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Ex-vivo tolerogenic F4/80⁺ antigen-presenting cells (APC) induce efferent CD8⁺ regulatory T cell-dependent suppression of experimental autoimmune uveitis.

Hsu SM, Mathew R, Taylor AW, Stein-Streilein J - Clin. Exp. Immunol. (2014)

Bottom Line: We observed that retinal antigen-pulsed TolAPC suppressed the incidence and severity of the clinical expression of EAU and reduced the expression of associated inflammatory cytokines.Retinal antigen-pulsed TolAPC suppressed ongoing EAU by inducing CD8⁺ T(reg) cells that, in turn, suppressed the effector activity of the IRBP-specific T cells and altered the clinical symptoms of autoimmune inflammation in the eye.The ability to use retinal extract for the antigen raises the possibility that retinal extract could be used to produce autologous TolAPC and then used as therapy in human uveitis.

View Article: PubMed Central - PubMed

Affiliation: Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, National Cheng-Kung University Hospital, Tainan City, Taiwan.

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Effect of retinal antigen-pulsed tolerogenic antigen-presenting cells (TolAPC) on clinical course of experimental autoimmune uveitis (EAU) induced with interphotoreceptor retinoid-binding protein (IRBP). (a) Comparison of clinical scores of EAU mice treated with retinal extract-pulsed TolAPC (filled triangles, n = 7) or EAU mice not treated (open squares, n = 7). Data are shown as mean clinical EAU score ± standard error of the mean (s.e.m.) (ordinate) over time (abscissa). The retinal extract-pulsed TolAPC-treated mice show a significant (P ≤ 0·05) decrease in EAU clinical score over time compared to scores of EAU in untreated mice. (b) Antigen specificity of TolAPC-induced suppression. The EAU mice were treated with each type of TolAPC, 7 days post-induction of EAU (Materials and methods). Line graph of response of EAU mice to TolAPC pulsed with indicated antigens. The transferred antigen-presenting cells (APC) were not pulsed with antigen (black line, n = 15) or were treated with transforming growth factor (TGF)-β and pulsed with corneal extract (red line, n = 7), myelin basic protein (MBP) (blue line, n = 6), IRBP(1–20) (grey line, n = 14) or retinal extract (green line, n = 16). Data shown are mean clinical score (ordinate) over time (abscissa). An asterisk (*) indicates a significant difference between the areas under the curves. Statistics were performed using Prism software (Materials and methods).
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fig03: Effect of retinal antigen-pulsed tolerogenic antigen-presenting cells (TolAPC) on clinical course of experimental autoimmune uveitis (EAU) induced with interphotoreceptor retinoid-binding protein (IRBP). (a) Comparison of clinical scores of EAU mice treated with retinal extract-pulsed TolAPC (filled triangles, n = 7) or EAU mice not treated (open squares, n = 7). Data are shown as mean clinical EAU score ± standard error of the mean (s.e.m.) (ordinate) over time (abscissa). The retinal extract-pulsed TolAPC-treated mice show a significant (P ≤ 0·05) decrease in EAU clinical score over time compared to scores of EAU in untreated mice. (b) Antigen specificity of TolAPC-induced suppression. The EAU mice were treated with each type of TolAPC, 7 days post-induction of EAU (Materials and methods). Line graph of response of EAU mice to TolAPC pulsed with indicated antigens. The transferred antigen-presenting cells (APC) were not pulsed with antigen (black line, n = 15) or were treated with transforming growth factor (TGF)-β and pulsed with corneal extract (red line, n = 7), myelin basic protein (MBP) (blue line, n = 6), IRBP(1–20) (grey line, n = 14) or retinal extract (green line, n = 16). Data shown are mean clinical score (ordinate) over time (abscissa). An asterisk (*) indicates a significant difference between the areas under the curves. Statistics were performed using Prism software (Materials and methods).

Mentions: Although the retinal antigens that induce the EAU in the mice are known, the target antigens in human uveitis remain obscure. Here, we tested if retinal protein extract (containing IRBP and other retinal antigens) would provide the relevant antigens for producing the TolAPC that were effective in this model of suppression. In this experiment EAU was induced by injecting IRBP-specific cells as before, but the TolAPC were made by incubation with TGF-β and IRBP or mouse retinal extract. The retinal antigen-pulsed TolAPC were then injected (i.v.) into the EAU mice, 7 days post-induction with the IRBP-specific cells. As before, mice were monitored and clinical symptoms were scored every 3–30 days. We observed that the retinal extract (but not corneal extract, control)-pulsed TolAPC were as effective as IRBP1–20-pulsed TolAPC in reducing the clinical symptoms of EAU (Fig. 3a). Furthermore, if the TolAPC were pulsed with the irrelevant antigen MBP, they were not able to establish suppression of EAU (Fig. 3b). Therefore, it is possible to produce EAU-specific TolAPC when the TolAPC are pulsed with retina extract.


Ex-vivo tolerogenic F4/80⁺ antigen-presenting cells (APC) induce efferent CD8⁺ regulatory T cell-dependent suppression of experimental autoimmune uveitis.

Hsu SM, Mathew R, Taylor AW, Stein-Streilein J - Clin. Exp. Immunol. (2014)

Effect of retinal antigen-pulsed tolerogenic antigen-presenting cells (TolAPC) on clinical course of experimental autoimmune uveitis (EAU) induced with interphotoreceptor retinoid-binding protein (IRBP). (a) Comparison of clinical scores of EAU mice treated with retinal extract-pulsed TolAPC (filled triangles, n = 7) or EAU mice not treated (open squares, n = 7). Data are shown as mean clinical EAU score ± standard error of the mean (s.e.m.) (ordinate) over time (abscissa). The retinal extract-pulsed TolAPC-treated mice show a significant (P ≤ 0·05) decrease in EAU clinical score over time compared to scores of EAU in untreated mice. (b) Antigen specificity of TolAPC-induced suppression. The EAU mice were treated with each type of TolAPC, 7 days post-induction of EAU (Materials and methods). Line graph of response of EAU mice to TolAPC pulsed with indicated antigens. The transferred antigen-presenting cells (APC) were not pulsed with antigen (black line, n = 15) or were treated with transforming growth factor (TGF)-β and pulsed with corneal extract (red line, n = 7), myelin basic protein (MBP) (blue line, n = 6), IRBP(1–20) (grey line, n = 14) or retinal extract (green line, n = 16). Data shown are mean clinical score (ordinate) over time (abscissa). An asterisk (*) indicates a significant difference between the areas under the curves. Statistics were performed using Prism software (Materials and methods).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3958152&req=5

fig03: Effect of retinal antigen-pulsed tolerogenic antigen-presenting cells (TolAPC) on clinical course of experimental autoimmune uveitis (EAU) induced with interphotoreceptor retinoid-binding protein (IRBP). (a) Comparison of clinical scores of EAU mice treated with retinal extract-pulsed TolAPC (filled triangles, n = 7) or EAU mice not treated (open squares, n = 7). Data are shown as mean clinical EAU score ± standard error of the mean (s.e.m.) (ordinate) over time (abscissa). The retinal extract-pulsed TolAPC-treated mice show a significant (P ≤ 0·05) decrease in EAU clinical score over time compared to scores of EAU in untreated mice. (b) Antigen specificity of TolAPC-induced suppression. The EAU mice were treated with each type of TolAPC, 7 days post-induction of EAU (Materials and methods). Line graph of response of EAU mice to TolAPC pulsed with indicated antigens. The transferred antigen-presenting cells (APC) were not pulsed with antigen (black line, n = 15) or were treated with transforming growth factor (TGF)-β and pulsed with corneal extract (red line, n = 7), myelin basic protein (MBP) (blue line, n = 6), IRBP(1–20) (grey line, n = 14) or retinal extract (green line, n = 16). Data shown are mean clinical score (ordinate) over time (abscissa). An asterisk (*) indicates a significant difference between the areas under the curves. Statistics were performed using Prism software (Materials and methods).
Mentions: Although the retinal antigens that induce the EAU in the mice are known, the target antigens in human uveitis remain obscure. Here, we tested if retinal protein extract (containing IRBP and other retinal antigens) would provide the relevant antigens for producing the TolAPC that were effective in this model of suppression. In this experiment EAU was induced by injecting IRBP-specific cells as before, but the TolAPC were made by incubation with TGF-β and IRBP or mouse retinal extract. The retinal antigen-pulsed TolAPC were then injected (i.v.) into the EAU mice, 7 days post-induction with the IRBP-specific cells. As before, mice were monitored and clinical symptoms were scored every 3–30 days. We observed that the retinal extract (but not corneal extract, control)-pulsed TolAPC were as effective as IRBP1–20-pulsed TolAPC in reducing the clinical symptoms of EAU (Fig. 3a). Furthermore, if the TolAPC were pulsed with the irrelevant antigen MBP, they were not able to establish suppression of EAU (Fig. 3b). Therefore, it is possible to produce EAU-specific TolAPC when the TolAPC are pulsed with retina extract.

Bottom Line: We observed that retinal antigen-pulsed TolAPC suppressed the incidence and severity of the clinical expression of EAU and reduced the expression of associated inflammatory cytokines.Retinal antigen-pulsed TolAPC suppressed ongoing EAU by inducing CD8⁺ T(reg) cells that, in turn, suppressed the effector activity of the IRBP-specific T cells and altered the clinical symptoms of autoimmune inflammation in the eye.The ability to use retinal extract for the antigen raises the possibility that retinal extract could be used to produce autologous TolAPC and then used as therapy in human uveitis.

View Article: PubMed Central - PubMed

Affiliation: Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, National Cheng-Kung University Hospital, Tainan City, Taiwan.

Show MeSH
Related in: MedlinePlus