16 research outputs found
Function of the immunoregulatory CD4-CD8- T cells in the context of autoimmune diabetes
La tolĂ©rance immunitaire dĂ©pend de la distinction entre le soi et le non soi par le systĂšme immunitaire. Un bris dans la tolĂ©rance immunitaire mĂšne Ă l'auto-immunitĂ©, qui peut provoquer la destruction des organes, des glandes, des articulations ou du systĂšme nerveux central. Le diabĂšte auto-immun, Ă©galement connu sous le nom diabĂšte juvĂ©nile et diabĂšte de type 1, rĂ©sulte d'une attaque auto-immune sur les cellules ÎČ pancrĂ©atiques sĂ©crĂ©trices dâinsuline, localisĂ©es au niveau des Ăźlots de Langerhans du pancrĂ©as. Bien que le diabĂšte auto-immun soit traitable par une combinaison dâinjections quotidiennes dâinsuline dâorigine exogĂšne, de rĂ©gime et d'exercices, beaucoup de complications chroniques peuvent se manifester chez les patients, y compris, mais non limitĂ©es Ă , la cĂ©citĂ©, les maladies cardiovasculaires, lâinsuffisance rĂ©nale et l'amputation. En raison des nombreuses complications liĂ©es au diabĂšte auto-immun Ă long terme, la recherche continue afin de mieux comprendre tous les facteurs impliquĂ©s dans la progression de la maladie dans le but de dĂ©velopper de nouvelles thĂ©rapies qui empĂȘcheront, renverseront et/ou traiteront cette maladie.
Un rĂŽle primordial dans la gĂ©nĂ©ration et l'entretien de la tolĂ©rance immunitaire a Ă©tĂ© attribuĂ© au nombre et Ă la fonction des sous-populations de cellules rĂ©gulatrices. Une de ces populations est constituĂ©e de cellules T CD4-CD8- (double nĂ©gatives, DN), qui ont Ă©tĂ© Ă©tudiĂ©es chez la souris et l'humain pour leur contribution Ă la tolĂ©rance pĂ©riphĂ©rique, Ă la prĂ©vention des maladies et pour leur potentiel associĂ© Ă la thĂ©rapie cellulaire. En effet, les cellules de T DN sont d'intĂ©rĂȘt thĂ©rapeutique parce qu'elles montrent un potentiel immunorĂ©gulateur antigĂšne-spĂ©cifique dans divers cadres expĂ©rimentaux, y compris la prĂ©vention du diabĂšte auto-immun. Dâailleurs, en utilisant un systĂšme transgĂ©nique, nous avons dĂ©montrĂ© que les souris prĂ©disposĂ©es au diabĂšte auto-immun prĂ©sentent peu de cellules T DN, et que ce phĂ©notype contribue Ă la susceptibilitĂ© au diabĂšte auto-immun. En outre, un transfert des cellules T DN est suffisant pour empĂȘcher la progression vers le diabĂšte chez les souris prĂ©disposĂ©es au diabĂšte auto-immun. Ces rĂ©sultats suggĂšrent que les cellules T DN puissent prĂ©senter un intĂ©rĂȘt thĂ©rapeutique pour les patients diabĂ©tiques. Cependant, nous devons d'abord valider ces rĂ©sultats en utilisant un modĂšle non-transgĂ©nique, qui est plus physiologiquement comparable Ă l'humain.
L'objectif principal de cette thĂšse est de dĂ©finir la fonction immunorĂ©gulatrice des cellules T DN, ainsi que le potentiel thĂ©rapeutique de celles-ci dans la prĂ©vention du diabĂšte auto-immun chez un modĂšle non-transgĂ©nique. Dans cette thĂšse, on dĂ©montre que les souris rĂ©sistantes au diabĂšte auto-immun prĂ©sentent une proportion et nombre absolu plus Ă©levĂ©s de cellules T DN non-transgĂ©niques, lorsque comparĂ©es aux souris susceptibles. Cela confirme une association entre le faible nombre de cellules T DN et la susceptibilitĂ© Ă la maladie. On observe que les cellules T DN Ă©liminent les cellules B activĂ©es in vitro par une voie dĂ©pendante de la voie perforine et granzyme, oĂč la fonction des cellules T DN est Ă©quivalente entre les souris rĂ©sistantes et prĂ©disposĂ©es au diabĂšte auto-immun. Ces rĂ©sultats confirment que l'association au diabĂšte auto-immun est due Ă une insuffisance en terme du nombre de cellules T DN, plutĂŽt quâĂ une dĂ©ficience fonctionnelle. On dĂ©montre que les cellules T DN non-transgĂ©niques Ă©liminent des cellules B chargĂ©es avec des antigĂšnes d'Ăźlots, mais pas des cellules B chargĂ©es avec un antigĂšne non reconnu, in vitro. Par ailleurs, on Ă©tablit que le transfert des cellules T DN activĂ©es peut empĂȘcher le dĂ©veloppement du diabĂšte auto-immun dans un modĂšle de souris non-transgĂ©nique. De plus, nous observons que les cellules T DN migrent aux Ăźlots pancrĂ©atiques, et subissent une activation et une prolifĂ©ration prĂ©fĂ©rentielles au niveau des ganglions pancrĂ©atiques. D'ailleurs, le transfert des cellules T DN entraĂźne une diminution d'auto-anticorps spĂ©cifiques de l'insuline et de cellules B de centres germinatifs directement dans les Ăźlots, ce qui corrĂšle avec les rĂ©sultats dĂ©crits ci-dessus. Les rĂ©sultats prĂ©sentĂ©s dans cette thĂšse permettent de dĂ©montrer la fonction des cellules T DN in vitro et in vivo, ainsi que leur potentiel liĂ© Ă la thĂ©rapie cellulaire pour le diabĂšte auto-immun.Immune tolerance is dependent on the immune system discriminating between self and non-self. A break in immune tolerance results in autoimmunity, which can lead to the destruction of healthy organs, glands, joints or the central nervous system. Any disease that results from such an aberrant immune response is termed an autoimmune disease. Autoimmune diabetes, which is also referred to as juvenile diabetes and type 1 diabetes, results from an autoimmune attack on the insulin-producing ÎČ cells located within the islets of Langerhans of the pancreas. Although autoimmune diabetes is treatable through a combination of insulin therapy, diet and exercise, many chronic complications may arise in patients, including, but not limited to, blindness, cardiovascular disease, kidney failure and amputation. Due to the many complications associated with long-term autoimmune diabetes, research continues to better understand all the factors implicated in disease progression in order to develop new therapies that will prevent, reverse and/or cure this disease.
A prominent role in the generation and maintenance of immune tolerance has been attributed to the number and function of regulatory cell subsets. One of these regulatory cell populations, namely CD4-CD8- (double negative, DN) T cells, have been studied in both mice and humans for their contribution to peripheral tolerance, disease prevention and their potential for use in cellular therapy. DN T cells are of particular therapeutic interest because they exhibit an antigen-specific immunoregulatory potential in various experimental settings, including the prevention of autoimmune diabetes. Indeed, using a transgenic system, we have shown that autoimmune diabetes-prone mice carry fewer DN T cells and that this phenotype contributes to autoimmune diabetes susceptibility, where a single transfer of DN T cells is sufficient to prevent diabetes progression in otherwise autoimmune diabetes-prone mice. These results suggest that DN T cells may be of therapeutic interest for diabetic patients. However, we must first validate these results using a non-transgenic setting, which is more physiologically relevant to humans.
The main objective of this thesis is to determine the immunoregulatory function of the DN T cells as well as the therapeutic potential of these cells in the prevention of autoimmune diabetes in the non-transgenic setting. Here, we show that diabetes-resistant mice present with a higher proportion and cell number of DN T cells than diabetes-susceptible mice in the non-transgenic setting, which associates a deficiency in DN T cell number with disease susceptibility. We determine that DN T cells eliminate activated B cells in vitro via a perforin/granzyme-dependent pathway, where the function of DN T cells is equal between the diabetes-resistant and -susceptible mice, demonstrating that the association to autoimmune diabetes is due to a deficiency in DN T cell number rather than function. Interestingly, we show that non-transgenic DN T cells eliminate B cells loaded with islet antigen, but not B cells loaded with an irrelevant antigen, in vitro. Importantly, we establish that the transfer of activated DN T cells could prevent autoimmune diabetes development in the non-transgenic setting. Interestingly, we reveal that DN T cells migrate to the pancreatic islets and undergo preferential activation and proliferation within the pancreatic lymph nodes. Moreover, the transfer of DN T cells results in a decrease in both germinal center B cells directly within the pancreatic islets as well serum insulin autoantibody levels, which correlates with the aforementioned findings. Altogether, the results presented in this thesis have allowed us to enhance our understanding of the function of DN T cells both in vitro and in vivo as well as demonstrate the therapeutic potential for DN T cells as a novel cellular therapeutic for autoimmune diabetes
Immunoregulatory CD4-CD8- T cells as a potential therapeutic tool for transplantation, autoimmunity, and cancer
A central objective in organ transplantation and the treatment or prevention of autoimmune disease is the achievement of antigen-specific immune tolerance. An additional challenge in bone marrow transplantation for the treatment of hematological malignancies is the prevention of graft-vs-host disease (GVHD) while maintaining graft-vs-tumor activity. Interestingly, CD4-CD8- (double negative, DN) T cells, which exhibit a unique antigen-specific immunoregulatory potential, appear to exhibit all of the properties to respond to these challenges. Herein, we review the therapeutic potential of immunoregulatory DN T cells in various immunopathological settings, including graft tolerance, GVHD, cancer, and autoimmunity
Nearby Construction Impedes the Progression to Overt Autoimmune Diabetes in NOD Mice
Construction nearby animal houses has sporadically been reported to affect various aspects of animal health. Most of the reports have focussed on the impact on stress hormone levels and the hypersensitivity of animals relative to humans. There has also been an anecdotal report on the impact of construction on autoimmune diabetes in NOD mice. Here, we describe that nearby construction significantly impedes the progression to overt diabetes in female NOD mice offspring. We demonstrate that this was not due to a genetic drift or to particularities associated with our specific mouse colony. Interestingly, although the glycemia levels remained low in mice born from mothers subject to construction stress during gestation, we detected an active autoimmune reaction towards pancreatic islet cells, as measured by both the degree of insulitis and the presence of insulin autoantibody levels in the serum. These results suggest that the external stress imposed during embryonic development does not prevent but significantly delays the autoimmune process. Together, our findings emphasize the impact of surrounding factors during in vivo studies and are in agreement with the hypothesis that both environmental and genetic cues contribute to autoimmune diabetes development
Immunoregulatory CD4-CD8- T cells as a potential therapeutic tool for transplantation, autoimmunity and cancer
A central objective in organ transplantation and the treatment or prevention of autoimmune disease is the achievement of antigen-specific immune tolerance. An additional challenge in bone marrow transplantation for the treatment of hematological malignancies is the prevention of graft-vs-host disease (GVHD) while maintaining graft-vs-tumor activity. Interestingly, CD4-CD8- (double negative, DN) T cells, which exhibit a unique antigen-specific immunoregulatory potential, appear to exhibit all of the properties to respond to these challenges. Herein, we review the therapeutic potential of immunoregulatory DN T cells in various immunopathological settings, including graft tolerance, GVHD, cancer and autoimmunity
Development of a brief scale to assess frequency of symptoms and problems associated with tanning
TCR transgenic mice reveal the impact of type 1 diabetes loci on early and late disease checkpoints
Linkage analysis studies for autoimmune diabetes have revealed multiple non-major histocompatibility complex (MHC) chromosomal regions linked to disease susceptibility. To date, more than 20 insulin-dependent diabetes (Idd) loci linked to diabetes susceptibility have been identified in NOD mice and validated via congenic breeding. Importantly, evidence suggests that Idd loci may regulate at least two pathological steps during autoimmune diabetes development, namely the onset of insulitis and the transition from insulitis to overt diabetes. Here we assess the role of various non-MHC Idd diabetes-resistance loci, which have been validated in the non-transgenic setting, on autoimmune diabetes progression in the transgenic setting. Specifically, we generated multiple Idd congenic strains in the 3A9-TCR:insHEL NOD.H2(k) transgenic model and monitored their diabetes incidence. We show that 3A9-TCR:insHEL NOD.H2(k) mice congenic for Idd3 or Idd5 display a reduction in diabetes development, whereas mice congenic for Idd9 or Idd13 exhibit an increase, in comparison with 3A9-TCR:insHEL NOD.H2(k) mice. These results suggest that the presence of the 3A9-TCR and hen egg lysosyme transgenes can offset the regulatory function of certain diabetes-resistance genetic variants contained within the Idd loci, including Idd9 and Idd13. We propose the antigen-specific 3A9-TCR:insHEL transgenic model as a useful tool for the study of the genetics of autoimmune diabetes development.status: publishe
TCR transgenic mice reveal the impact of type 1 diabetes loci on early and late disease checkpoints
Nearby Construction Impedes the Progression to Overt Autoimmune Diabetes in NOD Mice
Construction nearby animal houses has sporadically been reported to affect various aspects of animal health. Most of the reports have focussed on the impact on stress hormone levels and the hypersensitivity of animals relative to humans. There has also been an anecdotal report on the impact of construction on autoimmune diabetes in NOD mice. Here, we describe that nearby construction significantly impedes the progression to overt diabetes in female NOD mice offspring. We demonstrate that this was not due to a genetic drift or to particularities associated with our specific mouse colony. Interestingly, although the glycemia levels remained low in mice born from mothers subject to construction stress during gestation, we detected an active autoimmune reaction towards pancreatic islet cells, as measured by both the degree of insulitis and the presence of insulin autoantibody levels in the serum. These results suggest that the external stress imposed during embryonic development does not prevent but significantly delays the autoimmune process. Together, our findings emphasize the impact of surrounding factors during in vivo studies and are in agreement with the hypothesis that both environmental and genetic cues contribute to autoimmune diabetes development
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Methylphenidate for methamphetamine use
Background and aimsNo effective pharmacotherapy for methamphetamine (MA) use disorder has yet been found. This study evaluated sustained-release methylphenidate (MPH-SR) compared with placebo (PLA) for treatment of MA use disorder in people also undergoing behavioral support and motivational incentives.DesignThis was a randomized, double-blind, placebo-controlled design with MPH-SR or PLA provided for 10 weeks (active phase) followed by 4 weeks of single-blind PLA. Twice-weekly clinic visits, weekly group counseling (CBT) and motivational incentives (MI) for MA-negative urine drug screens (UDS) were included.SettingTreatment sites were in Los Angeles, California (LA) and Honolulu, Hawaii (HH), USA.ParticipantsA total of 110 MA-dependent (via DSM-IV) participants (LAâ=â90; HHâ=â20).MeasurementsThe primary outcome measure is self-reported days of MA use during the last 30 days of the active phase. Included in the current analyses are drug use (UDS and self-report), retention, craving, compliance (dosing, CBT, MI), adverse events and treatment satisfaction.FindingsNo difference was found between treatment groups in self-reported days of MA use during the last 30 days of the active phase (Pâ=â0.22). In planned secondary outcomes analyses, however, the MPH group had fewer self-reported MA use days from baseline through the active phase compared with the PLA group (Pâ=â0.05). The MPH group also had lower craving scores and fewer marijuana-positive UDS than the PLA group in the last 30 days of the active phase. The two groups had similar retention, other drug use, adverse events and treatment satisfaction.ConclusionsMethylphenidate may lead to a reduction in concurrent methamphetamine use when provided as treatment for patients undergoing behavioral support for moderate to severe methamphetamine use disorder, but this requires confirmation