Background/Purpose: CCR7^– effector memory T (T_EM) lymphocytes are targets for immunomodulation for the treatment of rheumatoid arthritis (RA). Following activation, T_EM cells upregulate the expression of the potassium channel Kv1.3, and blocking this channel inhibits T_EM cell proliferation and secretion of pro-inflammatory cytokines with minimal effects of CCR7+ naïve and central memory T cells. Analogs of the small peptide ShK, engineered to enhance their selectivity for Kv1.3, are effective in reducing disease severity in animal models of RA and other autoimmune diseases and in patients with active plaque psoriasis. However, like most biologics, these peptides must be injected repeatedly. Here, we propose a novel approach for the delivery of the ShK analog ShK-235 by inducing its production and secretion by a probiotic bacterium, Lactobacillus reuteri, for oral delivery into the gastrointestinal tract.

Methods: We designed LrS235, a bioengineered L. reuteri that secretes the ShK-235 peptide and used a single-cell patch-clamp to quantify ShK-235 in the culture supernatant of LrS235 and in the circulation of healthy rats gavaged with LrS235. We used functional assays to define the effects of ShK-235 secreted by LrS235 on the proliferation of T_EM cells in vitro. We next tested the efficacy of LrS235 in two animal models, delayed-type hypersensitivity (DTH) and collagen-induced arthritis (CIA).

Results: Supernatants from LrS235 block Kv1.3 currents and inhibit human T_EM cells proliferation and IL-2 and IFN-g production in vitro. A single oral gavage of LrS235 in healthy rats results in sufficient levels of ShK-235 in the circulation to block Kv1.3 channels and reduces inflammation in the DTH model. The daily oral gavage of LrS235 is efficacious in reducing clinical signs of disease and joint inflammation in rats with CIA.

Conclusion: Our results demonstrate the potential of using the probiotic L. reuteri as a novel oral delivery system for ShK-235, and possibly other biologics, to treat RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-bioengineered-probiotic-for-the-oral-delivery-of-an-immunomodulator-in-rheumatoid-arthritis/