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IntroductionType 1 diabetes (T1D) is defined by immune cell infiltration of the pancreas, in particular the islets of Langerhans, referred to as insulitis, which is especially prominent during the early disease stages in association with decreased beta cell mass. An in-depth understanding of the dynamics and phenotype of the immune cells infiltrating the pancreas and the accompanying changes in their profiles in peripheral blood during T1D development is critical to generate novel preventive and therapeutic approaches, as well as to find biomarkers for the disease process.MethodsUsing multi-parameter flow cytometry, we explored the dynamic changes of immune cells infiltrating the pancreas and the pancreatic draining lymph nodes (PLN), compared to those in peripheral blood in female and male non-obese diabetic (NOD) mice during T1D progression.ResultsThe early stages of T1D development were characterized by an influx of innate dendritic cells and neutrophils in the pancreas. While dendritic cells seemed to move in and out (to the PLN), neutrophils accumulated during the pre-symptomatic phase and reached a maximum at 8 weeks of age, after which their numbers declined. During disease progression, CD4+ and CD8+ T cells appeared to continuously migrate from the PLN to the pancreas, which coincided with an increase in beta cell autoimmunity and insulitis severity, and a decline in insulin content. At 12 weeks of age, CD4+ and especially CD8+ T cells in the pancreas showed a dramatic shift from naïve to effector memory phenotype, in contrast to the PLN, where most of these cells remained naïve. A large proportion of pancreas infiltrating CD4+ T cells were naïve, indicating that antigenic stimulation was not necessary to traffic and invade the pancreas. Interestingly, a pre-effector-like T cell dominated the peripheral blood. These cells were intermediates between naïve and effector memory cells as identified by single cell RNA sequencing and might be a potential novel therapeutic target.ConclusionThese time- and tissue-dependent changes in the dynamics and functional states of CD4+ and CD8+ T cells are essential steps in our understanding of the disease process in NOD mice and need to be considered for the interpretation and design of disease-modifying therapies.

Despite the increasing knowledge of pathophysiological mechanisms underlying the onset of type 1 diabetes (T1D), the quest for therapeutic options capable of delaying/reverting the diseases is still ongoing. Among all strategies currently tested in T1D, the use of hematopoietic stem cell (HSC)-based approaches and of teplizumab, showed the most encouraging results. Few clinical trials have already demonstrated the beneficial effects of HSCs in T1D, while the durability of the effect is yet to be established. Investigators are also trying to understand whether the use of selected and better-characterized HSCs subsets may provide more benefits with less risks. Interestingly, ex vivo manipulated HSCs showed promising results in murine models and the recent introduction of the humanized mouse models accelerated the translational potentials of such studies and their final road to clinic. Indeed, immunomodulatory as well as trafficking abilities can be enhanced in genetically modulated HSCs and genetically engineered HSCs may be viewed as a novel “biologic” therapy, to be further tested and explored in T1D and in other autoimmune/immune-related disorders.

Despite the increasing knowledge of pathophysiological mechanisms underlying the onset of type 1 diabetes (T1D), the quest for therapeutic options capable of delaying/reverting the diseases is still ongoing. Among all strategies currently tested in T1D, the use of hematopoietic stem cell (HSC)-based approaches and of teplizumab, showed the most encouraging results. Few clinical trials have already demonstrated the beneficial effects of HSCs in T1D, while the durability of the effect is yet to be established. Investigators are also trying to understand whether the use of selected and better-characterized HSCs subsets may provide more benefits with less risks. Interestingly, ex vivo manipulated HSCs showed promising results in murine models and the recent introduction of the humanized mouse models accelerated the translational potentials of such studies and their final road to clinic. Indeed, immunomodulatory as well as trafficking abilities can be enhanced in genetically modulated HSCs and genetically engineered HSCs may be viewed as a novel "biologic" therapy, to be further tested and explored in T1D and in other autoimmune/immune-related disorders. [ABSTRACT FROM AUTHOR]

Keywords: type 1 diabetes; autoimmunity; NOD mouse model; adaptive immunity; innate immunity EN type 1 diabetes autoimmunity NOD mouse model adaptive immunity innate immunity 1 3 3 03/14/22 20220310 NES 220310 Our understanding of the islet-immune interface in autoimmune diabetes has exploded with the vast array of knowledge coming from recent works. However, the events leading to the breakdown in tolerance towards islet cells, and the ensuing pro-inflammatory cytokine laden environment that perpetuates T cell-mediated cell destruction, remain elusive. It is noteworthy that specific NK cell markers, such as NKG2D, are also expressed on CD8 SP + sp T cells, especially human CD8 SP + sp T cells, which are central adaptive immune cell players in -cell destruction. [Extracted from the article]

Objective Activation of the cholinergic anti-inflammatory pathway ( CAP) has been shown to reduce inflammation in animal models, while abrogation of the pathway increases inflammation. We investigated whether modulation of CAP influences inflammation in the non-obese diabetic ( NOD) mouse model for Sjögren's syndrome and type 1 diabetes. Methods The alpha-7 nicotinic acetylcholine receptor ( α7n AChR) was stimulated with AR-R17779 or nicotine in NOD mice. In a second study, unilateral cervical vagotomy was performed. α7n AChR expression, focus scores, and salivary flow were evaluated in salivary glands ( SG) and insulitis score in the pancreas. Cytokines were measured in serum and SG. Results α7n AChR was expressed on myoepithelial cells in SG. Monocyte chemotactic protein-1 levels were reduced in SG after AR-R17779 treatment and tumor necrosis factor production was increased in the SG of the vagotomy group compared to controls. Focus score and salivary flow were unaffected. NOD mice developed diabetes more rapidly after vagotomy, but at completion of the study there were no statistically significant differences in number of mice that developed diabetes or in insulitis scores. Conclusion Intervention of the CAP in NOD mice leads to minimal changes in inflammatory cytokines, but did not affect overall inflammation and function of SG or development of diabetes. [ABSTRACT FROM AUTHOR]

Objectives: The non-obese diabetic (NOD) mouse is not only a widely used model for diabetes mellitus type I, but also for the chronic autoimmune disease Sjögren's syndrome (SS), mainly affecting salivary and lacrimal glands. We studied the efficacy of local recombinant serotype 2 adeno-associated viral (rAAV2) vector transfer of immunomodulatory transgenes to alter the SS-like disease in NOD mice. Data collected over a 2-year period indicated a changing SS phenotype in these mice and this phenomenon was investigated. Methods: 1010 particles rAAV2LacZ/gland were delivered to both submandibular glands (SMGs) of NOD/LtJ mice at 8 weeks (before sialadenitis onset) of age. Salivary flow rates were determined at 8 weeks and time of killing. Blood glucose levels and body weights were measured weekly. After killing, saliva and SMGs were harvested. Analyses of salivary output, inflammatory infiltrates (focus score), SMG cytokine profile, body weight, and diabetes mellitus status were performed. Data from six different experimental studies over 2 years were analyzed and compared. Results: Salivary flow rate, focus score, and SMG cytokines interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12(p70), tumor necrosis factor- α and IFN γ showed changes over time. There were no differences for body weight, diabetes mellitus prevalence, or blood glucose level of non-diabetic mice. Conclusion: This retrospective report is the first to describe longitudinal variability in the NOD mouse as a model for SS. We advise other investigators to continuously monitor the SS phenotype parameters and include appropriate controls when studying this disease in NOD mice. [ABSTRACT FROM AUTHOR]