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To evaluate the therapeutic potential of immunostimulatory sequence oligodeoxynucleotides ISS-ODN administration in ocular allergy, using a mouse model of ragweed-specific conjunctivitis. Multiple parameters of clinical symptoms evident during the acute-phase reaction and the cellular components of the late-phase reaction were evaluated in both groups of mice. All parameters of clinical symptoms were markedly inhibited after intraperitoneal injection of ISS-ODN, whereas topical application to the conjunctiva did not inhibit clinical symptoms significantly.
Remarkably, a single topical treatment with ISS-ODN as well as by intraperitoneal injection completely inhibited both eosinophilia and neutrophilia in the late-phase reaction. Systemic or conjunctival administration of ISS-ODN was shown to significantly inhibit allergic responses in this mouse model.
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Seasonal allergic conjunctivitis SAC is the most common allergic disease, with over 40 million patients affected in the United States alone. In both severe SAC and VC, the allergic response can interfere with normal vision, and damage to the cornea can be a consequence. Despite this, current treatment regimens are grossly inadequate, spurring the intensive search for new and more effective drugs.
Ocular allergies are most commonly initiated in response to airborne allergens, 1 2 3 with short ragweed SRW pollen being the major cause of late summer rhinoconjunctivitis in North America. Antihistamines or steroids are commonly used to treat ocular allergies; however, they only provide temporary relief for a subset of patients. Moreover, use of steroids can increase the incidence of serious complications such as the development of glaucoma or cataracts. For these reasons, immunotherapy may be preferable for providing long-term relief without medication.
Conventional immunotherapy through desensitization by repeated exposure of low-dose allergen has achieved some success, although the majority of patients remain unresponsive. Recently, considerable interest has materialized in the potential use of immunostimulatory sequence oligodeoxynucleotides ISS-ODN in the treatment of allergic diseases. After years of searching for the responsible sequences, Krieg et al.
These ISS-containing CpG motifs have now been shown to bias the immune response toward the development of an antigenspecific T helper Th cell type 1 response. As is the case for allergic reactions in other mucosal tissues, conjunctival allergy results from a prevalent Th2 response to allergen as determined by the analysis of conjunctiva-derived T-cell clones from patients with SAC. We show in this study that intraperitoneal injection of ISS-ODN prevents clinical effects of SAC in a mouse model, and effectively suppresses the late-phase reaction in the conjunctiva.
Moreover, although a single topical administration of ISS-ODN does not significantly affect the acute-phase reaction in this model, it completely inhibits inflammatory cell recruitment in late-phase reaction. Together with a recent report, these data indicate that ISS-ODN treatment of conjunctival allergy may be a highly promising future immunotherapy for this major human allergy.
To prevent any contamination of allergen, all mice were kept in cages with filter-topped lids. The present study conformed to the principles for laboratory animal research outlined by the Animal Welfare Act and the National Institutes of Health guidelines for the experimental use of animals. Mice were sensitized to SRW pollen according to the protocol originally reported by Magone et al.
Louis, MO were injected into the left hind footpad under anesthesia. On day 14, conjunctivitis was induced by topical application of 1. ISS-ODN is reported to have a prepriming effect as an immune modulator, 19 exerting an effect when administered 3 days before antigen challenge. Mice were observed in a double-blind study for clinical symptoms of immediate hypersensitivity response 20 minutes after the topical challenge with SRW.
Chemosis, conjunctival redness, lid edema and redness, and tearing and discharge were scored 0 to 4, after evaluation by slit lamp, according to the modified criteria described by Magone et al. The cumulative clinical score was calculated as the sum of the scores of each of these four parameters.
The sagittal sections were stained with Giemsa or hematoxylin and eosin. The mice were then challenged with SRW 14 days after initial sensitization. This provoked clear clinical symptoms, including conjunctival redness, lid edema and redness, and tearing and discharge in the SRW-immunized group.
Books by H. Wagner (Author of Economic and Medicinal Plant Research)
The total clinical response as well as each symptom measured was markedly inhibited by treatment with ISS-ODN intraperitoneal injection Fig. In contrast to the systemic administration, clinical symptoms including conjunctival edema, conjunctival redness, lid edema and redness, and tearing and discharge were not inhibited significantly with this dose regimen Fig. Furthermore, to examine whether longer prepriming may improve therapeutic effect on the clinical symptoms, we also treated the animals from day 0 to day 3 using ISS-ODN eyedrops.
However, the inhibitory effect on clinical symptoms corresponded to the effect shown in Figure 2 , and no significant inhibition was detected data not shown. The late-phase reaction of antigen-challenged conjunctival tissue is characterized by a profound inflammatory cell recruitment consisting of eosinophils and neutrophils.
Conjunctival eosinophilia was evaluated by counting eosinophils attracted to the forniceal region of the conjunctiva. SRW challenge to the sensitized mice control animals and those treated with control ODN resulted in a massive eosinophil recruitment into the conjunctival fornix, as expected. Intraperitoneal injection of ISS-ODN abolished the conjunctival eosinophilia, consistent with that observed in lung eosinophilia.
Surprisingly, a single topical application of ISS-ODN also abolished eosinophil recruitment, although the effect on clinical symptoms was insufficient Fig. Thus, two key parameters of chronic inflammation in ocular allergy: We also have shown that a single topical application of ISS-ODN effectively inhibited both eosinophilia and neutrophilia, although it did not affect the acute-phase reaction with this dose regimen. ISS-ODN are known to affect both the innate immune system by dendritic cells and macrophages and the acquired immune system by activation of B cells.
The dendritic cells and macrophages have two major roles in priming the immune responses.
Books by H. Wagner
It is now known that ISS-ODN induce the expression of various cytokines that in total contribute to the skewing of the T-cell response toward the Th1 phenotype systemically. Using murine allergic airway models, three research groups have shown that ISS-ODN treatment can effectively inhibit airway hyperresponsiveness and inflammation. There's a problem loading this menu right now. Get fast, free shipping with Amazon Prime.
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