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- Title
Kv1.3 channel-blocking immunomodulatory pep tides from parasitic worms: implications for autoimmune diseases.
- Authors
Chhabra, Sandeep; Shih Chieh Chang; Hai M. Nguyen; Huq, Redwan; Tanner, Mark R.; Londono, Luz M.; Estrada, Rosendo; Dhawan, Vikas; Chauhan, Satendra; Upadhyay, Sanjeev K.; Gindin, Mariel; Hotez, Peter J.; Valenzuela, Jesus G.; Mohanty, Biswaranjan; Swarbrick, James D.; Wulff, Heike; Iadonato, Shawn P.; Gutman, George A.; Beeton, Christine; Pennington, Michael W.
- Abstract
The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models, and human phase 1 trials of this agent in healthy volunteers have been completed. In this study, we identified and characterized a large family of Stichodactyla helianthus toxin (ShK)-related peptides in parasitic worms. Based on phylogenetic analysis, 2 worm peptides were selected for study: AcKl, a 51-residue peptide expressed in the anterior secretory glands of the dog-infecting hookworm Ancylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmKl, the C-terminal domain of a metalloprotease from the lilarial worm Brugia malayi. These peptides in solution adopt helical structures closely resembling that of ShK. At doses in the nanomolar-micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts. They preferentially suppress the proliferation of rat CCR7- effector memory T cells without affecting naive and central memory subsets and inhibit the delayed-type hypersen-sitivity (DTH) response caused by skin-homing effector memory T cells in rats. Further, they suppress IFNγ production by human T lymphocytes. ShK-related peptides in parasitic worms may contribute to the potential beneficial effects of probiotic parasitic worm therapy in human autoimmune diseases.
- Subjects
THERAPEUTIC use of probiotics; T cells; LYMPHOCYTES; ION channels; HOOKWORMS; THERAPEUTICS
- Publication
FASEB Journal, 2014, Vol 28, Issue 9, p3952
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.14-251967