title: Low dose rapamycin exacerbates autoimmune experimental uveitis.
abstract: BACKGROUND
  Rapamycin, a potent immune modulator, is used to treat transplant rejection and some autoimmune diseases. Uveitis is a potentially severe inflammatory eye disease, and 2 clinical trials of treating uveitis with rapamycin are under way. Unexpectedly, recent research has demonstrated that low dose rapamycin enhances the memory T cell population and function. However, it is unclear how low dose rapamycin influences the immune response in the setting of uveitis.
  
  
  METHODS
  B10.RIII mice were immunized to induce experimental autoimmune uveitis (EAU). Ocular inflammation of control and rapamycin-treated mice was compared based on histological change. ELISPOT and T cell proliferation assays were performed to assess splenocyte response to ocular antigen. In addition, we examined the effect of rapamycin on activation-induced cell death (AICD) using the MitoCapture assay and Annexin V staining.
  
  
  RESULTS
  Administration of low dose rapamycin exacerbated EAU, whereas treating mice with high dose rapamycin attenuated ocular inflammation. The progression of EAU by low dose rapamycin coincided with the increased frequency of antigen-reactive lymphocytes. Lastly, fewer rapamycin-treated T cells underwent AICD, which might contribute to exaggerated ocular inflammation and the uveitogenic immune response.
  
  
  CONCLUSIONS
  These data reveal a paradoxical role for rapamycin in uveitis in a dose-dependent manner. This study has a potentially important clinical implication as rapamycin might cause unwanted consequences dependent on dosing and pharmacokinetics. Thus, more research is needed to further define the mechanism by which low dose rapamycin augments the immune response.
authors.affiliation: Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America. zhangzi@ohsu.edu
authors.forename: Zili
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiumei
authors.initials: X
authors.lastname: Wu
authors.forename: Jie
authors.initials: J
authors.lastname: Duan
authors.forename: David
authors.initials: D
authors.lastname: Hinrichs
authors.forename: Keith
authors.initials: K
authors.lastname: Wegmann
authors.forename: Gary L
authors.initials: GL
authors.lastname: Zhang
authors.forename: Mark
authors.initials: M
authors.lastname: Hall
authors.forename: James T
authors.initials: JT
authors.lastname: Rosenbaum
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D020123:Sirolimus / Q000009:adverse effects* / Q000493:pharmacokinetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D014605:Uveitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D014157:Transcription Factors; D020123:Sirolimus