pyrimidinones and Rheumatic-Diseases

Helper T cell activity is dysregulated in a number of diseases including those associated with rheumatic autoimmunity. Treatment options are limited and usually consist of systemic immune suppression, resulting in undesirable consequences from compromised immunity. Hedgehog (Hh) signaling has been implicated in the activation of T cells and the formation of the immune synapse, but remains understudied in the context of autoimmunity. Modulation of Hh signaling has the potential to enable controlled immunosuppression but a potential therapy has not yet been developed to leverage this opportunity.. In this work, we developed biodegradable nanoparticles to enable targeted delivery of eggmanone (Egm), a specific Hh inhibitor, to CD4. Our novel delivery system achieved a highly specific association with the majority of CD4. This work is the first characterization of Egm's immunomodulatory potential. Importantly, this study also suggests the potential benefit of a biodegradable delivery vehicle that is rationally designed for preferential interaction with a specific immune cell subtype for targeted modulation of Hh signaling.

Topics: Animals; Autoimmunity; CD4-Positive T-Lymphocytes; Cytokines; Drug Delivery Systems; Female; Hedgehog Proteins; Immunoglobulin Fragments; Immunologic Factors; Mice, Inbred C57BL; Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer; Pyrimidinones; Rheumatic Diseases; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; Thiophenes

Topics: Aluminum Hydroxide; Aminopyrine; Anti-Inflammatory Agents; Biotransformation; Diclofenac; Drug Interactions; Humans; Indomethacin; Kinetics; Liver; Pyrimidinones; Rheumatic Diseases

Topics: Antirheumatic Agents; Gentisates; Pyrimidinones; Rheumatic Diseases