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Type 1 diabetes (T1D) is an autoimmune disease characterized by a selective destruction of insulin‑secreting β‑cells. Both T cells and B cells serve a crucial role in pathogenesis and development of T1D. CD20 is a specific membrane antigen of B lymphocytes, while interleukin (IL)‑10 is an important cytokine secreted by T helper 2 cells and has a short half‑life in vivo. The combined effect of anti‑CD20 and IL‑10 on immune function of mice with T1D remains unknown. In the present study, 30 non‑obese diabetic (NOD) mice were treated with anti‑CD20 and adenoviral vector‑mediated interleukin‑10 (Ad‑mIL‑10) therapy. Alterations in CD4+, CD8+, CD4+CD25+Foxp3+ T cells, T‑box expressed in T‑cells (T‑bet), GATA‑binding protein‑3 (GATA‑3) interferon‑γ (IFN‑γ) and IL‑4 were detected by flow cytometry, reverse transcription‑quantitative polymerase chain reaction in NOD mice spleen tissue. The present results suggested that anti‑CD20 and IL‑10 treatment in NOD mice can modulate the immune functions by upregulating GATA‑3 and IL‑4 expression as well as downregulating T‑bet and IFN‑γ expression, which are involved in the pathogenesis of T1D. The current findings may provide a potential method for T1D treatment and a novel preventive therapy for T1D. Combination of anti‑CD20 and Ad‑mIL‑10 treatment had not only immune regulatory effects but also protective effects on islet β‑cells in NOD mice with T1DM at the early stages, by regulating T‑bet/GATA‑3 expression and Th1/Th2 cell differentiation, which has the potential for diabetes prevention and therapy. [ABSTRACT FROM AUTHOR]

Background: Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of the insulinproducing β-cells in the pancreas. Therefore, approaches that effectively halt the pathogenic T cell response are predicted to have preventive or therapeutic benefit for type 1 diabetes patients. We previously demonstrated that long-term blocking of IL-7 signaling, which is critical for the survival and function of T cells, prevented and reversed type 1 diabetes in non-obese diabetic mice. However, such persistent inhibition of T cell responses raises concerns about causing immunodeficiency. Here, we asked whether a reduced duration of the treatment with anti-IL-7Rα antibodies retained efficacy in preventing diabetes. Moreover, we sought to identify immunoregulatory mechanisms induced by anti-IL-7Rα administration. Results: Anti-IL-7Rα antibodies were administered to prediabetic NOD mice for 3 weeks and blood samples were taken at the end of treatment and 2 weeks later to analyze changes in T cell phenotypes in response to IL-7Rα blockade. We found that the co-inhibitory receptors LAG-3, Tim-3 and PD-1 were increased on peripheral blood CD4+ and CD8+ T cells from anti-IL-7Rα-treated mice. Expression of these receptors contributed to reduced T cell cytokine production in response to TCR stimulation. In addition, the frequency of Tregs within the circulating CD4+ T cells was increased at the end of anti-IL-7Rα antibody treatment and these Tregs showed a more activated phenotype. In vitro restimulation assays revealed that effector T cells from anti-IL-7Rα-treated mice were more sensitive to co-inhibitory receptor induction after TCR stimulation. Importantly, these changes were accompanied by delayed type 1 diabetes disease kinetics. Conclusions: Together, our data show that short-term blockade of IL-7Rα induces detectable changes in co-inhibitory receptor expression and Treg frequencies in peripheral blood of NOD mice. These changes appear to have long-lasting effects by delaying or preventing type 1 diabetes incidence. Hence, our study provides further support for using anti-IL-7Rα antibodies to modulate autoreactive T cell responses. [ABSTRACT FROM AUTHOR]

Although type 1 diabetes (T1D) is a T-cell-mediated disease in the effector stage, the mechanism behind the initial beta cell assault is less understood. Metabolomic differences, including elevated levels of glutamic acid, have been observed in patients with T1D before disease onset, as well as in pre-diabetic non-obese diabetic ( NOD) mice. Increased levels of glutamic acid damage both neurons and beta cells, implying that this could contribute to the initial events of T1D pathogenesis. We investigated the underlying genetic factors and consequences of the increased levels of glutamic acid in NOD mice. Serum glutamic acid levels from a ( NOD×B6)F2 cohort ( n = 182) were measured. By genome-wide and Idd region targeted microsatellite mapping, genetic association was detected for six regions including Idd2, Idd4 and Idd22. In silico analysis of potential enzymes and transporters located in and around the mapped regions that are involved in glutamic acid metabolism consisted of alanine aminotransferase, glutamic-oxaloacetic transaminase, aldehyde dehydrogenase 18 family, alutamyl-prolyl- tRNA synthetase, glutamic acid transporters GLAST and EAAC1. Increased EAAC1 protein expression was observed in lysates from livers of NOD mice compared with B6 mice. Functional consequence of the elevated glutamic acid level in NOD mice was tested by culturing NOD. Rag2−/− Langerhans' islets with glutamic acid. Induction of apoptosis of the islets was detected upon glutamic acid challenge using TUNEL assay. Our results support the notion that a dysregulated metabolome could contribute to the initiation of T1D. We suggest that targeting of the increased glutamic acid in pre-diabetic patients could be used as a potential therapy. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) incidence has been steadily rising across the globe. Exposure to persistent organic pollutants (POP) has been implied as one potential cause of increased T1D occurrence. Since data regarding the role of POP polychlorinated biphenyl-153 (PCB-153) in autoimmune T1D development in experimental animal models are lacking, this study sought to evaluate the effect of PCB-153 exposure on T1D development in a non-obese diabetic (NOD) mouse model. As T1D is an autoimmune, T-cell-dependent disease, PCB-153 effects on T-cells were studied as well. Pre-diabetic 8–9-week-old NOD mice were exposed to intraperitoneal injections of PCB-153 in a 10-day short- (subacute exposure; 0.5 or 50 mg/kg) or 16-week long-term (subchronic exposure; 0.125 or 12.5 mg/kg) fashion. A significant decrease in incidence of T1D was observed in both low- and high-dose subchronically exposed mice. Analysis of various immune parameters, including T-cell types and subtypes, T-cell proliferative responses – as well as their cytokine secretions, revealed that both short- and long-term exposure to PCB-153 caused significant immunosuppression. PCB-153-induced immunosuppression was reflected in reductions in levels of T helper (TH)-type cells and their functions after subacute treatment with low- and high-dose PCB-153. In agreement, decreased levels of THcells, reduced proliferation and IL-2 secretion seemed to be a mechanism of PCB-153 action in the development of T1D in subchronically exposed mice. In conclusion, this study for the first time revealed the effects of PCB-153 on development of T1D, bridging the existing experimental knowledge gap regarding the association of non-dioxin-like PCBs and T1D. [ABSTRACT FROM PUBLISHER]

The aim of the present study was to provide an animal experimental basis for the protective effect of the adenoviral vector-mediated interleukin-10 (Ad-mIL-10) gene on islet β-cells during the early stages of type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. A total of 24 female NOD mice at the onset of diabetes were allocated at random into three groups (n=8 per group): Group 1, intraperitoneally injected with 0.1 ml Ad-mIL-10; group 2, intraperitoneally injected with 0.1 ml adenovirus vector; and group 3, was a diabetic control. In addition to groups 1, 2 and 3, 8 age- and gender-matched NOD mice were intraperitoneally injected with 0.1 ml PBS and assigned to group 4 as a normal control. All mice were examined weekly for body weight, urine glucose and blood glucose values prior to onset of diabetes, and at 1, 2 and 3 weeks after that, and all mice were sacrificed 3 weeks after injection. Serum levels of interleukin (IL)-10, interferon (IFN)-γ, IL-4, insulin and C-peptide were evaluated, and in addition the degree of insulitis and the local expression of IL-10 gene in the pancreas were detected. The apoptosis rate of pancreatic β-cells was determined using a TUNEL assay. Compared with groups 2 and 3, IL-10 levels in the serum and pancreas were elevated in group 1. Serum IFN-γ levels were decreased while serum IL-4 levels and IFN-γ/IL-4 ratio were significantly increased in group 1 (P<0.01). C-peptide and insulin levels were higher in group 1 compared with groups 2 and 3, (P<0.01). Furthermore, compared with groups 2 and 3, the degree of insulitis, islet β-cell apoptosis rate and blood glucose values did not change significantly (P>0.05). The administration of the Ad-mIL-10 gene induced limited immune regulatory and protective effects on islet β-cell function in NOD mice with early T1D, while no significant reduction in insulitis, islet β-cell apoptosis rate and blood glucose was observed. [ABSTRACT FROM AUTHOR]

The role of antigen presenting cells (APCs) in the pathogenesis of autoimmune and other inflammatory diseases is now better understood due to advances in multicolor flow cytometry, gene expression analysis of APC populations, and functional correlation of mouse to human APC populations. A simple but informative nomenclature of conventional and plasmacytoid dendritic cell subsets (cDC1, cDC2, pDC) and monocyte-derived populations incorporates these advances, but accurate subset identification is critical. Ambiguous gating schemes and alterations of cell surface markers in inflammatory condition can make comparing results between studies difficult. Both acute inflammation, such as TLR–ligand stimulation, and chronic inflammation as found in mouse models of autoimmunity can alter DC subset gating. Here, we address these issues using in vivo CpG stimulation as an example of acute inflammation and the non-obese diabetic (NOD) mouse as a model of chronic inflammation. We provide a flow cytometric antibody panel and gating scheme that differentiate 2 monocytic and 3 DC subsets in the spleen both at steady state and after CpG stimulation. Using this method, we observed differences in the composition of NOD DCs that have been previously reported, and newly identified increases in the number of NOD monocyte-derived DCs. Finally, we established a protocol for DC phosphoflow to measure the phosphorylation state of intracellular proteins, and use it to confirm functional differences in the identified subsets. Therefore, we present optimized methods for distinguishing monocytic and DC populations with and without inflammation and/or autoimmunity associated with NOD mice. [ABSTRACT FROM AUTHOR]

Toll-like receptor 4 (TLR4) activation has been proposed to be important for islet cell inflammation and eventually β cell loss in the course of type 1 diabetes (T1D) development. However, according to the “hygiene hypothesis”, bacterial endotoxin lipopolysaccharide (LPS), an agonist on TLR4, inhibits T1D progression. Here we investigated possible mechanisms for the protective effect of LPS on T1D development in non-obese diabetic (NOD) mice. We found that LPS administration to NOD mice during the prediabetic state neither prevented nor reversed insulitis, but delayed the onset and decreased the incidence of diabetes, and that a multiple-injection protocol is more effective than a single LPS intervention. Further, LPS administration suppressed spleen T lymphocyte proliferation, increased the generation of CD4 + CD25 + Foxp3 + regulatory T cells (Tregs), reduced the synthesis of strong Th1 proinflammatory cytokines, and downregulated TLR4 and its downstream MyD88-dependent signaling pathway. Most importantly, multiple injections of LPS induced a potential tolerogenic dendritic cell (DC) subset with low TLR4 expression without influencing the DC phenotype. Explanting DCs from repeated LPS-treated NOD mice into NOD/SCID diabetic mice conferred sustained protective effects against the progression of diabetes in the recipients. Overall, these results suggest that multiple mechanisms are involved in the protective effects of LPS against the development of diabetes in NOD diabetic mice. These include Treg induction, down-regulation of TLR4 and its downstream MyD88-dependent signaling pathway, and the emergence of a potential tolerogenic DC subset. [ABSTRACT FROM AUTHOR]

Sodium meta-arsenite (SA) is an orally available arsenic compound. We investigated the effects of SA on the development of autoimmune type 1 diabetes. Female non-obese diabetic (NOD) mice were orally intubated with SA (5 mg/kg/day) from 8 weeks of age for 8 weeks. The cumulative incidence of diabetes was monitored until 30 weeks of age, islet histology was examined, and lymphocytes including T cells, B cells, CD4+ IFN-γ+ cells, CD8+ IFN-γ+ cells, CD4+ IL-4+ cells, and regulatory T cells were analyzed. We also investigated the diabetogenic ability of splenocytes using an adoptive transfer model and the effect of SA on the proliferation, activation, and expression of glucose transporter 1 (Glut1) in splenocytes treated with SA in vitro and splenocytes isolated from SA-treated mice. SA treatment decreased the incidence of diabetes and delayed disease onset. SA treatment reduced the infiltration of immunocytes in islets, and splenocytes from SA-treated mice showed a reduced ability to transfer diabetes. The number of total splenocytes and T cells and both the number and the proportion of CD4+ IFN-γ+ and CD8+ IFN-γ+ T cells in the spleen were significantly reduced in SA-treated NOD mice compared with controls. The number, but not the proportion, of regulatory T cells was decreased in SA-treated NOD mice. Treatment with SA either in vitro or in vivo inhibited proliferation of splenocytes. In addition, the expression of Glut1 and phosphorylated ERK1/2 was decreased by SA treatment. These results suggest that SA reduces proliferation and activation of T cells, thus preventing autoimmune diabetes in NOD mice. [ABSTRACT FROM AUTHOR]

The non-obese diabetic ( NOD) mouse is a prevalent disease model of type 1 diabetes. Immune aberrations that cause and propagate autoimmune insulitis in these mice are being continually debated, with evidence supporting both dominance of effector cells and insufficiency of suppressor mechanisms. In this study we assessed the behaviour of NOD lymphocytes under extreme expansion conditions using adoptive transfer into immunocompromised NOD. SCID (severe combined immunodeficiency) mice. CD4+ CD25+ T cells do not cause islet inflammation, whereas splenocytes and CD4+ CD25− T cells induce pancreatic inflammation and hyperglycaemia in 80-100% of the NOD. SCID recipients. Adoptively transferred effector T cells migrate to the lymphoid organs and pancreas, proliferate, are activated in the target organ in situ and initiate inflammatory insulitis. Reconstitution of all components of the CD4+ subset emphasizes the plastic capacity of different cell types to adopt effector and suppressor phenotypes. Furthermore, similar immune profiles of diabetic and euglycaemic NOD. SCID recipients demonstrate dissociation between fractional expression of CD25 and FoxP3 and the severity of insulitis. There were no evident and consistent differences in diabetogenic activity and immune reconstituting activity of T cells from pre-diabetic (11 weeks) and new onset diabetic NOD females. Similarities in immune phenotypes and variable distribution of effector and suppressor subsets in various stages of inflammation commend caution in interpretation of quantitative and qualitative aberrations as markers of disease severity in adoptive transfer experiments. [ABSTRACT FROM AUTHOR]

Problem Impaired pregnancy in non-obese diabetic ( NOD) mice was related to limited vascular remodeling and autoimmune background. Vasoactive intestinal peptide ( VIP) has anti-inflammatory and immunosuppressant effects, so we explored its ability to modulate the immune microenvironment at the early maternal-placental interface and improve pregnancy in NOD mice. Method of study Implantation sites were isolated from pregnant NOD mice at gestational day 9.5 and were incubated with VIP for evaluation of cytokine or transcription factor expression by RT- PCR, immunoblotting, and immunohistochemistry. Alternatively, pregnant mice were injected with VIP at day 6.5 and studied at day 9.5. Results VIP and VPAC receptors were detected in viable implantation sites. VIP immunostaining was found predominantly on trophoblast giant cells. The in vitro treatment of viable implantation sites with VIP increased IL-10, TGF-β, and Foxp3 expression. Sites with resorption processes presented lower VIP expression, reduced suppressant markers, and increased IL-17 and RORγT expression compared with viable sites and VIP reduced RORγ T expression. Pregnant mice treated with VIP at day 6.5 presented an even distribution of viable implantation sites with an increased expression of IL-10, TGF- β, and Foxp3. Conclusion VIP induces an immunosuppressant profile at the early maternal-placental interface of NOD mice and improves pregnancy outcome. [ABSTRACT FROM AUTHOR]

Abstract: Leaves of Passiflora alata Curtis were characterized for their antioxidant capacity. Antioxidant analyses of DPPH, FRAP, ABTS, ORAC and phenolic compounds were made in three different extracts: aqueous, methanol/acetone and ethanol. Aqueous extract was found to be the best solvent for recovery of phenolic compounds and antioxidant activity, when compared with methanol/acetone and ethanol. To study the anti-inflammatory properties of this extract in experimental type 1 diabetes, NOD mice were divided into two groups: the P. alata group, treated with aqueous extract of P. alata Curtis, and a non-treated control group, followed by diabetes expression analysis. The consumption of aqueous extract and water ad libitum lasted 28weeks. The treated-group presented a decrease in diabetes incidence, a low quantity of infiltrative cells in pancreatic islets and increased glutathione in the kidney and liver (p<0.05), when compared with the diabetic and non-diabetic control-groups. In conclusion, our results suggest that the consumption of aqueous extract of P. alata may be considered a good source of natural antioxidants and compounds found in its composition can act as anti-inflammatory agents, helping in the control of diabetes. [Copyright &y& Elsevier]

Highlights: [•] Treatment with IL-1 Trap prolongs islet graft survival in type 1 diabetic mice. [•] The protective effect may be related to upregulation of IL-4. [•] The action of IL-1 Trap seems to be an “all or nothing” effect. [ABSTRACT FROM AUTHOR]

Highlights: [•] A newly isolated lotus plumule polysaccharide (LPPS) was used for study. [•] LPPS was administered to NOD mice for 15weeks. [•] LPPS markedly ameliorated pancreatic islets loss in NOD mice. [•] LPPS improved basal insulin secretion ability by pancreatic islets. [•] LPPS modulated serum lipid profiles in the diabetic mice. [ABSTRACT FROM AUTHOR]

Abstract: Among the active components in traditional anti-diabetic herbal plants, berberine which is an isoquinoline alkaloid exhibits promising potential for its potent anti-inflammatory and hypoglycemic effects. However, the berberine effect on serum glucose levels in type 1 diabetes (T1D) subjects still remains unknown. This study investigated berberine''s effects on serum glucose levels using non-obese diabetic (NOD) mice that spontaneously develop T1D. The NOD mice were randomly divided into four groups, administered water with 50, 150, and 500mg berberine/kg bw, respectively, through 14weeks. ICR mice were also selected as a species control group to compare with the NOD mice. Changes in body weight, oral glucose challenge, and serum glucose levels were determined to identify the protective effect of berberine on T1D. After the 14-week oral supplementation, berberine decreased fasting serum glucose levels in NOD mice close to the levels in normal ICR mice in a dose dependent manner. Serum berberine levels showed a significantly (P <0.05) negative and non-linear correlation with fasting glucose levels in berberine-administered NOD mice. Our results suggested that berberine supplemented at appropriate doses for 14weeks did not cause toxic side effects, but improved hyperglycemia in NOD mice. [Copyright &y& Elsevier]

Abstract: A novel lotus plumule polysaccharide (LPPS) was administered to non-obese diabetic (NOD) mice for 15weeks to evaluate the protective effects of LPPS on type 1 diabetes. After the 15-week feeding experiment, tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10 expressions in the spleen, liver and kidney of the experimental mice were measured using enzyme-linked immunosorbent assay or real-time quantitative polymerase chain reaction assay. The results showed that LPPS significantly (p <0.05) decreased the absolute weights of the enlarged spleens in the NOD mice in a dose-dependent manner, inhibited pro-inflammatory TNF-α and IL-6 cytokine production and decreased the secretion ratio of IL-6/IL-10 in splenocyte cultures. LPPS markedly decreased the relative expression of pro-/anti-inflammatory cytokine genes (TNF-α/IL-10 and IL-6/IL-10) in the livers of NOD mice. Our results suggest that LPPS protected the spleen and liver from spontaneous inflammation in NOD mice by modulating pro-/anti-inflammatory cytokine gene expression. [Copyright &y& Elsevier]

Abstract: Objective: We have recently shown increased sensitivity to IGF-I induced signal transduction in kidneys of diabetic mice. Accordingly we investigated the effects of PQ401, a novel diarylurea compound that inhibits IGF1R autophosphorylation in type I diabetes. Methods: Control (C) and Diabetic (D) mice were administered PQ401 (CP, DP) or vehicle (C, D) for 3weeks. Results: CP animals showed a decrease in renal phosphorylated (p-)AKT and p-IGF1R. However, PQ401 had no effect on diabetic state (hyperglycemia, weight loss) or renal disease parameters (hypertrophy, hyperfiltration and albuminuria). Type IV collagen as well as TGF-β mRNA increased in DP and D compared to C. In the CP group renal hypertrophy with fat accumulation in proximal tubuli and increased renal IGF-I, collagen IV and TGF-β mRNA were seen. Conclusions: IGF1R inhibition by PQ401 exerted no significant effects on diabetic kidney disease parameters, arguing against a role for IGF-I in the pathogenesis of diabetic kidney disease. However, PQ401 affects normal kidneys, inducing renal hypertrophy as well as collagen and fat accumulation, with increased renal IGF-I mRNA, suggestive of a damage-regeneration process. Therefore, this diarylurea compound is not beneficial in early diabetic kidney disease. Its potential deleterious effects on kidney tissue need to be further investigated. [Copyright &y& Elsevier]

Abstract: Polysaccharide (PLP) isolated from Phellinus linteus inhibits tumor growth and metastasis by enhancing immune functions of macrophages, dendritic cells, NK cells, T cells, and B cells. Here, we report that PLP can inhibit the development of autoimmune diabetes in non-obese diabetic (NOD) mice. Although 80% of the NOD mice had developed diabetes by 24weeks of age, none of the PLP-treated NOD mice developed diabetes. The mean blood glucose levels were 110mg/dl in PLP-treated mice and 499mg/dl in control NOD mice. Histological examination of the pancreatic islets revealed that most of the islets isolated from PLP-treated mice were less infiltrated with lymphocytes compared with those of control mice. Spleen cells from diabetic NOD mice could adaptively transfer diabetes into NOD/SCID mice, but those from PLP-treated NOD mice showed delayed transfer of diabetes. PLP inhibited the expression of inflammatory cytokines, including IFN-γ, IL-2, and TNF-α by Th1 cells and macrophages, but up-regulated IL-4 expression by Th2 cells in NOD mice. PLP did not prevent streptozotocin-induced diabetic development in ICR mice. Taken together, these results suggest that PLP inhibits the development of autoimmune diabetes by regulating cytokine expression. [Copyright &y& Elsevier]

Abstract: Significance: Protection of glandular cells from autoimmune-induced damage would be of significant clinical benefit to Sjogren''s syndrome (SS) patients. Epigallocatechin-3-gallate (EGCG) possesses anti-apoptotic, anti-inflammatory, and autoantigen-inhibitory properties. Aims: To investigate if EGCG protects against certain autoimmune-induced pathological changes in the salivary glands of the non-obese diabetic (NOD) mouse model for SS. Main methods: Animals were provided with either water or water containing 0.2% EGCG. At the age of 8, 16 and 22 weeks, submandibular salivary gland tissue and serum samples were collected for pathological and serological analysis. Key findings: Significant lymphocyte infiltration was observed in the salivary glands of the water-fed group at the age of 16 weeks, while the EGCG group showed reduced lymphocyte infiltration. By 22 weeks of age, water-fed animals demonstrated elevated levels of apoptotic activity within the lymphocytic infiltrates, and high levels of serum total anti-nuclear antibody, compared to EGCG-fed animals. Remarkably, proliferating cell nuclear antigen (PCNA) and Ki-67 levels in the salivary glands of water-fed NOD mice were significantly elevated in comparison to BALB/c control mice; in contrast, PCNA and Ki-67 levels in EGCG-fed NOD animals were similar to BALB/c mice. These results indicate that EGCG protects the NOD mouse submandibular glands from autoimmune-induced inflammation, and reduces serum autoantibody levels. Abnormal proliferation, rather than apoptosis, appears to be a characteristic of the NOD mouse gland that is normalized by EGCG. The evidence suggests that EGCG could be useful in delaying or managing SS-like autoimmune disorders. [Copyright &y& Elsevier]

Abstract: Most studies performed to investigate the role of the inducible bradykinin B1 receptor in the pathology and complications of type 1 diabetes have been carried out using the model of streptozotocin (STZ)-induced diabetes. The model of spontaneous autoimmune diabetes in non-obese diabetic (NOD) mice involves a long-term inflammatory process that closely resembles the human type 1 diabetes. In the present study, we aimed at establishing the correlation between the progress of diabetic hyperalgesia and the incidence of diabetes, as a function of age, in NOD mice. We also evaluated the implication of the bradykinin B1 receptor, a receptor up-regulated during the inflammatory progress of diabetes, in the development of diabetic hyperalgesia in NOD mice. Female NOD mice were followed up from the 4th to the 32nd week of age for the incidence of diabetes. Only NOD mice with plasma glucose concentration >20 mmol/l were considered diabetic. The nociception was assessed using the hot plate and the tail immersion pain tests and the effect of acute and chronic administration of the selective bradykinin B1 receptor agonist, desArg9bradykinin and its selective antagonists, R-715 (Ac-Lys-[D-β Nal7, Ile8]desArg9bradykinin) and R-954 (Ac-Orn-[Oic2, α-MePhe5, D-β Nal7, Ile8]desArg9bradykinin), on the development of diabetic hyperalgesia was studied. Diabetic NOD mice developed a significant time-dependent hyperalgesia, as measured in both tests, starting from the 8th week of age with the maximum effect observed over 16 to 20 weeks, whereas the incidence of diabetes in the tested NOD mice was only 40.16% at the age of 16 weeks and reached a maximum of 73.23% at the age 24 weeks. Both acute and chronic administration of desArg9bradykinin (400 μg/kg) markedly increased the hyperalgesic activity in diabetic NOD mice in the hot plate and tail immersion nociceptive tests. The selective bradykinin B1 receptor antagonist R-715 (400 μg/kg) and its more potent and long acting analogue R-954 (200 μg/kg), administered in acute or chronic manner, significantly attenuated diabetic hyperalgesia in NOD mice in both thermal pain tests and restored nociceptive responses to values observed in control non-diabetic siblings. Our results bring the first evidence that the development of hyperalgesia in NOD mice, a model of spontaneous type 1 diabetes, precedes the occurrence of hyperglycemia and is mediated by the bradykinin B1 receptor. It is suggested that bradykinin B1 receptor antagonism could become a novel therapeutic approach to the treatment of diabetic neuropathic complications. [Copyright &y& Elsevier]

Abstract: In addition to providing a large source of donor tissue, xenogeneic islet transplantation might avoid recurrent autoimmunity in patients with type 1 diabetes. To examine this possibility further, xenogeneic pig islets were transplanted into recipient mice in the presence or absence of autoimmunity. Spontaneously, non-obese diabetic (NOD) recipients rejected isografts rapidly whether or not the recipients were depleted of CD4+ T-cells. Young NOD mice made diabetic with streptozotocin accepted islet isografts without immunosuppression, indicating that destructive autoimmunity did not develop in these recipients. Pig xenografts were rejected equally quickly in the two types of NOD recipients in the absence of immunosuppression and survived for up to 9 weeks in both types of NOD recipients after CD4 depletion. BALB/c mice often accepted pig xenografts indefinitely after anti-CD4 antibody treatment. These results suggest that pig islets are resistant to recurrent autoimmunity when CD4+ T-cells are depleted. The difficulty in obtaining indefinite islet xenograft survival in NOD recipients occurs independently from the development of destructive autoimmunity. [ABSTRACT FROM AUTHOR]