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

Healey, Dan; Ozegbe, Patricia; Arden, Susan D.; Chandler, P; Hutton, John C.; Cooke, Anne

doi:10.1172/jci118006

Cited by 139 publications

(100 citation statements)

References 33 publications

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“…Diabetes in NOD mice occurs through a Th1-mediated autoimmune process [4][5][6][7][8]. For this reason, this strain is generally considered "Th1-prone".…”

Section: Discussionmentioning

confidence: 99%

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Exacerbated Th2‐mediated airway inflammation and hyperresponsiveness in autoimmune diabetes‐prone NOD mice: a critical role for CD1d‐dependent NKT cells

et al. 2004

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The NOD mouse has proved to be a relevant model of insulin-dependent diabetes mellitus, closely resembling the human disease. However, it is unknown whether this strain presents a general bias toward Th1-mediated autoimmunity or remains capable of mounting complete Th2-mediated responses. Here, we show that NOD mice have the capacity to develop a typical Th2-mediated disease, namely experimental allergic asthma. In contrast to what might have been expected, they even developed a stronger Th2-mediated pulmonary inflammatory response than BALB/c mice, a strain that shows a typical Th2 bias in this model. Thus, after allergen sensitization and intra-nasal challenge, the typical features of experimental asthma were exacerbated in NOD mice, including enhanced bronchopulmonary responsiveness, mucus production and eosinophilic inflammation in the lungs as well as specific IgE titers in serum. These hallmarks of allergic asthma were associated with increased IL-4, IL-5, IL-13 and eotaxin production in the lungs, as compared with BALB/c mice. Notwithstanding their quantitative and functional defect in NOD mice, CD1d-dependent NKT cells contribute to aggravate the disease, since in OVA-immunized CD1d -/-NOD mice, which are deficient in this particular T cell subset, airway eosinophilia was clearly diminished relative to NOD littermates. This is the first evidence that autoimmune diabetesprone NOD mice can also give rise to enhanced Th2-mediated responses and might thus provide a useful model for the study of common genetic and cellular components, including NKT cells that contribute to both asthma and type 1 diabetes.

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“…Diabetes in NOD mice occurs through a Th1-mediated autoimmune process [4][5][6][7][8]. For this reason, this strain is generally considered "Th1-prone".…”

Section: Discussionmentioning

confidence: 99%

“…Among these, the contribution of Th1 cells seems to be determinant [4][5][6][7][8]. Indeed, destructive insulitis is paralleled by predominant secretion of IFN-+ , IL-2, IL-12, TNF- § and IL-18, while the Th2 type cytokine IL-4 is associated with non-destructive insulitis [4, [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Exacerbated Th2‐mediated airway inflammation and hyperresponsiveness in autoimmune diabetes‐prone NOD mice: a critical role for CD1d‐dependent NKT cells

et al. 2004

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“…As shown in other experimental systems, regulatory T cells generated by repeated feeding of an antigen can secrete antigennonspecific suppressive cytokines when recruited and thus reexposed to the fed antigen in the target organ, thereby antagonizing the proinflammatory activity of bystander T cells with a distinct antigen specificity (36). It will thus be worthwhile to compare the protective efficacy of conjugates of CTB linked to other beta cell constitutants (39,40) or peptides (41).…”

Section: Discussionmentioning

confidence: 99%

A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes

Bergerot

Ploix

Petersen

et al. 1997

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

220

182

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Mucosally induced immunological tolerance is an attractive strategy for preventing or treating illnesses resulting from untoward inf lammatory immune reactions against self-or non-self-antigens. Oral administration of relevant autoantigens and allergens has been reported to delay or suppress onset of clinical disease in a number of experimental autoimmune and allergic disorders. However, the approach often requires repeated feeding of large amounts of tolerogens over long periods and is only partly effective in animals already systemically sensitized to the ingested antigen such as in animals already harboring autoreactive T cells, and thus presumably also in humans with an autoimmune disease. We have recently shown that oral administration of microgram amounts of antigen coupled to cholera toxin B subunit (CTB), can effectively suppress systemic T cell reactivity in naive as well as in immune animals. We now report that feeding small amounts (2-20 g) of human insulin conjugated to CTB can effectively suppress beta cell destruction and clinical diabetes in adult nonobese diabetic (NOD) mice. The protective effect could be transferred by T cells from CTBinsulin-treated animals and was associated with reduced lesions of insulitis. Furthermore, adoptive co-transfer experiments involving injection of Thy-1,2 recipients with diabetogenic T cells from syngeneic mice and T cells from congenic Thy-1,1 mice fed with CTB-insulin demonstrated a selective recruitment of Thy-1,1 donor cells in the peripancreatic lymph nodes concomitant with reduced islet cell infiltration. These results suggest that protection against autoimmune diabetes can be achieved by feeding minute amounts of a pancreas islet cell autoantigen linked to CTB and appears to involve the selective migration and retention of protective T cells into lymphoid tissues draining the site of organ injury.

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“…The presence of IL-4-secreting cells in the pancreas is controversial [16,33]. One Th2 T cell clone (stimulated by rat insulinoma membrane extracts) derived from spleens of diabetic NOD mice promotes a nondestructive peri-insulitis when injected into neonatal mice [12]. Whether CD4 suppressor cells detected in non-diabetic NOD mice carry a Th2 or a Th1 cytokine secretion profile has remained elusive.…”

Section: Discussionmentioning

confidence: 99%

Absence of significant Th2 response in diabetes-prone non-obese diabetic (NOD) mice

Hartemann

Richard

1999

Clinical and Experimental Immunology

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SUMMARYAccumulating evidence suggests that Th1 T cells play a pivotal role in the development of autoimmune diabetes. Conversely, promoting a Th2 response inhibits disease progression. However, it has not been determined whether Th2 cells are regulatory T cells that fail at the time of diabetes development in naive non-diabetic NOD mice. Therefore, in order to evaluate cytokine secretion by spleen and islet infiltrating T cells in NOD mice at different stages of the autoimmune process, we developed an ELISPOT assay that detects IL-2, IL-4, and interferon-gamma (IFN-g) secretion in vitro at the singlecell level. We showed that, whatever the age considered, IFN-g is predominantly secreted, and that no IL-4-secreting cells are detected in the islets of male and female NOD mice. Spleen cells from 8-weekold female NOD mice, which include regulatory suppressor T cells, do not secrete IL-4, either upon presentation of islet cell antigens in vitro, or after transfer in vivo, but do secrete IFN-g. IFN-g secretion by T cells from diabetic mice results from CD4 but not CD8 T cells in transfer experiments into NOD/ severe combined immunodeficient (SCID) recipients. These results suggest that (i) detection of regulatory CD4 T cells in NOD mice is not paralleled by a Th2 response; (ii) b cell destruction does not depend on a switch from a Th2 to a Th1-type response; and (iii) CD8 T cells do not participate in induction of diabetes by secreting IFN-g.

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

Cited by 139 publications

References 33 publications

Exacerbated Th2‐mediated airway inflammation and hyperresponsiveness in autoimmune diabetes‐prone NOD mice: a critical role for CD1d‐dependent NKT cells

Exacerbated Th2‐mediated airway inflammation and hyperresponsiveness in autoimmune diabetes‐prone NOD mice: a critical role for CD1d‐dependent NKT cells

A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes

Absence of significant Th2 response in diabetes-prone non-obese diabetic (NOD) mice

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