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Koju Kamoi, Delyth M. Reid, Joyce S. Yeoh, John V. Forrester; Regulatory T Cell Expansion in Eye Draining Lymph Nodes Plays a Role in Suppressing Inflammation in Spontaneous EAU and Offers a Strategy for Cell-Based Therapy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2275.
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Therapies based on altering humoral immune responses, e.g. anti-TNF-α for suppressing immunity and INF-αfor promoting tolerance, are currently used for treating uveitis. However, these drugs are not specific and also cause side effects. Cell-based immune-therapy potentially offers organ specific treatment of autoimmunity. The tolerance-promoting regulatory T cell population (Tregs) is a strong contender. We have compared the efficacy of Treg expansion both ex vivo and in vivo using a spontaneous model of experimental autoimmune uveitis (EAU).
Double transgenic (DTg) mice which develop EAU spontaneously were obtained by crossing single Tg 3A9 TCR mice with Tg mice expressing hen egg lysozyme (Hel) in photoreceptor cells.1) Ex vivo Tregs from DTg or 3A9 mice were expanded in culture and adoptively transferred to DTg mice.2) In vivo T reg expansion was induced in DTg mice following treatment with LPS- activated HEL-peptide pulsed dendritic cells (DC).
In untreated spontaneous EAU, ocular inflammation began day 20-21 with severe disease developing by day 28-30. After the onset of inflammation, a Th1 shift was detected in the eye draining sub-mandibular lymph nodes (LNs) with a reduced T reg response compared to non-eye draining LNs. However, at age 2 months, the numbers of T regs had risen considerably. Adoptive transfer of ex vivo expanded Tregs from a 2 month donor DTg mouse with EAU suppressed ocular inflammation in recipient DTg. However, Tregs derived from naïve non-antigen experienced TCR mice failed to suppress EAU. Adoptively transferred naïve Tregs were shown by flow cytometry to accumulate in LNs and spleen with very few entering the retina as shown by confocal microscopy. However, expansion of T regs in the draining lymph node using Hel-peptide pulsed DC significantly suppressed ocular inflammation.
Expansion of Th1 cells in the eye-draining lymph node is associated with progressive development of EAU in this spontaneous model. However, delayed T reg expansion occurs pari passu with Th1 expansion. Prevention of disease can be induced either by directly administering antigen-experienced Tregs or by expanding Tregs with LPS- activated HEL-peptide pulsed DC.
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