title: Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells.
abstract: OBJECTIVE
  Elevated proportions of regulatory T cells (T(reg)) are present in patients with a variety of cancers, including malignant glioma, yet recapitulative murine models are wanting. We therefore examined T(regs) in mice bearing malignant glioma and evaluated anti-CD25 as an immunotherapeutic adjunct.
  
  
  METHODS
  CD4+CD25+Foxp3+GITR+ T(regs) were quantified in the peripheral blood, spleens, cervical lymph nodes, and bone marrow of mice bearing malignant glioma. The capacities for systemic anti-CD25 therapy to deplete T(regs), enhance lymphocyte function, and generate antiglioma CTL responses were assessed. Lastly, survival and experimental allergic encephalitis risks were evaluated when anti-CD25 was combined with a dendritic cell-based immunization targeting shared tumor and central nervous system antigens.
  
  
  RESULTS
  Similar to patients with malignant glioma, glioma-bearing mice show a CD4 lymphopenia. Additionally, CD4+CD25+Foxp3+GITR+ T(regs) represent an increased fraction of the remaining peripheral blood CD4+ T cells, despite themselves being reduced in number. Similar trends are observed in cervical lymph node and spleen, but not in bone marrow. Systemic anti-CD25 administration hinders detection of CD25+ cells but fails to completely eliminate T(regs), reducing their number only moderately, yet eliminating their suppressive function. This elimination of T(reg) function permits enhanced lymphocyte proliferative and IFN-gamma responses and up to 80% specific lysis of glioma cell targets in vitro. When combined with dendritic cell immunization, anti-CD25 elicits tumor rejection in 100% of challenged mice without precipitating experimental allergic encephalitis.
  
  
  CONCLUSIONS
  Systemic anti-CD25 administration does not entirely eliminate T(regs) but does prevent T(reg) function. This leads to safe enhancement of tumor immunity in a murine glioma model that recapitulates the tumor-induced changes to the CD4 and T(reg) compartments seen in patients with malignant glioma.
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Fecci
authors.forename: Alison E
authors.initials: AE
authors.lastname: Sweeney
authors.forename: Peter M
authors.initials: PM
authors.lastname: Grossi
authors.forename: Smita K
authors.initials: SK
authors.lastname: Nair
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Learn
authors.forename: Duane A
authors.initials: DA
authors.lastname: Mitchell
authors.forename: Xiuyu
authors.initials: X
authors.lastname: Cui
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Cummings
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Eli
authors.initials: E
authors.lastname: Gilboa
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001854:Bone Marrow Cells / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism* / Q000628:therapy*; D015704:CD4 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000378:metabolism; D005434:Flow Cytometry; D005910:Glioma / Q000378:metabolism* / Q000628:therapy*; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis* / Q000737:chemistry; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D013601:T-Lymphocytes / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma