Although highly effective, biologics targeting IL-23/Th17 axis should be continuously injected to suppress recurrence of psoriasis. My long-term goal is to cure psoriasis without recurrence guided by personal immune tolerance. The overall objectives in this application are to (i) identify regulatory immune cell interactions induced by anti-IL-23p19 antibody administration in the skin of patients whose psoriasis is cleared without recurrence and (ii) develop pre-treatment predictive models for psoriasis patients that anticipate disease recurrence after short-term anti-IL-23p19 antibody injection. The central hypothesis is that IL-23p19 inhibition promotes regulatory immune cells in psoriasis patients whose disease is cleared without recurrence, and their pre-treatment single-cell immune signatures are different from those of patients whose disease recurs. The rationale for this project is that molecular evidence of immune tolerance induction by IL-23p19 inhibition in human skin is likely to offer a strong clinical framework whereby new strategies to prevent recurrence of chronic inflammatory diseases can be developed. The central hypothesis will be tested by pursuing two specific aims: 1) Testing the hypothesis that regulatory immune cell interactions are promoted by short-term anti-IL-23p19 antibody administration in the skin of psoriasis patients whose disease becomes clear without recurrence; and 2) Developing predictive models with pretreatment skin biopsy single-cell genomic data that anticipate long-term disease clearance off drug after short-term anti-IL-23p19 antibody administration. To achieve the specific aims, we have recently developed two innovative complementary single-cell approaches to obtain gene expression profiles of heterogeneous immune cells from psoriasis and control skin without enzyme digestion. The first single-cell experimental approach is microfluidic partitioning of emigrating cells from human skin after 48-hour incubation in culture medium without enzyme digestion, which empowers single-cell transcriptomic profiling of heterogeneous immune cells and keratinocytes in different layers of epidermis under ex vivo condition. The second single-cell experimental approach is Combinatorial indexing RNA sequencing, developed by the co-mentor of the proposal, which enables co-profiling transcriptome and single-cell chromatin accessibility. At the completion of the proposed research, our expected outcomes are to have novel single-cell genomic techniques to study immune cell interactions in human skin, defined single-cell gene signatures of regulatory immune cells that are promoted by anti-IL-23p19 antibody administration in psoriasis skin, and the ability to elucidate how pathologic immunity is suppressed at the single-cell level by highly effective biologics. We also expect to have pre-treatment biomarkers that can predict long-term disease clearance off drugs after short-term anti-IL-23p19 antibody administration.