RESUMEN
Discovery of insulin in 1921 changed the lives of patients with type 1 diabetes (T1DM) forever. What had been a death sentence became a manageable, albeit chronic, disease. Insulin did not cure the disease, as it did not address the actual disease process, but instead treated its sequelae, namely elevated blood sugars. Importantly, insulin administration fails to ensure normoglycaemia. Even with the most sophisticated 'near closed-loop' methods, glucose homeostasis is not restored to normal. T1DM patients face complications, both short-term, such as hypo- and hyperglycaemia, and long-term, with increased glycosylation of proteins leading to eye, kidney, nervous system and other sequelae. These complications are associated with significant morbidity and mortality even after intensive insulin treatment. Nearly 100 years after the discovery of insulin, we continue to face the challenge of addressing the disease process itself, in order to fundamentally improve the life of these patients. There are major efforts to achieve just that: to completely arrest the autoimmune process destroying the insulin-producing cells in the pancreas, or at least significantly slow the process to blunt and delay short- and long-term complications. The aim of this Communication is to propose a novel assessment tool that would serve as a quantitative outcome measure by which therapies, short of clinical cure, may be compared and their true benefit to the treatment of diabetes assessed.
Asunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hiperglucemia/prevención & control , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Recuperación de la Función , Medición de Riesgo/métodos , Diabetes Mellitus Tipo 1/patología , HumanosRESUMEN
To determine whether serum levels of 25-hydroxyvitamin D (25(OH)D) in young adults are associated with risk of type 1 diabetes mellitus (T1D), we conducted a prospective, nested case-control study among US active-duty military personnel with serum in the US Department of Defense Serum Repository, identifying 310 T1D cases diagnosed between 1997 and 2009 with at least 2 serum samples collected before disease onset and 613 controls matched to cases on age, sex, race/ethnicity, branch of military service, and dates of serum collection. Conditional logistic regression was used to estimate rate ratios and 95% confidence intervals. Among non-Hispanic whites, those with average 25(OH)D levels of ≥ 100 nmol/L had a 44% lower risk of developing T1D than those with average 25(OH)D levels < 75 nmol/L (rate ratio = 0.56, 95% confidence interval: 0.35, 0.90, P for trend = 0.03) over an average follow-up of 5.4 years. In quintile analyses, T1D risk was highest among individuals whose 25(OH)D levels were in the lowest 20% of those measured. There was no association between 25(OH)D levels and risk of T1D among non-Hispanic blacks or Hispanics. Low 25(OH)D levels may predispose healthy, young, non-Hispanic white adults to the development of T1D.
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Diabetes Mellitus Tipo 1 , Personal Militar/estadística & datos numéricos , Vitamina D/análogos & derivados , Vitaminas/sangre , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/etnología , Femenino , Humanos , Masculino , Estudios Prospectivos , Riesgo , Estados Unidos/epidemiología , Vitamina D/sangreRESUMEN
BACKGROUND: The immunopathogenesis of type 1 diabetes mellitus is associated with T-cell autoimmunity. To be fully active, immune T cells need a co-stimulatory signal in addition to the main antigen-driven signal. Abatacept modulates co-stimulation and prevents full T-cell activation. We evaluated the effect of abatacept in recent-onset type 1 diabetes. METHODS: In this multicentre, double-blind, randomised controlled trial, patients aged 6-45 years recently diagnosed with type 1 diabetes were randomly assigned (2:1) to receive abatacept (10 mg/kg, maximum 1000 mg per dose) or placebo infusions intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over 2 years. Computer-generated permuted block randomisation was used, with a block size of 3 and stratified by participating site. Neither patients nor research personnel were aware of treatment assignments. The primary outcome was baseline-adjusted geometric mean 2-h area-under-the-curve (AUC) serum C-peptide concentration after a mixed-meal tolerance test at 2 years' follow-up. Analysis was by intention to treat for all patients for whom data were available. This trial is registered at ClinicalTrials.gov, NCT00505375. FINDINGS: 112 patients were assigned to treatment groups (77 abatacept, 35 placebo). Adjusted C-peptide AUC was 59% (95% CI 6·1-112) higher at 2 years with abatacept (n=73, 0·378 nmol/L) than with placebo (n=30, 0·238 nmol/L; p=0·0029). The difference between groups was present throughout the trial, with an estimated 9·6 months' delay (95% CI 3·47-15·6) in C-peptide reduction with abatacept. There were few infusion-related adverse events (36 reactions occurred in 17 [22%] patients on abatacept and 11 reactions in six [17%] on placebo). There was no increase in infections (32 [42%] patients on abatacept vs 15 [43%] on placebo) or neutropenia (seven [9%] vs five [14%]). INTERPRETATION: Co-stimulation modulation with abatacept slowed reduction in ß-cell function over 2 years. The beneficial effect suggests that T-cell activation still occurs around the time of clinical diagnosis of type 1 diabetes. Yet, despite continued administration of abatacept over 24 months, the decrease in ß-cell function with abatacept was parallel to that with placebo after 6 months of treatment, causing us to speculate that T-cell activation lessens with time. Further observation will establish whether the beneficial effect continues after cessation of abatacept infusions. FUNDING: US National Institutes of Health.
Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Inmunosupresores/uso terapéutico , Abatacept , Adolescente , Adulto , Autoinmunidad , Niño , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/fisiopatología , Método Doble Ciego , Femenino , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/inmunología , Inmunosupresores/efectos adversos , Células Secretoras de Insulina/fisiología , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Linfocitos T/inmunología , Adulto JovenRESUMEN
BACKGROUND: Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. We aimed to assess whether immunisation with GAD formulated with aluminum hydroxide (GAD-alum) would preserve insulin production in recent-onset type 1 diabetes. METHODS: Patients aged 3-45 years who had been diagnosed with type 1 diabetes for less than 100 days were enrolled from 15 sites in the USA and Canada, and randomly assigned to receive one of three treatments: three injections of 20 µg GAD-alum, two injections of 20 µg GAD-alum and one of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The randomisation sequence was computer generated at the TrialNet coordinating centre. Patients and study personnel were masked to treatment assignment. The primary outcome was the baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in glycated haemoglobin A(1c) (HbA(1c)) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with ClinicalTrials.gov, number NCT00529399. FINDINGS: 145 patients were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or alum (n=48). At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0·412 nmol/L (95% CI 0·349-0·478) in the GAD-alum group, 0·382 nmol/L (0·322-0·446) in the GAD-alum plus alum group, and 0·413 nmol/L (0·351-0·477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0·998 (95% CI 0·779-1·22; p=0·98) for GAD-alum versus alum, and 0·926 (0·720-1·13; p=0·50) for GAD-alum plus alum versus alum. HbA(1c), insulin use, and the occurrence and severity of adverse events did not differ between groups. INTERPRETATION: Antigen-based immunotherapy therapy with two or three doses of subcutaneous GAD-alum across 4-12 weeks does not alter the course of loss of insulin secretion during 1 year in patients with recently diagnosed type 1 diabetes. Although antigen-based therapy is a highly desirable treatment and is effective in animal models, translation to human autoimmune disease remains a challenge. FUNDING: US National Institutes of Health.
Asunto(s)
Enfermedades Autoinmunes/terapia , Diabetes Mellitus Tipo 1/terapia , Glutamato Descarboxilasa/uso terapéutico , Inmunoterapia Activa , Adolescente , Antígenos/inmunología , Antígenos/uso terapéutico , Enfermedades Autoinmunes/inmunología , Canadá , Niño , Preescolar , Diabetes Mellitus Tipo 1/inmunología , Método Doble Ciego , Femenino , Glutamato Descarboxilasa/inmunología , Humanos , Masculino , Persona de Mediana Edad , Estados Unidos , Adulto JovenRESUMEN
Recently described forkhead box protein 3 (FoxP3) transcription factor is a key molecule in CD4+ CD25hi+ T-cell characterization. Invariant NK T (iNKT) cells are also characterized as regulatory cells modulating the immune response by rapidly producing T(h)1 and T(h)2 cytokines. We aimed to analyze cellular markers important in regulatory features of human iNKT cells and to study their role in functional assays. iNKT cells were single cell sorted from peripheral mononuclear cells of healthy individuals after immunostaining of invariant TCR α-chain. We found FoxP3 expression in human iNKT clones. Randomly selected iNKT cell clones (CD4+, double negative, CD8+) expressed FoxP3 mRNA and protein at different levels upon stimulation as supported by various approaches. FoxP3 mRNA and protein expression was detected in unstimulated iNKT cells as well. Furthermore, different stimulations changed the FoxP3 expression in iNKT cells over time and the most dramatic changes were observed upon anti-CD3 stimulation. Both the supernatant of iNKT cells and iNKT cells themselves exerted similar stimulation effects on PBMC proliferation in functional assays and these stimulations showed a negative correlation with FoxP3 expression. Our data indicate that the FoxP3 expression in iNKT cells may be a key transcriptional factor in controlling the regulatory function of the iNKT cells.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Células T Asesinas Naturales/inmunología , Proliferación Celular , Células Cultivadas , Citocinas/biosíntesis , Epítopos/inmunología , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica/inmunología , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Activación de Linfocitos/inmunología , Células T Asesinas Naturales/metabolismo , ARN Mensajero/genética , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
The secretion of IL-9, initially recognized as a Th2 cytokine, was recently attributed to a novel CD4 T cell subset termed Th9 in the murine system. However, IL-9 can also be secreted by mouse Th17 cells and may mediate aspects of the proinflammatory activities of Th17 cells. Here we report that IL-9 is secreted by human naive CD4 T cells in response to differentiation by Th9 (TGF-beta and IL-4) or Th17 polarizing conditions. Yet, these differentiated naive cells did not coexpress IL-17 and IL-9, unless they were repeatedly stimulated under Th17 differentiation-inducing conditions. In contrast to the naive cells, memory CD4 T cells were induced to secrete IL-9 by simply providing TGF-beta during stimulation, as neither IL-4 nor proinflammatory cytokines were required. Furthermore, the addition of TGF-beta to the Th17-inducing cytokines (IL-1beta, IL-6, IL-21, IL-23) that induce memory cells to secrete IL-17, resulted in the marked coexpression of IL-9 in IL-17 producing memory cells. The proinflammatory cytokine mediating TGF-beta-dependent coexpression of IL-9 and IL-17 was identified to be IL-1beta. Moreover, circulating monocytes were potent costimulators of IL-9 production by Th17 cells via their capacity to secrete IL-1beta. Finally, to determine whether IL-9/IL-17 coproducing CD4 cells were altered in an inflammatory condition, we examined patients with autoimmune diabetes and demonstrated that these subjects exhibit a higher frequency of memory CD4 cells with the capacity to transition into IL-9(+)IL-17(+) cells. These data demonstrate the presence of IL-17(+)IL-9(+) CD4 cells induced by IL-1beta that may play a role in human autoimmune disease.
Asunto(s)
Interleucina-17/biosíntesis , Interleucina-9/biosíntesis , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Factor de Crecimiento Transformador beta1/fisiología , Adulto , Polaridad Celular/inmunología , Células Cultivadas , Técnicas de Cocultivo , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Regulación de la Expresión Génica/inmunología , Humanos , Inmunohistoquímica , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/fisiología , Interleucina-9/genética , Interleucina-9/metabolismo , Persona de Mediana Edad , Fase de Descanso del Ciclo Celular/inmunología , Adulto JovenRESUMEN
Autoimmune diseases including type 1 diabetes (T1D) are thought to have a Th1/Th17 bias. The underlying mechanisms driving the activation and differentiation of these proinflammatory T cells are unknown. We examined the monocytes isolated directly from the blood of T1D patients and found they spontaneously secreted the proinflammatory cytokines IL-1beta and IL-6, which are known to induce and expand Th17 cells. Moreover, these in vivo-activated monocytes from T1D subjects induced more IL-17-secreting cells from memory T cells compared with monocytes from healthy control subjects. The induction of IL-17-secreting T cells by monocytes from T1D subjects was reduced in vitro with a combination of an IL-6-blocking Ab and IL-1R antagonist. In this study, we report a significant although modest increase in the frequency of IL-17-secreting cells in lymphocytes from long-term patients with T1D compared with healthy controls. These data suggest that the innate immune system in T1D may drive the adaptive immune system by expanding the Th17 population of effector T cells.
Asunto(s)
Diferenciación Celular/inmunología , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Mediadores de Inflamación/fisiología , Interleucina-17/biosíntesis , Monocitos/inmunología , Células TH1/inmunología , Adolescente , Adulto , Recuento de Linfocito CD4 , Proliferación Celular , Niño , Técnicas de Cocultivo , Citocinas/sangre , Citocinas/fisiología , Diabetes Mellitus Tipo 1/patología , Femenino , Humanos , Inmunidad Innata , Memoria Inmunológica , Mediadores de Inflamación/sangre , Interleucina-17/sangre , Interleucina-17/metabolismo , Interleucina-1beta/sangre , Interleucina-1beta/metabolismo , Interleucina-6/sangre , Interleucina-6/metabolismo , Masculino , Monocitos/metabolismo , Monocitos/patología , Células TH1/metabolismo , Células TH1/patología , Adulto JovenRESUMEN
There is a growing body of evidence to suggest that the autoimmunity observed in type 1 diabetes mellitus (T1DM) is the result of an imbalance between autoaggressive and regulatory cell subsets. Therapeutics that supplement or enhance the existing regulatory subset are therefore a much sought after goal in this indication. Here, we report the results of a double blind, placebo controlled, phase I clinical trial of a novel antigen-specific therapeutic in 12 subjects with recently diagnosed T1DM. Our primary objective was to test its safety. The study drug, human insulin B-chain in incomplete Freund's adjuvant (IFA) was administered as a single intramuscular injection, with subjects followed for 2 years. All subjects completed therapy and all follow-up visits. The therapy was generally safe and well-tolerated. Mixed meal stimulated C-peptide responses, measured every 6 months, showed no statistical differences between arms. All patients vaccinated with the autoantigen, but none who received placebo, developed robust insulin-specific humoral and T cell responses. Up to two years following the single injection, in peripheral blood from subjects in the experimental arm, but not the control arm, insulin B-chain-specific CD4+ T cells could be isolated and cloned that showed phenotypic and functional characteristics of regulatory T cells. The induction of a lasting, robust immune response generating autoantigen-specific regulatory T cells provides strong justification for further testing of this therapy in type 1 diabetes. (clinicaltrials.gov identifier NCT00057499).
Asunto(s)
Autoantígenos/administración & dosificación , Insulina/administración & dosificación , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Autoantígenos/uso terapéutico , Autoinmunidad/efectos de los fármacos , Proliferación Celular , Células Clonales/inmunología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/terapia , Método Doble Ciego , Humanos , Inmunoterapia , Insulina/inmunología , Insulina/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Resultado del Tratamiento , Vacunación , Adulto JovenRESUMEN
Cell surface determinants, cytokines and antibodies secreted by hematopoietic cells are used to classify their lineage and function. Currently available techniques are unable to elucidate multiple secreted proteins while also assigning phenotypic surface-displayed markers to the individual living cells. Here, a soft lithographic method, microengraving, was adapted for the multiplexed interrogation of populations of individual human peripheral blood mononuclear cells for secreted cytokines (IFN-gamma and IL-6), antigen-specific antibodies, and lineage-specific surface-expressed markers. Application of the method to a clinical sample from a recent-onset Type 1 diabetic subject with a positive titer of anti-insulin antibodies showed that approximately 0.58% of circulating CD19(+) B cells secreted proinsulin-reactive antibodies of the IgG isotype and 2-3% of circulating cells secreted IL-6. These data demonstrate the utility of microengraving for interrogating multiple phenotypes of single human cells concurrently and for detecting rare populations of cells by their secreted products.
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Anticuerpos/análisis , Citocinas/análisis , Inmunoensayo/métodos , Leucocitos Mononucleares/inmunología , Análisis de Matrices Tisulares/métodos , Anticuerpos/inmunología , Citocinas/inmunología , Humanos , Interferón gamma/análisis , Interferón gamma/inmunología , Interleucina-6/análisis , Interleucina-6/inmunología , Leucocitos Mononucleares/metabolismoRESUMEN
BACKGROUND: We report the immunological and pathological findings of a 52-year-old woman, who died two years after the second of two islet transplants performed using the Edmonton protocol. After each islet transplant, she gradually lost insulin independence while maintaining low levels of C-peptide secretion. METHODS: A complete autopsy was performed including pathological and immunohistochemical analysis of hepatic allogeneic islets and native pancreatic islets to identify rejection or autoimmunity. Elispots assays for allogeneic sensitization and autoantibody assays for autoimmunity were performed antemortem after her islet transplantations to test in vitro for evidence of allogeneic sensitization or autoimmunity. RESULTS: The cause of death was a hypertensive stroke. Small numbers of islets without inflammation were identified within portal venules and stained with insulin. The atrophic pancreas contained small numbers of islets, which stained for insulin, and lacked any inflammation within or adjacent to the islets. In vitro assays for alloantibodies were negative, and Elispots assays failed to identify allogeneic sensitization. In vitro assays for diabetic associated autoantibodies did not identify autoimmune resensitization. The allografted kidney showed only early changes of recurrent diabetic nephropathy, and no evidence of rejection. CONCLUSIONS: In summary, no evidence was found to support an immunological basis (either allo or autoimmunity) for the slow loss of intrahepatic islets, which may, therefore, be related to nonimmunological anatomic and physiological abnormalities of islets infused into the portal veins or to drug toxicity.
Asunto(s)
Diabetes Mellitus Tipo 1/cirugía , Rechazo de Injerto/patología , Supervivencia de Injerto , Trasplante de Islotes Pancreáticos , Islotes Pancreáticos/patología , Atrofia , Autopsia , Péptido C/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Resultado Fatal , Femenino , Hemoglobina Glucada/metabolismo , Rechazo de Injerto/inmunología , Rechazo de Injerto/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/sangre , Insulina/uso terapéutico , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/cirugía , Persona de Mediana Edad , Vena Porta/patología , Insuficiencia del TratamientoRESUMEN
Invariant NKT (iNKT) cells are considered to be important in some autoimmune diseases including Type 1 diabetes mellitus (T1DM). So far, the published data are contradictory in regard to the role of iNKT cells in T1DM. We aimed to study iNKT cell frequency and the function of different iNKT cell subgroups in T1DM. We compared the results of four subject groups: healthy (H), long-term T2DM (ltT2DM; more than 1 year), newly diagnosed T1DM (ndT1DM; less than 3 months), and ltT1DM (more than 1 year) individuals. We measured the iNKT cell frequencies by costaining for the invariant TCR alpha-chain with 6B11-FITC and Valpha24-PE. After sorting the Valpha24+6B11+ cells, the generated iNKT clones were characterized. We tested CD4, CD8, and CD161 expression and IL-4 and IFN-gamma production on TCR stimulation. The CD4+ population among the iNKT cells was decreased significantly in ltT1DM versus ndT1DM, ltT2DM, or H individuals. The T1DM iNKT cell cytokine profile markedly shifted to the Th1 direction. There was no difference in the frequency of iNKT cells in PBMC among the different patient groups. The decrease in the CD4+ population among the iNKT cells and their Th1 shift indicates dysfunction of these potentially important regulatory cells in T1DM.
Asunto(s)
Antígenos CD4/biosíntesis , Linfocitos T CD4-Positivos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Células Asesinas Naturales/inmunología , Células TH1/inmunología , Adulto , Antígenos de Superficie/biosíntesis , Antígenos CD8/biosíntesis , Recuento de Células , Células Cultivadas , Células Clonales , Femenino , Humanos , Interferón gamma/biosíntesis , Interleucina-4/biosíntesis , Células Asesinas Naturales/clasificación , Lectinas Tipo C/biosíntesis , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Subfamilia B de Receptores Similares a Lectina de Células NK , Receptores de Antígenos de Linfocitos T/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosRESUMEN
Insulin-dependent type 1 diabetes is an autoimmune disease mediated by T lymphocytes recognizing pancreatic islet cell antigens. Glutamic acid decarboxylase 65 (GAD65) appears to be an important autoantigen in the disease. However, T cells from both patients with type 1 diabetes and healthy subjects vigorously proliferate in response to GAD65 stimulation ex vivo, leading us to postulate that the critical event in the onset of human diabetes is the activation of autoreactive T cells. Thus, we investigated whether GAD65-reactive T cells in patients with diabetes functioned as previously activated memory T cells, no longer requiring a second, costimulatory signal for clonal expansion. We found that in patients with new-onset type 1 diabetes, GAD65-reactive T cells were strikingly less dependent on CD28 and B7-1 costimulation to enter into cell cycle and proliferate than were equivalent cells derived from healthy controls. We hypothesize that these autoreactive T cells have been activated in vivo and have differentiated into memory cells, suggesting a pathogenic role in type 1 diabetes. In addition, we observed different effects with selective blockade of either B7-1 or B7-2 molecules; B7-1 appears to deliver a negative signal by engaging CTLA-4, while B7-2 engagement of CD28 upregulates T cell proliferation and cytokine secretion.
Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Glutamato Descarboxilasa/inmunología , Inmunoconjugados , Isoenzimas/inmunología , Transducción de Señal/inmunología , Linfocitos T/inmunología , Abatacept , Adulto , Antígenos CD/inmunología , Antígenos de Diferenciación/inmunología , Autoinmunidad , Antígeno B7-1/inmunología , Antígeno B7-2 , Antígenos CD28/inmunología , Antígeno CTLA-4 , División Celular , Diabetes Mellitus Tipo 1/sangre , Femenino , Glutamato Descarboxilasa/farmacología , Humanos , Interferón gamma/biosíntesis , Interleucina-13/biosíntesis , Isoenzimas/farmacología , Masculino , Glicoproteínas de Membrana/inmunología , Linfocitos T/citología , Linfocitos T/efectos de los fármacosRESUMEN
CONTEXT: Human leukocyte antigen (HLA) DQ haplotypes have the strongest genetic association with type 1 diabetes (T1DM) risk. OBJECTIVE: The objective of the study was to analyze whether HLA DQ alleles influence the development of antiislet autoantibodies, the progression to T1DM among autoantibody-positive relatives, or both. DESIGN: The Diabetes Prevention Trial-1 screened more than 90,000 nondiabetic relatives of patients for cytoplasmic islet-cell autoantibody (ICA) expression between 1994 and 2002. SETTING: The study was conducted in the general community. PARTICIPANTS: The Diabetes Prevention Trial-1 found 2817 ICA-positive relatives who were tested for biochemical autoantibodies (GAD65, ICA512, and insulin) and HLA-DQ haplotypes, and 2796 of them were followed up for progression to diabetes for up to 8 yr (median, 3.6 yr). MAIN OUTCOME MEASURE: Progression to T1DM was measured. RESULTS: High-risk DQ haplotypes and genotypes were associated with a higher percentage of relatives expressing multiple biochemical autoantibodies and higher T1DM risk (e.g., respectively, 59 and 36% at 5 yr for carriers of the DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype). The number of autoantibodies expressed significantly increased T1DM risk and across different DQ genotypes, autoantibody positivity directly correlated with diabetes risk. However, multivariate analyses indicated that the influence of most genotypes on T1DM risk was not independent from autoantibody expression, with the possible exception of DQA1*0102-DQB1*0602. Specific genotypic combinations conferred 5-yr diabetes risks significantly lower (e.g. 7%-DQA1*0201-DQB1*0201/DQA1*0501-DQB1*0201 and 14%-DQA1*0301-DQB1*0301/DQA1*0501-DQB1*0201) than when those haplotypes were found in other combinations. CONCLUSION: HLA DQ alleles determine autoantibody expression, which is correlated with diabetes progression. Among autoantibody-positive relatives, most HLA DQ genotypes did not further influence T1DM risk.
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Autoanticuerpos/biosíntesis , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Antígenos HLA-DQ/genética , Islotes Pancreáticos/inmunología , Adolescente , Adulto , Alelos , Niño , Preescolar , Cromosomas Humanos Par 6/genética , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Genotipo , Haplotipos , Humanos , Tablas de Vida , Masculino , Análisis de SupervivenciaAsunto(s)
Autoanticuerpos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Enfermedades en Gemelos/inmunología , Islotes Pancreáticos/inmunología , Gemelos Monocigóticos/inmunología , Adolescente , Adulto , Autoinmunidad , Niño , Preescolar , Humanos , Lactante , Estudios Longitudinales , Persona de Mediana Edad , Adulto JovenRESUMEN
The objective of this study was to determine the extent to which different screening strategies could identify a population of nondiabetic relatives of a proband with type 1 diabetes who had two or more immunologic markers from the group consisting of islet cell antibodies (ICA), micro insulin autoantibodies (MIAA), GAD65 autoantibodies (GAA), and ICA512 autoantibodies (ICA512AA). Relatives of subjects with type 1 diabetes were screened for ICA as part of the Diabetes Prevention Trial-Type 1. A total of 71,148 samples were also tested for GAA and ICA512AA. IAA results were available on 17,207 of these samples using a protein A/protein G MIAA assay as well. The study population was defined to be those in which all four antibodies were tested. There were 1010 (5.9%) relatives with a single autoantibody on initial screening and 394 (2.3%) with two or more autoantibodies. GAA was more sensitive than ICA [GAA, 91% (357 of 394); ICA, 82% (324 of 394)] in the detection of multiple antibody-positive individuals. The addition of ICA512AA to GAA as a screening test increased sensitivity to 97% (381 of 394), whereas adding ICA512AA to ICA as a screening test increased sensitivity to 93% (367 of 394). GAA and ICA identified somewhat nonoverlapping subgroups of multiple antibody-positive subjects. Thus, the substitution of GAA or ICA for the other failed to detect 8-17% of multiple antibody subjects. Higher ICA titers were associated with increased percentages of multiple antibody-positive subjects; 86% of subjects having Juvenile Diabetes Foundation titers of at least 160 were positive for two or more antibodies. A screening strategy combining GAA and ICA512AA resulted in a higher sensitivity than using any marker individually, although statistically it was not significantly higher than using GAA alone. Screening for any three antibodies guaranteed that all multiple antibody-positive subjects were detected. Screening for two antibodies at one time and testing for the remaining antibodies among those who are positive for one resulted in a sensitivity of 99% for GAA and ICA, 97% for GAA and MIAA or GAA and ICA512AA, 93% for ICA512AA and ICA, 92% for MIAA and ICA, and 73% for ICA512AA and MIAA. From a laboratory perspective, screenings for GAA, ICA512AA, and MIAA are semiautomated tests with high throughput that, if used as initial screen, would identify at first testing 67% of the 2.3% of multiple antibody-positive relatives (100% if antibody-positive subjects are subsequently tested for ICA) as well as 4.7% of relatives with a single biochemical autoantibody, some of whom may convert to multiple autoantibody positivity on follow-up. Testing for ICA among relatives with one biochemical antibody would identify the remaining 33% of multiple antibody-positive relatives. Further follow-up and analysis of actual progression to diabetes will be essential to define actual diabetes risk in this large cohort.
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Autoanticuerpos/análisis , Diabetes Mellitus Tipo 1/inmunología , Tamizaje Masivo/métodos , Adolescente , Adulto , Niño , Femenino , Glutamato Descarboxilasa/inmunología , Humanos , Anticuerpos Insulínicos/análisis , Isoenzimas/inmunología , MasculinoRESUMEN
We previously reported that continuous 24-month costimulation blockade by abatacept significantly slows the decline of ß-cell function after diagnosis of type 1 diabetes. In a mechanistic extension of that study, we evaluated peripheral blood immune cell subsets (CD4, CD8-naive, memory and activated subsets, myeloid and plasmacytoid dendritic cells, monocytes, B lymphocytes, CD4(+)CD25(high) regulatory T cells, and invariant NK T cells) by flow cytometry at baseline and 3, 6, 12, 24, and 30 months after treatment initiation to discover biomarkers of therapeutic effect. Using multivariable analysis and lagging of longitudinally measured variables, we made the novel observation in the placebo group that an increase in central memory (CM) CD4 T cells (CD4(+)CD45R0(+)CD62L(+)) during a preceding visit was significantly associated with C-peptide decline at the subsequent visit. These changes were significantly affected by abatacept treatment, which drove the peripheral contraction of CM CD4 T cells and the expansion of naive (CD45R0(-)CD62L(+)) CD4 T cells in association with a significantly slower rate of C-peptide decline. The findings show that the quantification of CM CD4 T cells can provide a surrogate immune marker for C-peptide decline after the diagnosis of type 1 diabetes and that costimulation blockade may exert its beneficial therapeutic effect via modulation of this subset.
Asunto(s)
Péptido C/sangre , Linfocitos T CD4-Positivos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Inmunoconjugados/uso terapéutico , Inmunosupresores/uso terapéutico , Subgrupos de Linfocitos T/inmunología , Abatacept , Adolescente , Adulto , Niño , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Femenino , Humanos , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of ß-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Of 112 subjects (ages 6-36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years. The primary outcome-baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years-showed higher C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months. RESULTS C-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168-0.268) and 0.141 nmol/L (95% CI 0.071-0.215) for abatacept and placebo groups, respectively (P = 0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months' delay with abatacept. Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group. The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years. CONCLUSIONS Costimulation modulation with abatacept slowed decline of ß-cell function and improved HbA1c in recent-onset T1D. The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Inmunosupresores/uso terapéutico , Privación de Tratamiento , Abatacept , Adolescente , Adulto , Péptido C/sangre , Niño , Femenino , Estudios de Seguimiento , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Placebos , Adulto JovenRESUMEN
Abatacept delayed progression of type 1 diabetes (T1D) when administered soon after diagnosis. Its use in T1D is expanding to prevention trials and, therefore, it is important to fully characterize its immunosuppressive effect. We compared antibody responses to trivalent inactivated influenza vaccine (TIIV) administered during 2 consecutive seasons and to tetanus toxoid (TT) vaccine administered after 24 months of treatment in115 early onset T1D subjects randomly assigned to 24 months of abatacept (N=71) or placebo (N=34). Anti-influenza titers before TIIV were similar between the 2 treatment groups and both groups had significant increases after vaccination. Although the magnitude of antibody responses against some influenza serotypes was significantly lower (p<0.05) in abatacept compared with placebo recipients, no differences were observed in the proportion of subjects with protective titers against influenza after vaccination. The magnitude of antibody responses against TT also tended to be lower (p=0.06) in abatacept compared with placebo recipients, without affecting the proportion of subjects who achieved protective titers. We conclude that abatacept moderately decreases the magnitude of antibody responses to recall vaccination. Further studies are needed to assess its effect on primary immunization.
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Diabetes Mellitus Tipo 1/inmunología , Inmunoconjugados/administración & dosificación , Inmunosupresores/administración & dosificación , Vacunas contra la Influenza/inmunología , Toxoide Tetánico/inmunología , Abatacept , Adolescente , Adulto , Anticuerpos Antibacterianos/sangre , Anticuerpos Antivirales/sangre , Niño , Femenino , Humanos , Vacunas contra la Influenza/administración & dosificación , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Toxoide Tetánico/administración & dosificación , Adulto JovenRESUMEN
Type 1 diabetes mellitus (T1DM) affects 1 in 300 people and the incidence of the disease is rising worldwide. T1DM is caused by chronic autoimmune destruction of the insulin-producing ß-cells. The exact etiology and primary auto-antigen are not yet known. The autoimmune, chronic, and progressive nature of the disease raises the possibility of intervention, preferably by slowing down or stopping the destruction of the ß-cells as early as the prediabetic stage. Since the 1980s, several attempts have been made to maintain ß-cell function using immunosuppressive agents, immune modulation such as plasmapheresis, cytokine therapy, or antibody treatment. These agents were not diabetes specific; the occasionally observed beneficial effect did not compensate for the often very severe side effects. According to the latest assumption, the administration of diabetes-specific auto-antigens can elicit tolerance, which can prevent the destruction of the ß-cells, hopefully without serious side effects. The authors summarize current understanding of the immunology of T1DM, review the trials on prevention, and discuss their vaccination study.
RESUMEN
OBJECTIVE: We examined changes in GAD65 and ICA-512 autoantibodies (GADA and IA-2A) during progression to type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Diabetes Prevention Trial-Type 1 (DPT-1) participants were assessed for changes in positivity and titers of GADA and IA-2A during the progression to T1D. RESULTS: Among 99 progressors to T1D with GADA and IA-2A measurements at baseline and diagnosis (mean interval = 3.3 ± 1.5 years), GADA positivity changed little and GADA titers decreased (P < 0.01). In contrast, both IA-2A positivity and titers increased substantially (P < 0.001). Even among those positive at baseline, IA-2A titers increased from baseline to diagnosis (n = 57; P < 0.001), whereas GADA titers decreased (n = 80; P < 0.01). The same patterns of change were also evident among those positive for both autoantibodies (n = 48) at baseline. CONCLUSIONS: IA-2A titers increase during the years before the diagnosis of T1D, even among those positive for IA-2A. In contrast, GADA titers tend to decline during those years.