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J. Tang, W. Zhu, P. B. Sliver, S.-B. Su, C.-C. Chan, R. R. Caspi; Autoimmune Uveitis Elicited With Antigen-Pulsed Dendritic Cells Has a Distinct Clinical Signature and Is Driven by Unique Effector Mechanisms: Initial Encounter With Autoantigen Defines Disease Phenotype. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2831.
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© ARVO (1962-2015); The Authors (2016-present)
Autoimmune uveitis in humans is a heterogeneous group of diseases targeting the retina, which can be blinding. It is modeled by Experimental Autoimmune Uveitis (EAU) induced by immunization of mice with a retinal antigen or peptide in complete Freund's adjuvant (CFA). The present study aims to establish an alternative experimental model for uveitis of immune origin.
Splenic dendritic cells(DC) were expanded by hydrodynamic injection of Flt3-L DNA into B10RIII mice via tail vein. The DC were magnetically sorted from Flt3-L elicited spleen. LPS and agonistic anti CD40 were used separately or jointly to mature the DC being pulsed with IRBP 161-180, a known uevitogenic peptide. To induce uveitis, in vitro matured, peptide-loading DC were injected sc into naive mice with or without pertussis toxin administration. The induction of uveitis was monitored by funduscopy examination and confirmed by histology assay of the resulted eye balls after HE staining. The cytokines released by DC-primed lymph nodes or spleens in restimulation to Ag were assayed by ELISA or intracellular cytokine staining. The proliferation of Lymph nodes and splenic cells driven by Ag were assayed by tritium incoporation. The intraocular cytokine profile was demonstrated by assaying the cyokines from soluble extract from the inflamed eye balls.
Uveitis was ideally induced by peripheral injection of two doses of LPS/anti CD40 matured and retinal peptide loaded DC plus on dose of pertussis toxin ip. The new model demonstrated distinct effector manifestations compared to traditional EAU induced by immunization with autologous Ag in CFA in terms of clinical manifestations, the nature of the inflammatory infiltrating cells, the cytokine response profile and a requirement for IFN-gamma, whereas IL-17 appeared to play a minor role. Disease was self-limiting, but could be re-induced in recovered mice by a challenge with the antigen in CFA, albeit with a reduced severity compared to controls, suggesting a level of post-recovery resistance.
We established an autoimmune uveitis model by elicitation of mice with in vitro matured, Ag loaded DC. This model provides evidence that the context in which the same autoantigen is presented to the immune system can lead to distinct forms of disease on the same genetic background. This model may represent certain types of human uveitis which were not well represented by the traditional uveitis model.
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