Modified immune cell therapy targets kidney-resident tertiary lymphoid structures and ameliorates murine lupus nephritis

Introduction Modified immune cells (MIC), i.e. mononuclear cells challenged with mitomycin C can induce immunotolerance. MIC treatment has been successful in several animal models of autoimmunity and in clinical trials after solid organ transplantation, but the mechanism for reduced inflammation is not fully understood. Methods To investigate the efficacy of MIC therapy in lupus nephritis, splenocytes from syngeneic NZB/W F1 (BWF1) donor mice were incubated with mitomycin C, and then into BWF1 recipients at 25 weeks of age. Animals were followed for another five weeks to assess disease progression by histological, flow cytometric, and serological parameters. An in vitro phagocytosis assay was conducted to determine the clearance of MIC from 25 patients with lupus and from matched healthy individuals by autologous macrophages. Results In BWF1 mice, MIC therapy reduced the clinical burden of lupus nephritis disease progression with lower protein excretion and lower serum creatinine levels in the standard-dose compared to the control group. High-dose MIC therapy during active diseases showed no additional benefit. More than 86% of animals had dense lymphocytic aggregates close to the kidney pelvis. These tertiary lymphoid structures differed between MIC-treated animals and controls, with a loss of organization, loss of separation of B-cell and T-cell areas and disintegration of germinal centers after MIC treatment. In the peripheral blood, MIC-treated animals had higher numbers of CD19 + CD5 + CD1d high regulatory-like B lymphocytes. Although MIC treatment was beneficial, higher dosing offered no additional clinical benefit in mice. Macrophages from the patients with lupus efficiently cleared MIC in vitro , ruling out defective clearance as a limiting factor. Conclusion Our clinically applicable cell therapy approach has the potential to control lupus nephritis by specifically dampening deleterious autoimmune responses.