A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin.
The 9-23 amino acid region of the insulin B chain (B9-23) is a dominant epitope recognized by pathogenic T lymphocytes in nonobese diabetic mice, the animal model for type 1 diabetes. We describe herein similar (B9-23)-specific T-cell responses in peripheral lymphocytes obtained from patients with recent-onset type 1 diabetes and from prediabetic subjects at high risk for disease. Short-term T-cell lines generated from patient peripheral lymphocytes showed significant proliferative responses to (B9-23), whereas lymphocytes isolated from HLA and/or age-matched nondiabetic normal controls were unresponsive. Antibody-mediated blockade demonstrated that the response was HLA class II restricted. Use of the highly sensitive cytokine-detection ELISPOT assay revealed that these (B9-23)-specific cells were present in freshly isolated lymphocytes from only the type 1 diabetics and prediabetics and produced the proinflammatory cytokine IFN-gamma. This study is, to our knowledge, the first demonstration of a cellular response to the (B9-23) insulin epitope in human type 1 diabetes and suggests that the mouse and human diseases have strikingly similar autoantigenic targets, a feature that should facilitate development of antigen-based therapeutics.
Alleva
D G
DG
Immunology Department, Neurocrine Biosciences Inc., 10555 Science Center Drive, San Diego, California 92121-1102, USA. dalleva@neurocrine.com
Crowe
P D
PD
Jin
L
L
Kwok
W W
WW
Ling
N
N
Gottschalk
M
M
Conlon
P J
PJ
Gottlieb
P A
PA
Putnam
A L
AL
Gaur
A
A
D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology*; D005260:Female; D006801:Humans; D016056:Immunodominant Epitopes / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D011236:Prediabetic State / Q000097:blood / Q000276:immunology*; D012307:Risk Factors; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D016056:Immunodominant Epitopes; D007328:Insulin; D010446:Peptide Fragments; C097877:insulin B (9-23); D007371:Interferon-gamma