Isolation of nonobese diabetic mouse T-cells that recognize novel autoantigens involved in the early events of diabetes.
Insulin-dependent diabetes mellitus (IDDM) is thought to result from chronic, cell-mediated, autoimmune islet damage. Our aim was to identify the earliest T-cell autoantigen in IDDM, reasoning that this antigen could be causally involved in the initiation of the disease. Identification of the earliest beta-cell-specific autoantigen is extremely important in allowing advances in prevention and treatment of initial events in the development of inflammatory insulitis that precedes beta-cell destruction and overt diabetes. Therefore, we analyzed the proliferative responses of peripheral T-cells from young, female nonobese diabetic (NOD) mice to extracts of pancreatic beta-cell lines. We were able to demonstrate that T-cells responsive to beta-cell antigens exist in the peripheral lymphoid tissue of these mice in the absence of deliberate priming before the manifestation of histologically detectable insulitis. T-cell lines and clones isolated from the peripheral lymphatic tissues of young, unimmunized, female NOD mice were also shown to react with extracts of beta-cells. Fractionation of the beta-cell extracts showed that these T-cell clones recognized multiple beta-cell-specific autoantigens but none of the previously reported putative autoantigens (glutamic acid decarboxylase [GAD]65, GAD67, Hsp65, insulin, ICA 69, carboxypeptidase-H, and peripherin). Thus, we can conclude that these responses are specific for novel beta-cell autoantigens. Finally, NOD T-cell proliferative responses were also seen to an extract of human islets suggesting potential shared antigenic determinants between human and mouse beta-cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Gelber
C
C
ImmuLogic Pharmaceutical, Palo-Alto, CA 94304.
Paborsky
L
L
Singer
S
S
McAteer
D
D
Tisch
R
R
Jolicoeur
C
C
Buelow
R
R
McDevitt
H
H
Fathman
C G
CG
D000818:Animals; D001324:Autoantigens / Q000032:analysis* / Q000276:immunology; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology; D006360:Heat-Shock Proteins / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD / Q000276:immunology*; D008969:Molecular Sequence Data; D010182:Pancreatic Diseases / Q000276:immunology / Q000473:pathology; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*
D001324:Autoantigens; D017931:DNA Primers; D006360:Heat-Shock Proteins; D005968:Glutamate Decarboxylase