-3) was also administered from day 9 and like B20-4.1.1 produced a delayed reduction in clinical score, beginning at day 16 with significant reductions between days 18–21 (P<0.05–0.001, fig. 1B). Healthy controls treated with either B20.4.1.1 or K(1-3) showed no increase in clinical score. Similarly, no effect was observed in IgG controls (fig. 1C).


Murine experimental autoimmune encephalomyelitis is diminished by treatment with the angiogenesis inhibitors B20-4.1.1 and angiostatin (K1-3).

MacMillan CJ, Doucette CD, Warford J, Furlong SJ, Hoskin DW, Easton AS - PLoS ONE (2014)

B20-4.1.1 and K(1-3) Reduce Clinical Scores in EAE.A. EAE treated with B20-4.1.1. B. Treatment with K(1-3). C. Treatment with IgG. Arrows indicate treatment days. Data shown are mean ± standard error of the mean (SEM). Indicated significance is either relative to control (*–***; P<0.05–0.001) or else compares untreated EAE with treated EAE (#,###; P<0.05, 0.001). Number of mice (n): B20-4.1.1 group: EAE only, n = 3, treated group, n = 24 up to day 14, 12 after day 14, B20-4.1.1 only, n = 3. K(1-3) group: EAE only: n = 6, treated group, n = 16 up to day 14, 8 after day 14, K(1-3) only, n = 4; IgG group: EAE only: n = 4, IgG treated, n = 12 up to day 14, 6 after day 14, IgG only, n = 2.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3935931&req=5

pone-0089770-g001: B20-4.1.1 and K(1-3) Reduce Clinical Scores in EAE.A. EAE treated with B20-4.1.1. B. Treatment with K(1-3). C. Treatment with IgG. Arrows indicate treatment days. Data shown are mean ± standard error of the mean (SEM). Indicated significance is either relative to control (*–***; P<0.05–0.001) or else compares untreated EAE with treated EAE (#,###; P<0.05, 0.001). Number of mice (n): B20-4.1.1 group: EAE only, n = 3, treated group, n = 24 up to day 14, 12 after day 14, B20-4.1.1 only, n = 3. K(1-3) group: EAE only: n = 6, treated group, n = 16 up to day 14, 8 after day 14, K(1-3) only, n = 4; IgG group: EAE only: n = 4, IgG treated, n = 12 up to day 14, 6 after day 14, IgG only, n = 2.
Mentions: Both treatments were given to mice on the day of symptom onset (around day 9) and subsequently administered every 3 days until death. Fig. 1A shows the effect of B20.4.1.1 on clinical score. While treatment was started on day 9, a decline in clinical score only became apparent at day 16, with significant reductions between days 18–21 (P<0.001). K(1-3) was also administered from day 9 and like B20-4.1.1 produced a delayed reduction in clinical score, beginning at day 16 with significant reductions between days 18–21 (P<0.05–0.001, fig. 1B). Healthy controls treated with either B20.4.1.1 or K(1-3) showed no increase in clinical score. Similarly, no effect was observed in IgG controls (fig. 1C).

Bottom Line: B20-4.1.1 reduced spinal cord vascular permeability while K(1-3) had no effect.B20-4.1.1 reduced peripheral T cell proliferation while K(1-3) had no effect.We conclude that these angiogenesis inhibitors mitigate EAE by both suppressing spinal cord angiogenesis and reducing peripheral T cell activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.

ABSTRACT
Angiogenesis is the formation of new blood vessels form pre-existing vasculature whose contribution to inflammatory conditions of the Central Nervous System is being studied in order to generate novel therapeutic targets. This study is the first to investigate the impact of two particular angiogenesis inhibitors on murine Experimental Autoimmune Encephalomyelitis (EAE), an inflammatory disease that mimics aspects of the human disease Multiple Sclerosis. The inhibitors were chosen to reduce angiogenesis by complimentary means. Extrinsic factors were targeted with B20-4.1.1 through its ability to bind to murine Vascular Endothelial Growth Factor (VEGF). Vascular processes connected to angiogenesis were targeted directly with K(1-3), the first three kringle domains of angiostatin. Mice treated with B20-4.1.1 and K(1-3) from onset of signs had reduced clinical scores 18-21 days after EAE induction. Both agents suppressed spinal cord angiogenesis without effect on local VEGF expression. B20-4.1.1 reduced spinal cord vascular permeability while K(1-3) had no effect. T cell infiltration into the spinal cord at day 21 was unaffected by either treatment. B20-4.1.1 reduced peripheral T cell proliferation while K(1-3) had no effect. Lymphoid cells from treated mice produced reduced levels of the T helper-17 (Th-17) cell cytokine interleukin (IL)-17 with no effect on the Th-1 cytokine interferon (IFN)-γ or Th-2 cytokine IL-4. However, when both drugs were added in vitro to naive T cells or to antigen stimulated T cells from mice with untreated EAE they had no effect on proliferation or levels of IL-17 or IFN-γ. We conclude that these angiogenesis inhibitors mitigate EAE by both suppressing spinal cord angiogenesis and reducing peripheral T cell activation.

Show MeSH
Related in: MedlinePlus