Establishment of Islet-specific T-cell Lines and Clones from Islet Isografts Placed in Spontaneously Diabetic NOD Mice

Wegmann, Dale; Shehadeh, Naim; Lafferty, Kevin J.; Norbury-Glaser, Mary; Gill, Ronald G.; Daniel, Dylan

doi:10.1006/jaut.1993.1043

Cited by 26 publications

(13 citation statements)

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“…In fact, with one exception (12), most T cell clones, T cell lines, and TCR-transgenic T cells specific for GAD65 either failed to induce diabetes or in some cases protected against diabetes progression (17,43). T cells shown to be capable of causing insulitis and͞or diabetes are specific either for insulin (44) or for unknown pancreatic islet antigens (45,46).…”

Section: Discussionmentioning

confidence: 99%

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

Kim

Tarbell

Sanna

et al. 2004

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

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Glutamic acid decarboxylase (GAD) 65 is one of the major pancreatic antigens targeted by self-reactive T cells in type I diabetes mellitus. T cells specific for GAD65 are among the first to enter inflamed islets and may be important for the initiation of autoimmune diabetes. However, we previously reported that nonobese diabetic (NOD) mice transgenic for a T cell antigen receptor (TCR) specific for one of the immunodominant epitopes of GAD65, peptide 286-300 (G286), are protected from insulitis and diabetes. To examine whether other GAD65-reactive T cells share this phenotype, we have generated TCR transgenic NOD mice for a second immunodominant epitope of GAD65, peptide 206-220 (G206). As in G286 mice, G206 mice do not develop islet inflammation or diabetes. When adoptively transferred along with diabetogenic T cells, activated G206 T cells significantly delayed the onset of diabetes in NOD.scid recipients. Both G206 and G286 T cells produce immunoregulatory cytokines IFN-␥ and IL-10 at low levels when activated by cognate antigens. These data suggest that GAD65-specific T cells may play a protective role in diabetes pathogenesis by regulating pathogenic T cell responses. A better understanding of the functions of autoreactive T cells in type I diabetes will be necessary for choosing desirable targets for immunotherapy.T ype I diabetes mellitus in humans is an autoimmune disease that results from the selective destruction of pancreatic ␤-cells by T cells (1, 2). The nonobese diabetic (NOD) mouse develops spontaneous autoimmune diabetes that shares many characteristics with the human disease (1, 3, 4). The principal islet cell antigens targeted by autoreactive T cells in NOD mice include insulin (5), glutamic acid decarboxylase 65 (GAD65) (6), 65-kDa heat shock protein (7), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) (8). Among these, T cell responses to GAD65 and insulin are detected early preceding the onset of clinical disease (3-5 weeks of age in the NOD mouse) (9-11). This result has led to the speculation that GAD65 may be among the first autoantigens targeted by T cells that initiate the diabetes pathogenesis.The hypothesis for a pathogenic role of GAD65 is supported by a GAD65-specific T cell clone that induces insulitis and diabetes upon adoptive transfer (12) and by the finding that prevention of GAD65 expression in the pancreatic islets by GAD antisense cDNA prevented diabetes (13). In contrast, induction of deletional T cell tolerance by widespread expression of a GAD65 transgene did not alter diabetes pathogenesis (14) but exacerbated the disease (15). In addition, several GAD65-specific T cell clones, lines, and T cell antigen receptor (TCR) transgenic mice were not pathogenic and exhibited a diabetesdelaying capacity (16-18). Thus, it appears that GAD65 may not be a required initiating antigen for diabetes pathogenesis but rather induces a protective response.To further examine the functions of GAD65-reactive T cells in the pathogenesis of diabetes, we have ge...

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Section: Discussionmentioning

confidence: 99%

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

Kim

Tarbell

Sanna

et al. 2004

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

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“…As in human diabetes, the NOD mouse exhibits a T cell-mediated destruction of the islet ␤ cells of the pancreas (3)(4)(5)(6)(7)(8)(9)(10)(11). To understand the role of T cells in diabetes in the NOD mouse, isletspecific T cell clones have been produced by several groups (1,(12)(13)(14)(15)(16)(17)(18)(19). These cells have been primarily CD4 ϩ and of the Th1 phenotype, and many have been shown to be diabetogenic in the young NOD mouse (18, 20 -25).…”

Section: Induction Of Diabetes In Nonobese Diabetic Mice By Th2 T Celmentioning

confidence: 99%

Induction of Diabetes in Nonobese Diabetic Mice by Th2 T Cell Clones from a TCR Transgenic Mouse

Poulin

Haskins

2000

The Journal of Immunology

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We have produced a panel of cloned T cell lines from the BDC-2.5 TCR transgenic (Tg) mouse that exhibit a Th2 cytokine phenotype in vitro but are highly diabetogenic in vivo. Unlike an earlier report in which T cells obtained from the Tg mouse were cultured for 1 wk under Th2-promoting conditions and were found to induce disease only in NOD.scid recipients, we found that long-term T cell clones with a fixed Th2 cytokine profile can transfer disease only to young nonobese diabetic (NOD) mice and never to NOD.scid recipients. Furthermore, the mechanism by which diabetes is transferred by a Tg Th2 T cell clone differs from that of the original CD4+ Th1 BDC-2.5 T cell clone made in this laboratory. Whereas the BDC-2.5 clone rapidly causes disease in NOD.scid recipients less than 2 wk old, the Tg Th2 T cell clones can do so only when cotransferred with other diabetogenic T cells, suggesting that the Th2 T cell requires the presence of host T cells for initiation of disease.

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“…T cell responses have been reported in the NOD mouse against a number of candidate autoantigens including glutamic acid decarboxylase (GAD), carboxypeptidase H, peripherin, heat shock protein (hsp 60), and insulin (14). However, although pathogenic T cell clones specific for hsp 60 and insulin have been isolated (15,16), the identity of the antigens recognized by the majority of pathogenic T cell clones remains elusive. The existence of clones that do not recognize these candidate antigens, but do induce disease, would suggest that other novel antigens remain to be discovered.…”

Section: Introductionmentioning

confidence: 99%

In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice.

Healey

Ozegbe²,

Arden³

et al. 1995

J. Clin. Invest.

139

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CD4' T cell lines were generated from the spleens of diabetic NOD mice against crude membrane preparations derived from a rat insulinoma. Adoptive transfer of these lines into neonatal mice confirms that overt diabetes is induced by v-IFN-secreting Thl cells, whereas transfer of IL-4-secreting Th2 cells resulted in a nondestructive peni-islet insulitis. Analysis of the antigens recognized by individual T cell clones from the Thl line included reactivity against an insulinoma membrane fraction enriched in proteins of -38 kD. Immune responses to the same antigen preparation have been associated with T cell clones derived from human insulin-dependent diabetes mellitus. The specificity of Th2 cells includes reactivity to a fraction enriched in proteins of 30 kD. The data suggest that in insulin-dependent diabetes mellitus the balance between fB cell destruction, associated with intra-islet infiltration, and nondestructive (potential protective) peri-islet insulitis may depend on both the antigens recognized, and the prevailing cytokine environment. (J. CliA. Invest 1995. 95:2979-2985

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Establishment of Islet-specific T-cell Lines and Clones from Islet Isografts Placed in Spontaneously Diabetic NOD Mice

Cited by 26 publications

References 0 publications

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

Induction of Diabetes in Nonobese Diabetic Mice by Th2 T Cell Clones from a TCR Transgenic Mouse

In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice.

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