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Chantal Mathieu

Publications and source records attributed to Chantal Mathieu.

At least 55 records · Page 3Linked to original sources
PubMed2005

Disruption of the gamma-interferon signaling pathway at the level of signal transducer and activator of transcription-1 prevents immune destruction of beta-cells.

beta-cells under immune attack are destroyed by the aberrant activation of key intracellular signaling cascades. The aim of the present study was to evaluate the contribution of the signal transducer and activator of transcription (STAT)-1 pathway for beta-cell apoptosis by studying the sensitivity of beta-cells from STAT-1 knockout (-/-) mice to immune-mediated cell death in vitro and in vivo. Whole islets from STAT-1-/- mice were completely resistant to interferon (IFN)-gamma (studied in combination with interleukin [IL]-1beta)-mediated cell death (92 +/- 4% viable cells in STAT-1-/- mice vs. 56 +/- 3% viable cells in wild-type controls, P < or = 0.001) and had preserved insulin release after exposure to IL-1beta and IFN-gamma. Moreover, analysis of cell death in cytokine-exposed purified beta-cells confirmed that protection was due to absence of STAT-1 in the beta-cells themselves. Deficiency of STAT-1 in islets completely prevented cytokine-induced upregulation of IL-15, interferon inducible protein 10, and inducible nitric oxide synthase transcription but did not interfere with monocyte chemoattractant protein 1 and macrophage inflammatory protein 3alpha expression. In vivo, STAT-1-/- mice were partially resistant to development of diabetes after multiple low-dose streptozotocin injections as reflected by mean blood glucose at 12 days after first injection (159 +/- 28 vs. 283 +/- 81 mg/dl in wild-type controls, P < or = 0.05) and diabetes incidence at the end of the follow-up period (39 vs. 73% in wild-type controls, P < or = 0.05). In conclusion, the present results indicate that STAT-1 is a crucial transcription factor in the process of IFN-gamma-mediated beta-cell death and the subsequent development of immune-mediated diabetes.

Animals↗
PubMed2004

Early accumulation of interferon-gamma in grafts tolerized by donor-specific blood transfusion: friend or enemy?

BACKGROUND: We previously documented an early (day-2) interferon (IFN)-gamma accumulation in cardiac allografts of rats made tolerant by donor-specific blood transfusion (DSBT) but not in rejecting controls. This contrasted with the IFN-gamma peak seen later (day 5) in rejecting but not in tolerant rats. METHODS: To further examine the role of early intragraft IFN-gamma in DSBT-induced tolerance, we studied whether IFN-gamma up-regulation correlates with the magnitude of the DSBT effect and how IFN-gamma is influenced by interventions abrogating tolerance. RESULTS: The protective effect of DSBT depended upon the timing of administration: day-12 DSBT induced indefinite graft survival; day-6 DSBT gave a moderate, and day-0 DSBT, no graft prolongation. IFN-gamma up-regulation correlated with the DSBT effect: it was maximal after day-12 DSBT, intermediate after day-6 DSBT, and absent after day-0 DSBT. Tolerant splenocytes transferred tolerance into naive rats in a donor-specific manner, indicating that alloantigen-specific regulatory cells operate. Thymectomy prevented regulatory cells development, caused further amplification of intragraft IFN-gamma, and led to rejection, although graft survival was still prolonged. CONCLUSIONS: Day 2 intragraft IFN-gamma correlates with the DSBT protective effect. Thymectomy abrogates DSBT-induced tolerance, prevents regulatory cell development, and paradoxically causes further accumulation of intragraft IFN-gamma. These data indicate that DSBT has a stimulatory and a (thymus-dependent) inhibitory effect on early intragraft IFN-gamma. Intragraft IFN-gamma is beneficial, providing it occurs early and remains moderate. The role of intragraft IFN-gamma in tolerance and rejection depends upon the timing and the degree of production and perhaps the type of IFN-gamma producing cells (regulatory or effector).

Adoptive Transfer↗
PubMed2004

1alpha,25-dihydroxyvitamin D3 or analogue treated dendritic cells modulate human autoreactive T cells via the selective induction of apoptosis.

Epidemiological evidence indicates that the vitamin D status after birth modulates the risk for development of type 1 diabetes mellitus (T1DM). We previously demonstrated that the biologically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), as well as its analogue TX527 permanently alter the morphology and T cell stimulatory function of human dendritic cells (DC). Here, we studied the mechanism of T cell modulation by 1,25(OH)2D3 or analogue treated DC. By using CFSE-labelled autoreactive T cells, we observed that T cell proliferation is hampered upon coculture with modulated DCs, i.e. T cells underwent fewer cycles of cell divisions when compared to T cells stimulated by nontreated DCs. Moreover, 1,25(OH)2D3 or analogue modulated DCs induced significantly higher numbers of early apoptotic (annexin V+/PI-) and/or late apoptotic (annexin V+/PI+) T cells. Apoptosis was selectively induced in T cells activated by modulated DC, since other T cells present in the same cultures, either resting or activated by control untreated DC, were unaffected. Thus, in vitro preconditioning of DC with 1,25(OH)2D3 or analogue yields regulatory DC that may interfere with ongoing autoimmunity in vivo without affecting T cells with other specificities.

Apoptosis↗
PubMed2004

Microarray analysis of 1alpha,25-dihydroxyvitamin D3-treated MC3T3-E1 cells.

The active form of Vitamin D, 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], demonstrates potent antiproliferative actions on normal as well as on malignant cell types by blocking the transition from the G1- to the S-phase of the cell cycle. Key target genes for 1,25-(OH)(2)D(3) in this non-classic effect remain largely unknown. Therefore, this study aims to identify genes that, through changes in expression after 1,25-(OH)(2)D(3) treatment, contribute to the observed antiproliferative effect. cDNA microarrays containing 4600 genes were used to investigate changes in gene expression in MC3T3-E1 mouse osteoblasts at 6 and at 12h after treatment with 1,25-(OH)(2)D(3) (10(-8)M), preceding (6h) or coinciding with (12h) the G1/S block in these cells. Approximately one fifth of the genes that were significantly down-regulated after a 12h incubation period with 1,25-(OH)(2)D(3) were genes involved in the DNA replication process, a basic process for cell growth that starts at the end of G1-phase and continues in S-phase. Down-regulation of these genes by 1,25-(OH)(2)D(3) was confirmed by quantitative RT-PCR in MC3T3-E1. In conclusion, cDNA microarrays revealed that treatment of MC3T3-E1 cells with 1,25-(OH)(2)D(3) resulted in the down-regulation of DNA replication genes in parallel with the observed G1/S-arrest.

3T3 Cells↗
PubMed2004

Vitamin D and 1,25-dihydroxyvitamin D3 as modulators in the immune system.

Treatment from weaning until old age with 1,25-dihydroxyvitamin D (1,25(OH)(2)D(3)) prevents diabetes in NOD mice. It is mainly through its actions on dendritic cells (DCs), that 1,25(OH)(2)D(3) changes the function of potentially autoreactive T lymphocytes. In contrast, early life treatment (from 3 to 70 days of age) of NOD mice with vitamin D or 1,25(OH)(2)D(3) did not influence final diabetes incidence at 200 days of age. Also in spontaneous diabetic BB rats, diabetes could not be prevented by early life treatment (from 3 to 50 days of age) with vitamin D (1000 IU per day) or 1,25(OH)(2)D(3) (0.2 microg/kg per day or 1 microg/kg per 2 days). However, when NOD mice were made vitamin D deficient in early life (until 100 days of age), diabetes onset occurred earlier and final incidence was increased. These data further support a role for vitamin D and its metabolites in the pathogenesis of type 1 diabetes in NOD mice.

Animals↗
PubMed2004

Regulation of 25-hydroxyvitamin d-1alpha-hydroxylase by IFNgamma in human monocytic THP1 cells.

1,25-DihydroxyVitamin D(3) (1,25(OH)(2)D(3)), a molecule with well-known actions in bone and mineral homeostasis, also plays a role in the immune system. Indeed, the receptor for 1,25(OH)(2)D(3) is found in most immune cells and important immunological effects have been described in vitro, reflected by its capacity to prevent autoimmunity and to prolong graft survival. The aim of this study was to elucidate the intracellular pathways used by the immune system to regulate 1,25(OH)(2)D(3) production. Therefore we studied the regulation of 25-hydroxyvitamin-D-1alpha-hydroxylase (1alpha hydroxylase) in THP1 cells by IFNgamma, demonstrating that its induction is highly dependent on the activation/differentiation by PMA and occurred at a late time point (140-fold at 72 h, P < 0.05). Complete inhibition with actinomycin D indicated that the observed induction was, at least in part, a transcriptional event. Dose-dependent inhibition with cycloheximide demonstrated that the induction was dependent on "de novo" protein synthesis, a finding that correlates with the late time point of up-regulation. The data presented indicate a role for 1,25(OH)(2)D(3), activated by 1alpha hydroxylase, as a late down-tapering signal in the immune cascade.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2004

NOD bone marrow-derived dendritic cells are modulated by analogs of 1,25-dihydroxyvitamin D3.

The immune effects of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) are mainly mediated through dendritic cells (DCs). In vitro, 1,25(OH)(2)D(3) treatment renders murine bone marrow (BM)-derived DCs more tolerogenic, indirectly altering behavior and fate of T lymphocytes. In vivo, treatment with 1,25(OH)(2)D(3) or its analogs prevents diabetes in NOD mice. The aim of this study was to investigate the effects of the 1,25(OH)(2)D(3)-analog TX527 on the expression of antigen-presenting and costimulatory/migratory molecules on BM-derived DCs from NOD mice. After culture with 20 ng/ml GM-CSF + 20 ng/ml IL-4 (8 days) followed by 1000 ng/ml LPS + 100 U/ml IFN-gamma (2 days), with or without 10(-8)M TX527, cells were counted and analyzed by FACS for MHC II, CD86, CD40 and CD54 expression within the CD11c(+) DC population. Upon TX527 treatment, cell recovery was significantly reduced whereas the CD11c(+) DC fraction remained constant. On CD11c(+) DCs, MHC II, CD86 and CD54 were significantly down-regulated and CD40 was twofold upregulated. Globally, BM-derived DCs from NOD mice become more tolerogenic upon TX527 treatment, confirming the effects of 1,25(OH)(2)D(3) on murine DCs and possibly explaining the protective effects of 1,25(OH)(2)D(3) and its analogs from diabetes in NOD mice.

Alkynes↗
PubMed2004

Combined 'en bloc' liver and pancreas transplantation in patients with liver disease and type 1 diabetes mellitus.

Liver disease alters the glucose metabolism and may cause diabetes, but this condition is potentially reversible with liver transplantation (LTx). Type 1 diabetes mellitus may be coincidentally present in a LTx candidate and immunosuppressive drugs will aggravate diabetes and make its management more difficult for posttransplant. In addition, diabetes negatively influences outcome after LTx. Therefore, the question arises as to why not transplanting the pancreas in addition to the liver in selected patients suffering from both liver disease and Type 1 diabetes. We report two cases of en bloc combined liver and pancreatic transplantation, a technique originally described a decade ago in the treatment of upper abdominal malignancies but rarely used for the treatment of combined liver disease and Type 1 diabetes. Both recipients are currently liver disease-free and insulin-free more than 2 and 4 years posttransplant, respectively. Surgical, medical and immunological aspects of combined liver-pancreas transplantation are discussed in the light of the existing relevant literature.

Adult↗
PubMed2004

Monocytic expression behavior of cytokines in diabetic patients upon inflammatory stimulation.

Cytokines are involved in the pathogenesis of type 1 diabetes. The disease is characterized by T cell-mediated beta cell destruction and a biased Th1 cytokine pattern. Type 2 diabetes also presents an inflammatory cytokine imbalance. In this study, mRNA expression of cytokines IL-12, TNF-alpha, IL-1, and IL-6 was studied in monocytes from diabetic patients after in vitro immune stimulation. Whereas IL-12(p40) was highly expressed in type 1 diabetic patients, TNF-alpha, IL-1, and IL-6 transcripts were elevated in type 1 but especially type 2 diabetic patients compared with healthy controls, suggesting an important proinflammatory milieu. We conclude that circulating monocytes from type 1 as well as type 2 diabetic patients have an aberrant cytokine profile when stimulated by an immune stimulus such as IFNgamma. This condition not only is likely to be involved in disease pathogenesis, but may contribute to its later complications.

Adult↗
PubMed2004

1,25-Dihydroxyvitamin D3 alters the profile of bone marrow-derived dendritic cells of NOD mice.

1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] prevents autoimmune diabetes in nonobese diabetic (NOD) mice. A major target for 1,25(OH)(2)D(3) in the immune system is the dendritic cell (DC). Since important DC abnormalities have been described in NOD mice, we investigated the effects of 1,25(OH)(2)D(3) on the yield and phenotype of DCs generated from bone marrow of NOD mice compared to control congenic nonobese diabetes-resistant (NOR) mice. In both mouse strains, exposure of the bone marrow-derived cells to 1,25(OH)(2)D(3) increased the proportion of CD11c(+) DCs after culture. Surface expression of MHC II, CD86, and CD54 on NOR-derived DCs was decreased after 1,25(OH)(2)D(3) treatment, while CD40 remained unchanged. On NOD-derived DCs, 1,25(OH)(2)D(3) only inhibited the expression of MHC II and CD86. 1,25(OH)(2)D(3) inhibited IL-12 and IL-10 secretion after IFNgamma and LPS stimulation. In vitro treatment with 1,25(OH)(2)D(3) alters DC yield from bone marrow cultures and alters the phenotype of the cells in NOD as well as in NOR mice. NOD-derived DCs were more resistant to the 1,25(OH)(2)D(3) effects than were NOR-derived DCs.

Animals↗
PubMed2004

The effects of 1alpha,25-dihydroxyvitamin D3 on the expression of DNA replication genes.

UNLABELLED: To identify key genes in the antiproliferative action of 1,25(OH)2D3, MC3T3-E1 mouse osteoblasts were subjected to cDNA microarray analyses. Eleven E2F-driven DNA replication genes were downregulated by 1,25(OH)2D3. These results were confirmed by quantitative RT-PCR in different cell types, showing the general nature of this action of 1,25(OH)2D3. INTRODUCTION: 1Alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] has a potent antiproliferative action characterized by a blocked transition from the G1- to the S-phase of the cell cycle. This study aims to identify genes whose expression is markedly altered after 1,25(OH)2D3 treatment in parallel with or preceding the observed G1-arrest. MATERIALS AND METHODS: The cDNA microarray technique was used, and the expression of approximately 4600 genes in MC3T3-E1 mouse osteoblasts was studied 6 and 12 h after treatment with 10(-8) M 1,25(OH)2D3. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analyses were performed on MC3T3-E1 cells and on wildtype and vitamin D receptor (VDR) knockout primary murine epidermal keratinocytes (VDRwt MEKs, VDR-/- MEKs) and murine mammary tumor cells (GR) to confirm the microarray data. RESULTS AND CONCLUSIONS: After 12 h of treatment, in parallel with the 1,25(OH)2D3-induced G1 arrest, a particular set of DNA replication genes including a cell division cycle 6 homolog, a DNA polymerase alpha subunit, proliferating cell nuclear antigen, two DNA polymerase delta subunits, and flap-structure specific endonuclease 1, was downregulated at least 2-fold. These genes are known targets of the E2F family of transcription factors, which are probably the central mediators of this action of 1,25(OH)2D3. Indeed, as shown by transfection assays with an E2F reporter construct, 12- and 24-h treatment of MC3T3-E1 cells with 1,25(OH)2D3 reduced E2F activity by 49% and 73%, respectively. Quantitative RT-PCR analyses confirmed the downregulation of these DNA replication genes by 1,25(OH)2D3 in MC3T3-E1, GR, and VDRwt MEKs cells, but not in VDR-/- MEKs cells, showing that this 1,25(OH)2D3-driven antiproliferative action is of a general nature and depends on a functional VDR.

3T3 Cells↗
PubMed2003

Metabolic, endocrine, and immune effects of stress hyperglycemia in a rabbit model of prolonged critical illness.

Stress hyperglycemia is frequent in critically ill patients. The aim of this study was to investigate the effect of blood glucose control with insulin on endocrine, metabolic, and immune function in an animal model of severe injury. Seventy-two hours after alloxan injection and exogenous insulin infusion combined with continuous iv parenteral nutrition, male New Zealand White rabbits received a burn injury and were allocated to a normoglycemic (n = 17) or hyperglycemic (n = 13) group. In the normoglycemic group, blood glucose levels were kept between 3.3 and 6.1 mmol/liter by insulin infusion, whereas in the hyperglycemic group blood glucose levels were maintained at 13.8-16.6 mmol/liter. Blood was drawn for biochemical analysis at regular time points. At 24 and 72 h after burn injury, immune function of monocytes was assessed in vitro. Maintenance of normoglycemia with exogenous insulin after severe trauma to a large extent prevented weight loss, lactic acidosis, and hyponatremia. Furthermore, within 3 d after injury, the intervention improved phagocytosis of monocytes investigated in fresh cells by more than a mean 150% (P = 0.006) and after 24-h incubation with or without lipopolysaccharide by more than a mean 4-fold (P = 0.001) and 2-fold (P = 0.05), respectively. Oxidative killing after 24-h incubation was also improved by 2-fold (P = 0.05), but no effect on chemotaxis was detected. Concomitantly, inflammation and stress-induced growth hormone hypersecretion were suppressed. Prevention of catabolism, acidosis, excessive inflammation, and impaired innate immune function may explain previously documented beneficial effects of intensive insulin therapy on outcome of critical illness.

Alloxan↗
PubMed2003

Regulatory cell-mediated tolerance does not protect against chronic rejection.

BACKGROUND: Regulatory cells prevent graft loss to acute rejection and induce tolerance, possibly by promoting Th2 deviation. Th2 cytokines stimulate B cells, which cause alloantibody-mediated chronic rejection. We searched to determine whether regulatory cell-mediated tolerance protects or not against chronic rejection. METHODS: Heart transplantation (Htx) was performed using RA (RT1P) and PVG (RT1c) rats as donor and recipients. Donor-specific blood transfusion (DSBT) was given on preTx day 12. Secondary grafts were implanted at day 100. Splenocytes were transferred from tolerant rats (and controls) into lightly irradiated (450 rad) naive PVG, which received RA Htx. Primary Htx were investigated for the development of vascular occlusion (VO), the production of Th1/Th2 intragraft cytokines, and for the nature of graft infiltrate as well as for endothelial deposition of immunoglobulin (Ig)G isotypes and complement (C3) binding. Results were compared with rejecting controls (no DSBT) and syngeneic Htx. RESULTS: RA Htx were rejected within 10 days (8, 9, 10x4). PreTx DSBT prolonged primary Htx survival indefinitely (>140 days) with acceptance of secondary donor-specific (but not third-party) grafts (P<0.001). Naive irradiated PVG rats given splenocytes from tolerant rats but not from controls accepted RA Htx, showing the existence of regulatory cells in allograft acceptors. Despite being tolerant, DSBT-treated rats displayed typical features of chronic rejection at day 90 (VO=77%; P<0.001 vs. VO=4% in syngeneic rats). An overt Th2 deviation, particularly intragraft production of interleukin (IL)-4, was observed at day 30. Simultaneously to this Th2 deviation, B cells emerged in the grafts and endothelial deposition of IgG1 (Th2 dependent) and C3 binding were observed. CONCLUSIONS: Regulatory cells that prevent graft loss to acute rejection in primary and secondary grafts do not protect against the development of chronic rejection.

Adoptive Transfer↗
PubMed2003

Paradoxical early upregulation of intragraft Th1 cytokines is associated with graft acceptance following donor-specific blood transfusion.

Donor-specific blood transfusion (DSBT) promotes graft acceptance in certain experimental and clinical situations. However, the exact nature of the operating mechanisms, and in particular the role of Th1/Th2 cytokines, remains controversial. We recently described a fully mismatched rat combination [RA rat (RT1p) to PVG rat (RT1c)] in which a single pre-transplant (Tx) DSBT induces donor-specific tolerance following heart transplantation (Htx). In order to delineate better the role of Th1 and Th2 cytokines in the development of tolerance versus rejection, we studied the intragraft mRNA for Th1 and Th2 cytokines at different time points post-Tx in rejecting and DSBT-tolerized heart grafts. We performed reverse transcriptase-polymerase chain reaction (RT-PCR) to examine intragraft Th1/Th2 cytokines profile. In contrast to findings from previous data, we detected an early (post-Tx day 2) Th1 cytokine upregulation. Th1 downregulation/Th2 immune deviation was observed only at a later period (post-Tx day 30). Consistent with this Th1 early upregulation, a dense mononuclear cellular infiltrate was seen in tolerized grafts, which was equivalent to that seen in rejecting grafts. Despite in vivo unresponsiveness, peripheral lymphocyte derived from tolerant animals proliferated against donor-matched antigens to the same degree as against those of a third party until post-Tx day 30. Altogether, these observations (dense graft cellular infiltrate, early post-Tx Th1 cytokine production, early preserved cellular proliferative responses), suggest that the development of tolerance is preceded by an active Th1 cytokine-mediated immune response. The mechanisms by which an early Th1 response promotes tolerance need to be further studied.

Animals↗
PubMed2003

Analogs of 1alpha,25-dihydroxyvitamin D3 as pluripotent immunomodulators.

The active form of vitamin D(3), 1,25(OH)(2)D(3), is known, besides its classical effects on calcium and bone, for its pronounced immunomodulatory effects that are exerted both on the antigen-presenting cell level as well as directly on the T lymphocyte level. In animal models, these immune effects of 1,25(OH)(2)D(3) are reflected by a strong potency to prevent onset and even recurrence of autoimmune diseases. A major limitation in using 1,25(OH)(2)D(3) in clinical immune therapy are the adverse side effects on calcium and on bone. TX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)) is a structural 1,25(OH)(2)D(3) analog showing reduced calcemic activity associated with enhanced in vitro and in vivo immunomodulating capacity compared to the mother-molecule. Indeed, in vitro TX527 is more potent that 1,25(OH)(2)D(3) in redirecting differentiation and maturation of dendritic cells and in inhibiting phytohemagglutinin-stimulated T lymphocyte proliferation. In vivo, this enhanced potency of TX527 is confirmed by a stronger potential to prevent type 1 diabetes in nonobese diabetic (NOD) mice and to prolong the survival of syngeneic islets grafts, both alone and in combination with cyclosporine A, in overtly diabetic NOD mice. Moreover, these in vivo effects of TX527 are obtained without the adverse side effects observed for 1,25(OH)(2)D(3) itself. We believe therefore that TX527 is a potentially interesting candidate to be considered for clinical intervention trails in autoimmune diseases.

Adjuvants, Immunologic↗
PubMed2003

Prospects for vitamin D receptor modulators as candidate drugs for cancer and (auto)immune diseases.

The development of less calcemic vitamin D analogs creates possible therapeutic applications for immune modulation (e.g., autoimmune diseases and graft rejection), inhibition of cell proliferation and induction of cell differentiation (e.g., cancer). Recently more insight was obtained in the mechanism of action of the analogs at the biological and molecular level. Critical remarks are summarized on why the step towards the clinic has not yet been taken and how better selective vitamin D receptor modulators could be designed.

Animals↗
PubMed2003

Defect in activation-induced cell death in non-obese diabetic (NOD) T lymphocytes.

Activation-induced cell death (AICD) represents a major means of peripheral tolerance induction, eliminating effector cells. NOD mice, a widely used model for autoimmune diabetes, are characterized by high levels of circulating T lymphocytes and by resistance to several apoptosis-inducing signals. The aim of this study was to analyse AICD in peripheral NOD T lymphocytes. First, we demonstrated in an in vitro AICD model that NOD T lymphocytes are more resistant to AICD (64+/-2%) compared to non-autoimmune C57BL/6 T lymphocytes (73+/-2%), but also diabetes-resistant NOR T lymphocytes (76+/-3%, P<0.05). Moreover, both CD4(+)and CD8(+)subsets were affected. Analysis of the cellular and molecular pathways revealed lower caspase 8 levels, a central caspase proximally involved in the AICD-pathway (fluorescence of 258+/-47 in NOD vs. 441+/-16 in NOR and 414+/-61 in C57BL/6 T lymphocytes, P<0.05). Gene expression analysis using real-time RT-PCR additionally revealed low expression of Fas and FasL, the death receptor system activating caspase 8 and contributing to AICD. Additionally, low IL-2 levels, together with high TGFbeta and Bclx-L levels, confirm the presence of a NOD-specific AICD-resistance profile. In conclusion, we present cellular and molecular evidence for disturbed AICD mechanisms in NOD T lymphocytes. This resistance in AICD may contribute to defective tolerance induction to autoantigens in NOD mice.

Animals↗