Peptidylarginine Deiminase Inhibition Prevents Diabetes Development in NOD Mice

Protein citrullination plays a role in several autoimmune diseases. Its involvement in murine and human type 1 diabetes has recently been recognized through the discovery of antibodies and T-cell reactivity against citrullinated peptides. In the current study, we demonstrate that systemic inhibition of peptidylarginine deiminases (PADs), the enzymes mediating citrullination, through BB-Cl-amidine treatment, prevents diabetes development in NOD mice. This prevention was associated with reduced levels of citrullination in the pancreas, decreased circulating autoantibody titers against citrullinated GRP78 and reduced spontaneous NETosis of bone marrow-derived neutrophils. Moreover, BB-Cl-amidine treatment induced a shift from Th1 to Th2 cytokines in the serum and an increase in the frequency of regulatory T cells in the blood and spleen. In the pancreas, BB-Cl-amidine treatment preserved insulin production and was associated with a less destructive immune infiltrate, characterized by reduced frequencies of effector memory CD4+ T cells and a modest reduction in the frequency of IFNγ-producing CD4+ and CD8+ T cells. Our results point to a role of citrullination in the pathogenesis of autoimmune diabetes, with PAD inhibition leading to disease prevention through modulation of immune pathways. These findings provide insight in the potential of PAD inhibition for treating autoimmune diseases like type 1 diabetes

Key Role of the GITR/GITRLigand Pathway in the Development of Murine Autoimmune Diabetes: A Potential Therapeutic Target

BACKGROUND: The cross-talk between pathogenic T lymphocytes and regulatory T cells (Tregs) plays a major role in the progression of autoimmune diseases. Our objective is to identify molecules and/or pathways involved in this interaction and representing potential targets for innovative therapies. Glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand are key players in the T effector/Treg interaction. GITR is expressed at low levels on resting T cells and is significantly up-regulated upon activation. Constitutive high expression of GITR is detected only on Tregs. GITR interacts with its ligand mainly expressed on antigen presenting cells and endothelial cells. It has been suggested that GITR triggering activates effector T lymphocytes while inhibiting Tregs thus contributing to the amplification of immune responses. In this study, we examined the role of GITR/GITRLigand interaction in the progression of autoimmune diabetes. METHODS AND FINDINGS: Treatment of 10-day-old non-obese diabetic (NOD) mice, which spontaneously develop diabetes, with an agonistic GITR-specific antibody induced a significant acceleration of disease onset (80% at 12 weeks of age). This activity was not due to a decline in the numbers or functional capacity of CD4(+)CD25(+)Foxp3(+) Tregs but rather to a major activation of 'diabetogenic' T cells. This conclusion was supported by results showing that anti-GITR antibody exacerbates diabetes also in CD28(-/-) NOD mice, which lack Tregs. In addition, treatment of NOD mice, infused with the diabetogenic CD4(+)BDC2.5 T cell clone, with GITR-specific antibody substantially increased their migration, proliferation and activation within the pancreatic islets and draining lymph nodes. As a mirror image, blockade of the GITR/GITRLigand pathway using a neutralizing GITRLigand-specific antibody significantly protected from diabetes even at late stages of disease progression. Experiments using the BDC2.5 T cell transfer model suggested that the GITRLigand antibody acted by limiting the homing and proliferation of pathogenic T cells in pancreatic lymph nodes. CONCLUSION: GITR triggering plays an important costimulatory role on diabetogenic T cells contributing to the development of autoimmune responses. Therefore, blockade of the GITR/GITRLigand pathway appears as a novel promising clinically oriented strategy as GITRLigand-specific antibody applied at an advanced stage of disease progression can prevent overt diabetes

ETUDE, CHEZ LA SOURIS NON OBESE DIABETIC, DES MECANISMES IMMUNITAIRES IMPLIQUES DANS LE REJET DE XENOGREFFES D'ILOTS DE PORC ET EFFETS DE L'ADMINISTRATION ORALE DE XENOANTIGENES PORCINS

LA XENOTRANSPLANTATION, C'EST-A-DIRE LA GREFFE D'ORGANES ENTRE ESPECES DIFFERENTES, PERMETTRAIT DE PALIER L'INSUFFISANCE EN ORGANES HUMAINS. CETTE APPROCHE SOULEVE, TOUTEFOIS, DE NOMBREUSES QUESTIONS. OUTRE LES PROBLEMES ETHIQUES, SANITAIRES ET PHYSIOLOGIQUES, LA XENOGREFFE SE HEURTE A L'EXISTENCE D'UN REJET IMMUNOLOGIQUE INTENSE. SI LES ORGANES VASCULARISES SONT LA CIBLE D'UNE REACTION FULMINANTE, LES TISSUS NON VASCULARISES ECHAPPERAIENT A CE REJET SURAIGU. TEL EST LE CAS DES ILOTS DE LANGERHANS DE PORC, DONT L'UTILISATION POURRAIT CONSTITUER UNE SOLUTION THERAPEUTIQUE POUR LE TRAITEMENT DU DIABETE DE TYPE I. LA COMPREHENSION DES MECANISMES IMMUNITAIRES RESPONSABLES DU REJET D'ILOTS DE PORC CHEZ LA SOURIS NOD, MODELE XENOGENIQUE DISCORDANT, AINSI QUE L'EXPLORATION D'UNE NOUVELLE APPROCHE POUR MODULER LA REACTION XENOGENIQUE ANTI-PORC, FONT L'OBJET DE NOTRE TRAVAIL. TOUT D'ABORD, NOUS AVONS MONTRE QUE LES ILOT DE PORCS ADULTES EXEMPTS D'ORGANISMES PATHOGENE SPECIFIES (EOPS, I.E. GARANTISSANT UN RISQUE MINIMUM D'INFECTION), REPONDENT A DIVERS STIMULI DE MANIERE SIMILAIRE AUX ILOTS HUMAINS. AINSI, DE PART LEUR COMPATIBILITE PHYSIOLOGIQUE, CES ILOTS DE PORC POURRAIENT ETRE UTILISES A DES FINS DE XENOTRANSPLANTATION. NOS ETUDES IN VITRO, METTENT EN EVIDENCE UNE PROLIFERATION ET UNE AGRESSIVITE DES SPLENOCYTES DE SOURIS NOD VIS-A-VIS D'ILOTS PORCINS EOPS. LA REACTION XENOGENIQUE SEMBLE INITIEE PAR LA RECONNAISSANCE INDIRECTE DES CELLULES XENOGENIQUES PAR LES LYMPHOCYTES T CD4+, DE SOUS-TYPE MAJORITAIREMENT TH1 ET DANS UNE MOINDRE MESURE TH2. NOUS MONTRONS EGALEMENT UNE AGRESSION DES ILOTS DE PORC PAR DIFFERENTES POPULATIONS IMMUNITAIRES. DANS UN PREMIER TEMPS, LES CELLULES ADHERENTES (SUR BOITE PLASTIQUE), OU CELLULES PRESENTATRICES D'ANTIGENES, ALTERENT, DE MANIERE PRECOCE, L'INSULINOSECRETION DES ILOTS, CE QUI REFLETERAIT L'INDUCTION DU PHENOMENE DE PRIMARY NON FUNCTION. DANS UN DEUXIEME TEMPS, LA POPULATION CD4, RESTREINTE PAR LE CMH DE CLASSE II, DEVELOPPE UNE FORTE AGRESSIVITE ENVERS LES ILOTS DE PORC, QUI PERDENT ALORS LEURS CAPACITES INSULINOSECRETRICES. NOS OBSERVATIONS CHEZ LA SOURIS NOD, MODELE EXPERIMENTAL DU DIABETE INSULINODEPENDANT HUMAIN, SUGGERENT, PAR AILLEURS, UNE INFLUENCE DU CONTEXTE D'AUTOIMMUNITE ANTI-CELLULES SUR L'INTENSITE DE LA REPONSE XENOGENIQUE ANTI-ILOTS DE PORC. ENFIN, NOUS AVONS ETUDIE LES EFFETS DE L'ADMINISTRATION ORALE DE XENOANTIGENES PORCINS SUR LE SYSTEME IMMUNITAIRE MURIN. LES SPLENOCYTES DE SOURIS, GAVEES QUOTIDIENNEMENT AVEC DES SPLENOCYTES DE PORC, SEMBLENT MOINS AGRESSIFS ENVERS LES ILOTS DE PORC QUE LES SPLENOCYTES DE TEMOINS, ET CE, BIEN QU'ILS PROLIFERENT PLUS FORTEMENT VIS-A-VIS DE CES MEMES ILOTS. EN OUTRE, CES GAVAGES INDUISENT UNE REDUCTION DES REPONSES CELLULAIRES ANTI-PORC CHEZ DES SOURIS GREFFEES PAR VOIE INTRAPERITONEALE AVEC CES MEMES SPLENOCYTES PORCINS. CES EFFETS PEUVENT ETRE TRANSFERES CHEZ DES RECEVEURS SYNGENIQUES. LES TRAITEMENTS ORAUX MODIFIENT EGALEMENT LES REACTIONS HUMORALES QUI, ASSOCIEES A LA DETERMINATION DES CYTOKINES PRODUITES DANS LES CONDITIONS STIMULANTES, SUGGERENT UNE DIMINUTION DES REPONSES TH1 EFFECTRICES ANTI-PORC FAVORISANT UNE INFLUENCE TH2. AINSI, LES ADMINISTRATIONS ORALES DE XENOANTIGENES PORCINS SEMBLENT AVOIR INDUIT UN PROCESSUS CELLULAIRE ACTIF, TRANSFERABLE, INCLUANT DES MECANISMES SUPPRESSEURS, CAPABLES DE MODULER LES REACTIONS CELLULAIRES ET HUMORALE VIS-A-VIS DES ILOTS ET DES SPLENOCYTES PORCINS.NANTES-BU Sciences (441092104) / SudocSudocFranceF

Personalized Immunotherapies for Type 1 Diabetes: Who, What, When, and How?

Our understanding of the immunopathological features of type 1 diabetes (T1D) has greatly improved over the past two decades and has shed light on disease heterogeneity dictated by multiple immune, metabolic, and clinical parameters. This may explain the limited effects of immunotherapies tested so far to durably revert or prevent T1D, for which life-long insulin replacement remains the only therapeutic option. In the era of omics and precision medicine, offering personalized treatment could contribute to turning this tide. Here, we discuss how to structure the selection of the right patient at the right time for the right treatment. This individualized therapeutic approach involves enrolling patients at a defined disease stage depending on the target and mode of action of the selected drug, and better stratifying patients based on their T1D endotype, reflecting intrinsic disease aggressiveness and immune context. To this end, biomarker screening will be critical, not only to help stratify patients and disease stage, but also to select the best predicted responders ahead of treatment and at early time points during clinical trials. This strategy could contribute to increase therapeutic efficacy, notably through the selection of drugs with complementary effects, and to further develop precision multi-hit medicine

Coxsackievirus and Type 1 Diabetes: Diabetogenic Mechanisms and Implications for Prevention

International audienceThe evidence for an association between coxsackievirus B (CVB) infection, pancreatic islet autoimmunity, and clinical type 1 diabetes is increasing. Results from prospective cohorts and pancreas histopathology studies have provided a compelling case. However, the demonstration of a causal relationship is missing, and is likely to remain elusive until tested in humans by avoiding exposure to this candidate viral trigger. To this end, CVB vaccines have been developed and are entering clinical trials. However, the progress made in understanding the biology of the virus and in providing tools to address the long-standing question of causality contrasts with the scarcity of information about the antiviral immune responses triggered by infection. Beta-cell death may be primarily induced by CVB itself, possibly in the context of poor immune protection, or secondarily provoked by T-cell responses against CVB-infected beta cells. The possible involvement of epitope mimicry mechanisms skewing the physiological antiviral response toward autoimmunity has also been suggested. We here review the available evidence for each of these 3 non-mutually exclusive scenarios. Understanding which ones are at play is critical to maximize the odds of success of CVB vaccination, and to develop suitable tools to monitor the efficacy of immunization and its intermingling with autoimmune onset or prevention

A selective CD28 antagonist and rapamycin synergise to protect against spontaneous autoimmune diabetes in NOD mice

International audienc

Regulatory mechanisms of immune tolerance in type 1 diabetes and their failures

International audienc