title: The type and frequency of immunoregulatory CD4+ T-cells govern the efficacy of antigen-specific immunotherapy in nonobese diabetic mice.
abstract: Antigen-specific immunotherapy, an approach to selectively block autoimmune diabetes, generally declines in nonobese diabetic (NOD) mice as disease progresses. To define the parameters influencing the efficacy of antigen-specific immunotherapy once diabetes is established, plasmid DNA (pDNA) vaccination was used to suppress autoimmune-mediated destruction of syngeneic islet grafts in diabetic NOD recipients. pDNAs encoding a glutamic acid decarboxylase 65 (GAD65)-Ig molecule (pGAD65), interleukin (IL)-4 (pIL4), and IL-10 (pIL10) significantly delayed the onset of recurrent diabetes compared with pGAD65+pIL10-vaccinated recipients. Despite differences in efficacy, a similar frequency of GAD65-specific CD4(+) T-cells secreting IL-4, IL-10, or interferon-gamma were detected in mice treated with pGAD65+pIL4+pIL10 and pGAD65+pIL10. However, the frequency of FoxP3-expressing CD4(+)CD25(+)CD62L(hi) T-cells was increased in the renal and pancreatic lymph nodes of diabetic recipients vaccinated with pGAD65+pIL4+pIL10. These immunoregulatory CD4(+)CD25(+) T-cells (CD4(+)CD25(+) Treg) exhibited enhanced in vivo and in vitro suppressor activity that partially was transforming growth factor-beta dependent. Furthermore, duration of islet graft protection in pGAD65+pIL4+pIL10-vaccinated diabetic recipients correlated with the persistence of CD4(+)CD25(+) Treg. These data demonstrate that the frequency and maintenance of FoxP3-expressing CD4(+)CD25(+) Treg influence antigen-induced suppression of ongoing beta-cell autoimmunity in diabetic recipients.
authors.affiliation: Curriculum in Oral Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7290, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Pop
authors.forename: Carmen P
authors.initials: CP
authors.lastname: Wong
authors.forename: Qiuming
authors.initials: Q
authors.lastname: He
authors.forename: Yaming
authors.initials: Y
authors.lastname: Wang
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wallet
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Goudy
authors.forename: Roland
authors.initials: R
authors.lastname: Tisch
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology* / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000628:therapy; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005968:Glutamate Decarboxylase / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D050417:Insulin-Secreting Cells / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics; D015847:Interleukin-4 / Q000276:immunology; D007527:Isoenzymes / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D009113:Muramidase / Q000276:immunology; D016133:Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000032:analysis
chemical_list: D000941:Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D007527:Isoenzymes; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D009113:Muramidase; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2