4-1BB-mediated Signals Confer Protection Against Folic Acid-induced Nephrotoxicity

Background: The role of co-stimulatory molecules in renal diseases has been previously examined, however, little is known about the role of 4-1BB in the context of renal diseases resulting from nonimmune-mediated tubulointerstitial fibrosis. Folic acid induced Nephrotoxicity (FAN) in mice was used to explore the role of 4-1BB in this setting. Methods: CD1 mice were treated with folic acid and kidneys subsequently examined using histochemistry, in addition to defining T cell profiles and evaluating renal function. Increased CD3+ and CD4+ T lymphocytes present in blood and spleen at day 3 suggested immunopathological reactions during the early stages of FAN and decreased CD3+ and CD4+ T lymphocytes on day 14 were characteristic of an immunocompromised state observed during the late stages of FAN. Results: After 14 days of co-treatment with agonistic anti-4-1BB monoclonal antibodies, renal tubulointerstitial lesions were reduced. Renal function was improved, with Bun scores decreasing (pConclusions: Data presented in this report demonstrated that 4-1BB signals had immunoregulatory effects that attenuated early immune-mediated pathology and reversed the immunocompromised state observed during the later stages of disease.