Decoding the Retn-Cap1 Pathway in Intermediate Monocytes Mediating Liver Allograft Rejection

Lymphocytes are widely recognized as the primary mediators of cellular rejection post-liver transplantation. However, conventional immunosuppressive regimens that target lymphocytes, such as calcineurin phosphatase inhibitors, corticosteroids, or lymphocyte-depleting antibodies, can only partially mitigate rejection while inducing severe adverse effects. This necessitates the search for novel immunotherapeutic targets. Here, by creating the largest single-cell multi-omics database of liver transplantation to date and employing a souporcell-based strategy to distinguish between donor and recipient cells, we delineate the dynamic landscape of immune cells during allograft rejection and their spatial distributions across donors and recipients. Our findings underscore the pivotal role of recipient derived intermediate monocytes in cellular rejection. Using CellChat ligand-receptor analysis, we identify the Resistin-Cap1 pathway as a key mechanism by which intermediate monocytes participate in T cell-mediated rejection reactions. We confirm that Resistin knockdown significantly alleviates acute rejection after rat liver transplantation, markedly extending the survival of recipients using innovative nanogold technology. These findings offer insights into the dynamic changes in the alloimmune microenvironment, pinpointing intermediate monocytes as potential diagnostic and immunotherapeutic targets during allograft rejection. This study holds significant importance in advancing non-invasive diagnostic technologies and immunotherapeutic strategies for allogeneic rejection. Overall design: Liver transplantation was conducted from Lewis rats to BN rats to create a post-transplant rejection model, and from BN rats to BN rats to establish a syngeneic control model. Liver tissues and peripheral blood mononuclear cells (PBMCs) from both groups were collected on days 0, 1, 7, and 14 post-transplantation for single-cell sequencing.