Modified Immune Cell (MIC) Therapy disrupts Tertiary Lymphoid Structures in Murine Lupus Nephritis

Abstract

Induction of tolerance can be achieved with Modified Immune Cells (MIC) by infusion of mononuclear cells challenged with mitomycin C (MMC). Although MIC treatment has been successful in several animal models for autoimmunity and in clinical studies of solid organ transplantation, the mechanism of immunosuppression is not fully elucidated. In lupus nephritis, the glomerular deposition of immune complexes is associated with accumulating immune cells in the kidney. The infiltrating immune cells frequently establish tertiary lymphoid structures (TLS) supporting adaptive autoimmune responses toward locally displayed antigens. Since TLS display a high persistence to peripheral B cell depletion, the destruction of TLS presents an essential treatment goal in lupus nephritis. In this study, we used lupus nephritis prone NZB/W F1 mice to show the destruction of TLS in the kidney after MIC treatment. Independent of treatment, >86% of animals displayed dense lymphocytic aggregates proximal to the pelvic wall of the medulla and the arcuate arteries within the cortex of kidneys. Cell type composition of TLS changed drastically after MIC treatment leading to diminished B-cells, a decreased B-cell/T-cell ratio, and a T cell dominated phenotype. Furthermore, a loss of organization of the TLS was observed after MIC treatment. The strict separation of B-cell and T-cell areas was abrogated, and germinal centers were disintegrated. However, regulatory T-cells remained unchanged indicative of a B-cell centric treatment mechanism. Our data provides a putative in vivomechanism how MIC treatment inhibits progression of active lupus nephritis by the destruction of tertiary lymphoid structures within the kidney. Commercial Support - TolerogenixX GmbH