Antigen based therapies to prevent diabetes in NOD mice.
Interventional approaches that have been successful in delaying insulin-dependent diabetes mellitus (IDDM) using antigen-based immunotherapies include parenteral immunization. It has potential for clinical application provided that effective adjuvants suitable for human use can be found. We have previously shown that immunization with insulin and insulin B chain but not A chain in incomplete Freund's adjuvant (IFA) prevented diabetes by reducing IFN-gamma mRNA in the insulitis lesions. In this paper we show that the insulin B chain peptide (p9-23) contain the most protective epitope. Immunization with selected GAD peptides was ineffective. Immunization with B chain but not A chain using alum as adjuvant delayed diabetes onset (P = 0.012), whereas administration of alum alone was not protective. When Diphtheria-Tetanus toxoid-Acellular Pertussis (DTP) vaccine was used as the adjuvant vehicle, DTP itself induced significant protection (P < 0.003) which was associated with a Th2-like cytokine producing insulitis profile, IL-4 driven IgG1 antibody responses to insulin, GAD in the periphery and an augmentation of the autoimmune response to GAD. The anti-diabetic effect of DTP was enhanced when given with insulin B chain. These results encourage consideration of an approach using alum/DTP and insulin B chain immunization in clinical trials.
Ramiya
V K
VK
Department of Pathology and Laboratory Medicine, University of Florida, Gainesville 32610-0275, USA.
Shang
X Z
XZ
Pharis
P G
PG
Wasserfall
C H
CH
Stabler
T V
TV
Muir
A B
AB
Schatz
D A
DA
Maclaren
N K
NK
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D000941:Antigens / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D016207:Cytokines / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D015721:Diphtheria-Tetanus-Pertussis Vaccine / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D007515:Islets of Langerhans / Q000737:chemistry; D051379:Mice; D016688:Mice, Inbred NOD / Q000276:immunology*; D008969:Molecular Sequence Data; D010182:Pancreatic Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D010455:Peptides / Q000276:immunology; D018418:Th2 Cells / Q000737:chemistry
D000941:Antigens; D016207:Cytokines; D015721:Diphtheria-Tetanus-Pertussis Vaccine; D007074:Immunoglobulin G; D010455:Peptides