iSYNAPSE: Early signals of the transition from immune quiescence to activation in the liver allograft microenvironment and in the circulation

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iSYNAPSE Summary Children with liver transplants with excellent graft function according to clinical, biochemical, and histological criteria enjoy a harmonious equilibrium between the host immune system and the allograft. Reducing immunosuppression is challenge that, for some but not all, precipitates alloimmune activation that can result in graft injury. Previously, we have shown that objective quantification of inflammatory load using next generation pathology techniques can meaningfully differentiate allografts that appear normal by standard histological evaluation. The density of various inflammatory cells essentially maps allografts onto an alloreactivity spectrum that extends from quiescent to activated. Among inflammatory metrics, the density of immunologic synapses, defined as a lymphocyte proximal to and interacting with an antigen-presenting cell based on positional, morphometric, and molecular parameters, was the best predictor of those who could withstand the challenge of immunosuppression dose reduction to complete cessation. These data suggest that, within an apparently quiescent allograft, the intrahepatic microenvironment, comprised of immune cells and their cell-to-cell interactions, determines the likelihood of maintaining quiescence or succumbing to activation when IS is reduced. Our primary hypothesis is that the number and nature of interactions between intrahepatic immune cells at quiescence constitutes the basis of liver allograft immunogenicity and is the key determinant of outcome, when quiescence is challenged. To test this hypothesis, iSYNAPSE proposes the following specific aims: 1) Conduct a multicenter, single-arm trial for stable children with healthy liver allografts on calcineurin inhibitor monotherapy. Immunosuppression will be reduced by 50%, from twice to once daily dosing. This intervention offers direct prospect of benefit by reducing medication exposure and simplifying administration. 2) Determine how intrahepatic immune cell networks regulate liver allograft immunogenicity at baseline and following immunosuppression reduction. Using next generation pathology and single cell transcriptomics, we will characterize the phenotype and the transcriptome of the lymphocytes and the antigen-presenting cells participating in immunological synapses. The iterative analyses of these two data streams will fully inventory the immune cell subsets that comprise the liver microenvironment and elucidate the impact of cell-to-cell interactions on the maintenance or loss of quiescence when challenged. 3) Ascertain whether the nature of intrahepatic cell-to-cell interactions predict changes in donor-specific humoral and cellular responses in the circulation. Liver transplantation provides a unique context to safely study the host and graft respond when the equilibrium achieved by immunosuppression is challenged. Understanding these basic mechanisms of how allograft quiescence is maintained or lost when stressed is essential to navigate the treacherous balance between over- and under-immunosuppression that translate into suboptimal outcomes for either the patient or the graft.