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D Miyazaki, SJ Ono; CpG Oligodeoxynucleotides in the Treatment of Allergic Disease: Involvement of Interleukin-10 . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2257.
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Purpose: Pre-clinical and early clinical trials have indicated that immuno-stimulatory DNA sequences (ISS-ODN) have considerable potential in the treatment of allergic diseases. We have investigated the mechanism(s) of ISS-ODN action using an established model of allergic conjunctivitis. Methods: Mice were sensitized to short ragweed pollen (RW) by footpad injection of suspension of RW and alum. On day 14, conjunctivitis was induced by topical application of RW suspension. To test the therapeutic efficacy on allergic conjunctivitis, immuno-stimulatory DNA sequences (ISS-ODN) was administered intraperitoneally 3 days before final RW challenge. After the topical challenge with RW, LPR was evaluated by analyzing/quantifying the cellular infiltrates in the conjunctiva. The conjunctiva, cervical lymph nodes, and spleen was collected and extracted RNA was assayed for RNase protection assay (RPA). Expansion of splenocytes populations were determined using FACS. For adoptive transfer experiment, splenocyte suspensions were injected into recipient mice via the tail vein. To determine cytokine induction profile in the presensitized splenocytes, ISS-ODN was injected intraperitoneally on day 11 following initial immunization with RW. Splenocytes were prepared 3 days after injection and placed in culture with RW extract. The RNA profile was determined using RPA. Results: As previously reported in other systems, administration of ISS-ODN induces significant splenomegaly. Analysis of cytokines produced from splenocytes following ISS-ODN treatment showed a marked and sustained induction of IL-10 expression after ISS-ODN treatment. Using mice deficient in IL-10, we show that IL-10 is critical for both ISS-ODN-mediated splenocyte expansion and inhibition of the late phase reaction in this disease. Interestingly, adoptive transfer of the splenocytes isolated from ISS-ODN treated mice was able to confer resistance to allergen challenge in recipient mice. Conclusion: Taken together, these data suggest that in addition to their well documented effects on the local allergic response, ISS-ODN function via systemic immune remodeling using an IL-10-dependent pathway. The ability to adoptively transfer disease resistance suggests the participation of T regulatory cells.
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