Saturday, September 7, 2024
9/7/2024
ABSTRACT A broad-based immunotherapeutic with the capacity to stimulate regulatory cells is needed to resolve Sjögren's syndrome (SjS). SjS impacts several million people annually in the US with women being nine times more likely to be affected than men. To date, no vaccines or therapeutics exist to cure SjS, and patients are dependent on lifelong therapies focused on treating only their symptoms. Our previous work has shown that when colonization factor antigen I (CFA/I) fimbriae from enterotoxigenic E. coli are applied either nasally or orally, resolution of autoimmune diseases is observed. To enable testing in humans, a probiotic approach is exploited, whereby the cfaI operon was optimized for expression by Lactococcus lactis (LL-CFA/I). In the previous funding cycle, we demonstrated LL-CFA/I's ability to restore salivary flow in a genetically defined model for SjS, C57BL/6.NOD-Aec1Aec2 mice. Current work seeks to improve LL-CFA/I's activity and stability by generating a LL construct bearing the optimized cfaI operon inserted into the LL chromosome, referred to as, LL 301. To better understand the mode of action of LL-CFA/I, the tip protein from CFA/I fimbriae, CfaE, was episomally expressed by LL, and found to exhibit potent immune regulation of experimental rheumatoid arthritis. These fimbrial proteins are presumed to act by inducing infectious tolerance, resulting in the stimulation of antigen-specific regulatory T cells (Tregs) and regulatory B cells (Bregs) producing IL-10 and TGF-b. Such bystander immunity does not render global immunosuppression, and thus, the adaptive immune response capacity remains intact. When tested in a spontaneous, genetically defined murine model for SjS, both LL 301 and LL-CfaE showed remarkable retention in salivary flow compared to treatment with wild-type LL or LL vector. Based upon these findings, the proposed studies will test the hypothesis that CFA/I fimbriae and CfaE elicit bystander immunity, which in turn regulates pathogenic CD4+ and CD8+ T cells via Tregs and Bregs producing IL-10 and TGF-b. To test this hypothesis, three Specific Aims are proposed. Studies in Specific Aim 1 will determine the efficacy of LL 301 and LL-CfaE via Tregs during treatment of early and late stage SjS, and identify the molecular mechanisms responsible for salivary flow preservation. Studies in Specific Aim 2 will determine the distribution and degree of protection conferred by Bregs induced by LL 301 and LL-CfaE. Studies in Specific Aim 3 will determine whether protection elicited by LL 301 and LL-CfaE are FcgRIIb-dependent since CFA/I fimbriae were found to bind to the immunoregulatory FcgRIIb. These studies will provide the basis for future testing in SjS patients, and in the development of novel FcgRIIb agonists for treating SjS.
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