T-cell reactivity to 38 kD insulin-secretory-granule protein in patients with recent-onset type 1 diabetes

Roep, Bart O.; Kallan, A. A.; Hazenbos, Wouter L. W.; Vries, RenéR.P. de; Bruining, G. J.; Bailyes, E M; Arden, Susan D.; Hutton, John C.

doi:10.1016/0140-6736(91)93127-u

Cited by 109 publications

(34 citation statements)

References 15 publications

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“…However, progression of the diabetogenic process was not disturbed by pancreatectomy once the autoreactive T cells had been activated, as evidenced by moderate insulitis in 13-weekold pancreases. Although it is currently unknown whether the islet antigen(s) involved in the early T-cell activation is the conventional autoantigens (17)(18)(19)(20)(21)(22)(23)(24) or other early beta cellspecific autoantigens (27) destroyed by the autoimmune process (28). The mechanism(s) underlying slow development of autoimmune diabetes, regardless of the size of an islet mass, remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Although a T lymphocyte-mediated autoimmune etiology is suggested in this model (9)(10)(11)(12)(13)(14)(15)(16), the antigen(s) responsible for triggering the activation of autoreactive T lymphocytes has not been fully elucidated. Molecules localized in the islets that have been characterized as the candidate antigens include insulin (17), glutamic acid decarboxylase (18), glycolipids (19,20), carboxypeptidase H (21), and cellular proteins with molecular masses of 38 kDa (22), 52 kDa (23), and 69 kDa (24).…”

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confidence: 99%

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Protection of nonobese diabetic mice from autoimmune diabetes by reduction of islet mass before insulitis.

Itoh

Maki²

1996

Proc. Natl. Acad. Sci. U.S.A.

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Nonobese diabetic mice spontaneously develop diabetes that is caused by autoimmune cell-mediated destruction of pancreatic beta cells. Here we report that surgical removal of 90% of pancreatic tissue before onset of insulitis induced a long-term diabetes-free condition in nonobese diabetic mice. Pancreatectomy after development of moderate insulitis had no effect on the course of diabetes. The effect of pancreatectomy was abrogated with subsequent development of diabetes by infusion of islet-cell-specific T lymphocytes and by transplantation of pancreatic islets. Lymphocytes from pancreatectomized diabetes-free mice exhibited low response to islet cells but responded normally to alloantigens. These results suggest that the islet cell mass plays a critical role in development of autoimmune diabetes.Nonobese diabetic (NOD) mice spontaneously develop diabetes that has features similar to those of human insulindependent diabetes mellitus, a polygenic disease caused by autoimmune destruction of insulin-producing beta cells in the islets of Langerhans (1-3). The onset of this type of diabetes is preceded by a long period of insulitis that proceeds from lymphoid cell infiltration in the periphery of the islets (periinsulitis) to cellular infiltration invading the islets (insulitis) (4-8). Although a T lymphocyte-mediated autoimmune etiology is suggested in this model (9-16), the antigen(s) responsible for triggering the activation of autoreactive T lymphocytes has not been fully elucidated. Molecules localized in the islets that have been characterized as the candidate antigens include insulin (17), glutamic acid decarboxylase (18), glycolipids (19, 20), carboxypeptidase H (21), and cellular proteins with molecular masses of 38 kDa (22), 52 kDa (23), and 69 kDa (24).Regardless of the nature of islet autoantigen(s), initial activation of autoreactive T cells by the antigen(s) must take place sometime before the development of insulitis. Although it is likely that presentation of the autoantigen(s) to T cells occurs locally within the pancreas, there has been no study (to our knowledge) on whether the initiation of the diabetogenic process is a dose-dependent event in which a sufficient amount of islet antigen(s) in the pancreas must be presented to autoreactive T cells for activation. In this study, we examined whether reduction of overall islet mass by surgical removal of the pancreas has any influence in the subsequent development of diabetes in NOD mice. MATERIALS AND METHODSMice. Female NOD/MrkTacfBR mice were purchased from Taconic. In this strain of NOD mice, hyperglycemia is first observed when the mice are 14 weeks old, and the cumulative incidence of diabetes is 80% in females at 27 weeks (data provided by Taconic). Male C3H/He (H-2k) and DBA/1 (H-2q) mice (7-8 weeks old) were obtained from The Jackson Laboratory. All

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Protection of nonobese diabetic mice from autoimmune diabetes by reduction of islet mass before insulitis.

Itoh

Maki²

1996

Proc. Natl. Acad. Sci. U.S.A.

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“…Bereits Anfang der 90er Jahre gelang es der Arbeitsgruppe von Bart Roep, Leiden, Niederlande, aus dem Blut von frischmanifesten Typ-1-Diabetikern T-Zellen zu isolieren und zu klonieren, die spezifisch mit einem Autoantigen aus den Membranen von Insulinproduzierenden Zellen reagieren [2,3]. Diese autoreaktiven T-Zell-Klone eignen sich, um die Wirksamkeit von Immuntherapien in vitro zu testen.…”

Section: Wirkung Von Proteasen In Immunologischen Testsystemenunclassified

Immunmodulation durch Proteasen

Martin

2008

Dtsch med Wochenschr

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“…rounds of antigen-specific restimulation (13). The presence of circulating antibodies to proteins of 38 kDa in human (16,17) and experimental diabetes (18) and the isolation of a 38-kDa responsive diabetogenic T-cell line from NOD mice (19) further suggest that an antigen of this size is of pathological importance in the disease.…”

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confidence: 99%

“…We have shown previously that the majority of newly diagnosed type 1 diabetics have circulating T cells which proliferate in response to membrane proteins of rat insulinoma tissue (13,14). A series of T-cell lines and clones have been obtained using this antigen source including a CD4+ cytotoxic T-cell clone (1C6) which recognizes a 38-kDa membrane protein present in insulinoma subcellular fractions enriched in secretory granules (15).…”

mentioning

confidence: 99%

T-cell epitope analysis using subtracted expression libraries (TEASEL): application to a 38-kDA autoantigen recognized by T cells from an insulin-dependent diabetic patient.

Neophytou

Roep²,

Arden³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Studies on circulating T cells and antibodies in newly diagnosed type 1 diabetic patients and rodent models of autoimmune diabetes suggest that ,B-cell membrane proteins of 38 kDa may be important molecular targets of autoimmune attack Biochemical approaches to the isolation and identification of the 38-kDa autoantigen have been hampered by the restricted availability of islet tissue and the low abundance of the protein. A procedure of epitope analysis for CD4+ T cells using subtracted expression libraries (TEASEL) was developed and used to clone a 70-amino acid pancreatic (8-cell peptide incorporating an epitope recognized by a 38-kDa-reactive CD4+ T-cell clone (1C6) isolated from a human diabetic patient. The minimal epitope was mapped to a 10-amino acid synthetic peptide containing a DR1 consensus binding motif. Data base searches did not reveal the identity of the protein, though a weak homology to the bacterial superantigens SEA (Streptococcus pyogenes exotoxin A) and SEB (Staphylococcus aureus enterotoxin B) (23% identity) was evident. The TEASEL procedure might be used to identify epitopes of other autoantigens recognized by CD4+ T cells in diabetes as well as be more generally applicable to the study low-abundance autoantigens in other tissue-specific autoimmune diseases.

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T-cell reactivity to 38 kD insulin-secretory-granule protein in patients with recent-onset type 1 diabetes

Cited by 109 publications

References 15 publications

Protection of nonobese diabetic mice from autoimmune diabetes by reduction of islet mass before insulitis.

Protection of nonobese diabetic mice from autoimmune diabetes by reduction of islet mass before insulitis.

Immunmodulation durch Proteasen

T-cell epitope analysis using subtracted expression libraries (TEASEL): application to a 38-kDA autoantigen recognized by T cells from an insulin-dependent diabetic patient.

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