Intranasal vaccination with proinsulin DNA induces regulatory CD4+ T cells that prevent experimental autoimmune diabetes.
Insulin, an autoantigen in type 1 diabetes, when administered mucosally to diabetes-prone NOD mice induces regulatory T cells (T(reg)) that protect against diabetes. Compared with protein, Ag encoded as DNA has potential advantages as a therapeutic agent. We found that intranasal vaccination of NOD mice with plasmid DNA encoding mouse proinsulin II-induced CD4+ T(reg) that suppressed diabetes development, both after adoptive cotransfer with "diabetogenic" spleen cells and after transfer into NOD mice given cyclophosphamide to accelerate diabetes onset. In contrast to prototypic CD4+ CD25+ T(reg), CD4+ T(reg) induced by proinsulin DNA were both CD25+ and CD25- and not defined by markers such as glucocorticoid-induced TNFR-related protein (GITR), CD103, or Foxp3. Intriguingly, despite induction of T(reg) and reduced islet inflammation, diabetes incidence in proinsulin DNA-treated mice was unchanged. However, diabetes was prevented when DNA vaccination was performed under the cover of CD40 ligand blockade, known to prevent priming of CTL by mucosal Ag. Thus, intranasal vaccination with proinsulin DNA has therapeutic potential to prevent diabetes, as demonstrated by induction of protective T(reg), but further modifications are required to improve its efficacy, which could be compromised by concomitant induction of pathogenic immunity.
Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Alison L
AL
Every
David R
DR
Kramer
Stuart I
SI
Mannering
Andrew M
AM
Lew
Leonard C
LC
Harrison
D000281:Administration, Intranasal; D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D015870:Gene Expression; D007371:Interferon-gamma / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D011384:Proinsulin / Q000235:genetics* / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics*
D001324:Autoantigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D010446:Peptide Fragments; D015375:Receptors, Interleukin-2; D019444:Vaccines, DNA; D023201:CD40 Ligand; D007371:Interferon-gamma; D011384:Proinsulin