Insulin-secretory-granule specific T cell clones in human IDDM.
T cell clones reactive to beta-cell antigens prepared from different species were established in order to identify putative pathogenic T cells in human IDDM. We were able to generate T cell clones from patients, but not from controls, reactive specifically to the insulin secretory enriched fraction (ISG) of a rat insulinoma RIN cell line. This finding is suggestive of an in vivo priming by the antigen(s). To examine the relevance of these T cell clones in the pathogenesis of IDDM, we studied their cytokine profile. T cell clones from the newly onset patients had a Th1 cytokine profile, while those from the prediabetic patient were of the Th2 subtype. This segregation suggests that RIN-ISG contains antigen(s) involved in the pathogenesis of this disease, since IDDM is considered a cell-mediated or Th1 disease. Since two of these clones also responded to a hamster insulinoma cell line HIT, at least two antigens in RIN-ISG could be defined by this panel of T cell clones. Examination of CDR3 sequences confirmed the clonality of the dual-reactive T cell clones. The finding of HIT-reactive cells in IDDM patients may be useful in efforts to identify prediabetic patients for immune intervention. Dual reactivity may provide a better prognosis than single reactivity. In contrast to T cell clones reactive to insulinomas, T cell clones reactive to normal human ISG were not found after over 200 clones were screened. In addition, RIN-ISG specific clones did not respond to either normal human or rat ISG, suggesting that IDDM antigens are below detectable levels in normal beta cells.
Chang
J C
JC
Immune Response Corporation, Carlsbad, CA 92008, USA.
Linarelli
L G
LG
Laxer
J A
JA
Froning
K J
KJ
Caralli
L L
LL
Brostoff
S W
SW
Carlo
D J
DJ
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002999:Clone Cells / Q000276:immunology; D006224:Cricetinae; D003594:Cytoplasmic Granules / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006801:Humans; D007340:Insulinoma / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000378:metabolism; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology; D011236:Prediabetic State / Q000276:immunology / Q000473:pathology; D051381:Rats; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D008222:Lymphokines