#1685 Multimodal spatial profiling of microvascular inflammation in kidney allografts

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Abstract Background and Aims Kidney allograft microvascular inflammation (MVI) DSA-negative C4d-negative is a new entity recognized by the Banff 2022 classification, but the mechanisms driving this inflammation remain poorly understood. In this context, we aimed to decipher its immuno-molecular landscape. Method MVI cases were identified in a multicentric cohort of kidney transplant patients and compared to MVI-negative control cases (total n = 309). Biopsies were graded according to the Banff 2022 classification and sequenced using the Banff Human Organ Transplant panel. Whole-transcriptome digital spatial profiling and cellular deconvolution were performed on each phenotype of interest using the NanoString GeoMx® platform. Finally, microvascular infiltration was characterized using a multiplex immunofluorescence panel staining CD34, CD68, CD3, NKp46, CD15 and CD20. Results Three MVI phenotypes were analyzed: 1) MVI DSA− C4d− (n = 49, 15.9%), 2) MVI DSA+ C4d− (n = 45, 14.6%), 3) MVI DSA+ C4d+ (n = 46, 14.9%), as well as a control group of non-MVI cases (n = 169, 54.6%). When compared to controls, all MVI cases shared a common molecular signature, characterized by an upregulation of genes associated with antibody-mediated injury, interferon-gamma response, and activation of macrophages, NK cells, and T cells. This common signature was less intense in MVI DSA− C4d− cases, particularly regarding the interferon-gamma response. Spatial profiling analysis revealed that this molecular signal was more prominent in peritubular capillaries than in the glomeruli. Cellular deconvolution further demonstrated that MVI DSA− C4d− cases were particularly associated with NK cells and conventional dendritic cells. Automated quantification of immunofluorescence staining revealed that microvascular infiltration was predominantly composed of CD68+ macrophages, CD3+ T cells, and NKp46+ NK cells (Fig. 1). Conclusion We demonstrate that the immuno-molecular signature in kidney allograft MVI DSA− C4d− is moderate in intensity compared to MVI DSA+ C4d− and MVI DSA+ C4d+, and is predominantly characterized by the presence of NK cells and conventional dendritic cells in the peritubular capillaries. Our findings open avenues for more mechanistically driven therapeutic approaches for MVI.

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