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

Hartemann, A.; Richard, M F

doi:10.1046/j.1365-2249.1999.00883.x

Cited by 10 publications

(16 citation statements)

References 41 publications

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“…Although their most known immune feature is the Th 1 -driven destruction of pancreatic islets (4), literature data about their Th 2 activity are conflicting (25,26). The initial aim of our study was to check the safety of antigenic vaccination in this particular strain with respect to anaphylaxis.…”

Section: Discussionmentioning

confidence: 99%

Acute Shock Induced by Antigen Vaccination in NOD Mice

et al. 2003

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Type 1 diabetes in NOD mice can be prevented through autoantigen vaccination by shifting lymphocyte differentiation toward a T-helper 2 (Th 2 ) response. However, in other models of autoimmunity, this approach may be accompanied by unexpected triggering of Th 2 -dependent anaphylactic shock. To test the safety of vaccination therapy in the NOD mouse model, we evaluated the effects of immunization with a wide battery of antigens in NOD, BALB/c, and C57BL/6 mice. Surprisingly, a nondiabetogenic antigen, hen egg white lysozyme, induced severe shock exclusively in NOD mice (shock in 11 of 11 mice, lethal in 3 mice). Shock severity was further increased by a more pronounced Th 2 setting generated by 1␣,25(OH) 2 D 3 administration (17 of 17 mice, lethal in 14 mice, P < 0.0001). Pretreatment with dexamethasone resulted in full rescue, indicating an immune-mediated mechanism. Serum IgE levels and Th 1 /Th 2 cytokine profile analysis showed that the shock phenomenon was paralleled by a Th 2 response. mRNA expression of platelet-activating factor receptor (PAF-R) was significantly higher in NOD mice (P < 0.01) and was further increased by 1␣,25(OH) 2 D 3 . Pretreatment with WEB2086 (PAF-R antagonist) again protected all mice from lethal shock, indicating PAF as an anaphylaxis effector. In conclusion, in NOD mice, vaccination leading to a Th 2 immune shift can result in a lethal anaphylactic reaction. Diabetes 52:335-341, 2003

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Section: Discussionmentioning

confidence: 99%

Acute Shock Induced by Antigen Vaccination in NOD Mice

et al. 2003

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“…Indeed, differentiation toward the Th2 lineage requires high levels of recruited p56 lck kinase, and the introduction of a dominant-negative p56 lck transgene under the control of the distal promoter to target its expression toward mature T lymphocytes inhibits Th2 cell development (62,63). It has been proposed that the progression toward diabetes in the NOD mouse model might be associated with a relative reduction of the Th2/Th1 cell ratio (5,56,64,65). Thus, the lowered p56 lck expression could be the consequence of the Th1 bias in periphery, or more importantly a direct cause of the impaired Th2 lymphocyte differentiation.…”

Section: Figurementioning

confidence: 99%

Specific Deficiency of p56lck Expression in T Lymphocytes from Type 1 Diabetic Patients

Nervi

Atlan-Gepner

Kahn-Perlès

et al. 2000

The Journal of Immunology

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Peripheral T lymphocyte activation in response to TCR/CD3 stimulation is reduced in type 1 diabetic patients. To explore the basis of this deficiency, a comprehensive analysis of the signal transduction pathway downstream of the TCR/CD3 complex was performed for a cohort of patients (n = 38). The main result of the study shows that T cell hyporesponsiveness is positively correlated with a reduced amount of p56lck in resting T lymphocytes. Upon CD3-mediated activation, this defect leads to a hypophosphorylation of the CD3ζ-chain and few other polypeptides without affecting the recruitment of ZAP70. Other downstream effectors of the TCR/CD3 transduction machinery, such as phosphatidylinositol 3-kinase p85α, p59fyn, linker for activation of T cells (LAT), and phospholipase C-γ1, are not affected. In some patients, the severity of this phenotypic deficit could be linked to low levels of p56lck mRNA and resulted in the failure to efficiently induce the expression of the CD69 early activation marker. We propose that a primary deficiency in human type 1 diabetes is a defect in TCR/CD3-mediated T cell activation due to the abnormal expression of the p56lck tyrosine kinase.

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“…An Elispot assay was used to evaluate the stimulation of diabetic NOD splenocytes and their IL-2, IL-4 and IFNγ secretion profiles in response to βTC-tet cells [6]. We coated 96-well nitrocellulose plates (Millipore, St Quentin en Yvelines, France, MAHA S45) with relevant antibodies (anti-IL-2, Pharmingen, BD Bioscience, Le Pont de Claix, France, 18161D; anti-IL-4, Pharmingen 18191D; anti-IFN-γ, Pharmingen 18181D) at 10 µg/ml in PBS buffer at 37°C overnight.…”

Section: Methodsmentioning

confidence: 99%

“…Clusters of 2×10 6 βTC-tet cells, formed during a 48-h incubation on a rotary motion system, were transplanted under the left kidney capsule of mice [9]. In some experiments, animals were made diabetic by a single i.v.-injection, 3 days before transplantation, of STZ (200 mg/kg; Sigma-Aldrich) reconstituted in a citrate/citric acid buffer (0.01 M, pH 4.5).…”

Section: Stimulation Of Beta Cell Autoreactive T-cell Hybridomasmentioning

confidence: 99%

Destruction of conditional insulinoma cell lines in NOD mice: A role for autoimmunity

et al. 2003

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Aims/Hypothesis. βTC-tet (H2 k ) is a conditional insulinoma cell line derived from transgenic mice expressing a tetracycline-regulated oncogene. Transgenic expression of several proteins implicated in the apoptotic pathways increase the resistance of βTC-tet cells in vitro. We tested in vivo the sensitivity of the cells to rejection and the protective effect of genetic alterations in NOD mice. Methods. βTC-tet cells and genetically engineered lines expressing Bcl-2 (CDM3D), a dominant negative mutant of MyD88 or SOCS-1 were transplanted in diabetic female NOD mice or in male NOD mice with diabetes induced by high-dose streptozotocin. Survival of functional cell grafts in NOD-scid mice was also analyzed after transfer of splenocytes from diabetic NOD mice. Autoreactive T-cell hybridomas and splenocytes from diabetic NOD mice were stimulated by βTC-tet cells. Results. βTC-tet cells and genetically engineered cell lines were all similarly rejected in diabetic NOD mice and in NOD-scid mice after splenocyte transfer. In 3-to 6-week-old male NOD mice treated with highdose streptozotocin, the cells temporarily survived, in contrast with C57BL/6 mice treated with high-dose streptozotocin (indefinite survival) and untreated 3-to 6-week-old male NOD mice (rejection). The protective effect of high-dose streptozotocin was lost in older male NOD mice. βTC-tet cells did not stimulate autoreactive T-cell hybridomas, but induced IL-2 secretion by splenocytes from diabetic NOD mice. Conclusion/Interpretation. The autoimmune process seems to play an important role in the destruction of βTC-tet cells in NOD mice. Genetic manipulations intended at increasing the resistance of beta cells were inefficient. Similar approaches should be tested in vivo as well as in vitro. High dose streptozotocin influences immune rejection and should be used with caution. [Diabetologia (2003) 46:504-510]

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

Cited by 10 publications

References 41 publications

Acute Shock Induced by Antigen Vaccination in NOD Mice

Acute Shock Induced by Antigen Vaccination in NOD Mice

Specific Deficiency of p56lck Expression in T Lymphocytes from Type 1 Diabetic Patients

Destruction of conditional insulinoma cell lines in NOD mice: A role for autoimmunity

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