The Immune Microenvironment of Transplant Glomerulitis.

INTRODUCTION

Transplant glomerulitis is a morphological lesion seen in kidney allograft rejection that is associated with poor outcomes; however, little is known about how immune cells infiltrate and organize specifically within glomeruli.

METHODS

We used Co-Detection by Indexing (CODEX) multifluorescent imaging to measure 52 protein markers in a retrospective cohort of 41 human allograft nephrectomies (ANs) and evaluated the immunological landscape of transplant glomerulitis.

RESULTS

Characterization of 18 cell types identified diverse immune cells within inflamed glomeruli, with unique phenotypes and compositions compared with the extraglomerular microenvironment. Immunological phenotypes were conserved across glomeruli within individuals and associated with the general state of injury, with M1 macrophages and effector CD8 T cells associated with mild inflammation. Distance-based spatial analysis further revealed a profibrotic community composed of M2 macrophages, memory CD8 T cells and exhausted CD8 T cells surrounding endothelial cell hubs. These interaction networks were associated with regions of adverse glomerular remodeling, expression of profibrotic proteins, and were more prevalent in individuals with C4d-positive rejection.

CONCLUSION

These results implicate distinct cell-cell interactions as hallmarks of alloimmune injury and chronic remodeling during transplant glomerulitis and may give rise to new tools for histological risk assessment of clinical rejection syndromes.