Immunotherapy: Building a bridge to a cure for type 1 diabetes Bluestone, Jeffrey A; Buckner, Jane H; Herold, Kevan C
Science (American Association for the Advancement of Science),
2021-Jul-30, 2021-07-30, 20210730, Letnik:
373, Številka:
6554
Journal Article
Recenzirano
Type 1 diabetes (T1D) is an autoimmune disease in which T cells attack and destroy the insulin-producing β cells in the pancreatic islets. Genetic and environmental factors increase T1D risk by ...compromising immune homeostasis. Although the discovery and use of insulin have transformed T1D treatment, insulin therapy does not change the underlying disease or fully prevent complications. Over the past two decades, research has identified multiple immune cell types and soluble factors that destroy insulin-producing β cells. These insights into disease pathogenesis have enabled the development of therapies to prevent and modify T1D. In this review, we highlight the key events that initiate and sustain pancreatic islet inflammation in T1D, the current state of the immunological therapies, and their advantages for the treatment of T1D.
Children and youth infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have milder disease than do adults, and even among those with the recently described multisystem ...inflammatory syndrome, mortality is rare. The reasons for the differences in clinical manifestations are unknown but suggest that age-dependent factors may modulate the antiviral immune response. We compared cytokine, humoral, and cellular immune responses in pediatric (children and youth, age <24 years) (
= 65) and adult (
= 60) patients with coronavirus disease 2019 (COVID-19) at a metropolitan hospital system in New York City. The pediatric patients had a shorter length of stay, decreased requirement for mechanical ventilation, and lower mortality compared to adults. The serum concentrations of interleukin-17A (IL-17A) and interferon-γ (IFN-γ), but not tumor necrosis factor-α (TNF-α) or IL-6, were inversely related to age. Adults mounted a more robust T cell response to the viral spike protein compared to pediatric patients as evidenced by increased expression of CD25
on CD4
T cells and the frequency of IFN-γ
CD4
T cells. Moreover, serum neutralizing antibody titers and antibody-dependent cellular phagocytosis were higher in adults compared to pediatric patients with COVID-19. The neutralizing antibody titer correlated positively with age and negatively with IL-17A and IFN-γ serum concentrations. There were no differences in anti-spike protein antibody titers to other human coronaviruses. Together, these findings demonstrate that the poor outcome in hospitalized adults with COVID-19 compared to children may not be attributable to a failure to generate adaptive immune responses.
Type 1 diabetes (T1D) is a chronic autoimmune disease that involves immune-mediated destruction of β cells. How β cells respond to immune attack is unknown. We identified a population of β cells ...during the progression of T1D in non-obese diabetic (NOD) mice that survives immune attack. This population develops from normal β cells confronted with islet infiltrates. Pathways involving cell movement, growth and proliferation, immune responses, and cell death and survival are activated in these cells. There is reduced expression of β cell identity genes and diabetes antigens and increased immune inhibitory markers and stemness genes. This new subpopulation is resistant to killing when diabetes is precipitated with cyclophosphamide. Human β cells show similar changes when cultured with immune cells. These changes may account for the chronicity of the disease and the long-term survival of β cells in some patients.
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•Novel β cells with lower granularity develop during progression of T1D in NOD mice•The novel β cells show decreased expression of markers of mature β cells•The novel β cells are protected from immune killing•The novel β cells are less differentiated and show stem-like features
Type 1 diabetes (T1D) is due to the immune-mediated destruction of β cells. Rui et al. identify a population of β cells that survives immune attack during T1D progression in non-obese diabetic mice, which may account for the long-term survival of some β cells in patients.
BACKGROUNDCoronavirus disease 2019 (COVID-19) is more benign in children compared with adults for unknown reasons. This contrasts with other respiratory viruses where disease manifestations are often ...more severe in children. We hypothesize that a more robust early innate immune response to SARS coronavirus 2 (SARS-CoV-2) protects against severe disease.METHODSClinical outcomes, SARS-CoV-2 viral copies, and cellular gene expression were compared in nasopharyngeal swabs obtained at the time of presentation to the emergency department from 12 children and 27 adults using bulk RNA sequencing and quantitative reverse-transcription PCR. Total protein, cytokines, and anti-SARS-CoV-2 IgG and IgA were quantified in nasal fluid.RESULTSSARS-CoV-2 copies, angiotensin-converting enzyme 2, and TMPRSS2 gene expression were similar in children and adults, but children displayed higher expression of genes associated with IFN signaling, NLRP3 inflammasome, and other innate pathways. Higher levels of IFN-α2, IFN-γ, IP-10, IL-8, and IL-1β protein were detected in nasal fluid in children versus adults. Children also expressed higher levels of genes associated with immune cells, whereas expression of those associated with epithelial cells did not differ in children versus adults. Anti-SARS-CoV-2 IgA and IgG were detected at similar levels in nasal fluid from both groups. None of the children required supplemental oxygen, whereas 7 adults did (P = 0.03); 4 adults died.CONCLUSIONThese findings provide direct evidence of a more vigorous early mucosal immune response in children compared with adults and suggest that this contributes to favorable clinical outcomes.FUNDINGNIH grants R01 AI134367, UL1 TR002556, T32 AI007501, T32GM007288, P30 AI124414; an Albert Einstein College of Medicine Dean's COVID-19 Pilot Research Award; and the Eric J. Heyer, MD, PhD Translational Research Pilot Project Award.
Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but ...predictable rates through distinct identifiable stages prior to the onset of symptoms. Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease. Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease.
Current methods for comparing single-cell RNA sequencing datasets collected in multiple conditions focus on discrete regions of the transcriptional state space, such as clusters of cells. Here we ...quantify the effects of perturbations at the single-cell level using a continuous measure of the effect of a perturbation across the transcriptomic space. We describe this space as a manifold and develop a relative likelihood estimate of observing each cell in each of the experimental conditions using graph signal processing. This likelihood estimate can be used to identify cell populations specifically affected by a perturbation. We also develop vertex frequency clustering to extract populations of affected cells at the level of granularity that matches the perturbation response. The accuracy of our algorithm at identifying clusters of cells that are enriched or depleted in each condition is, on average, 57% higher than the next-best-performing algorithm tested. Gene signatures derived from these clusters are more accurate than those of six alternative algorithms in ground truth comparisons.
Following type 1 diabetes (T1D) diagnosis, declining C-peptide levels reflect deteriorating β cell function. However, the precise C-peptide levels that indicate protection from severe hypoglycemia ...remain unknown. In this issue of the JCI, Gubitosi-Klug et al. studied participants from the landmark and ongoing Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study that had long-standing (about 35 years) T1D. The authors correlated severe hypoglycemia and other disease outcomes with residual C-peptide levels. While C-peptide secretion failed to associate with hemoglobin A1c (HbA1c) or microvascular complications, C-peptide levels greater than 0.03 nmol/L were linked with fewer episodes of severe hypoglycemia. These findings suggest that efforts to preserve finite β cell function early in T1D can have meaningful, long-standing health benefits for patients.
Studies over the past 35 years in the nonobese diabetic (NOD) mouse have shown that a number of agents can prevent or even reverse type 1 diabetes mellitus (T1DM); however, these successes have not ...been replicated in human clinical trials. Although some of these interventions have delayed disease onset or progression in subsets of participants, none have resulted in a complete cure. Even in the most robust responders, the treatments do not permanently preserve insulin secretion or stimulate the proliferation of β cells, as has been observed in mice. The shortfalls of translating NOD mouse studies into the clinic questions the value of using this model in preclinical studies. In this Perspectives, we suggest how immunological and genetic differences between NOD mice and humans might contribute to the differential outcomes and suggest ways in which the mouse model might be modified or applied as a tool to develop treatments and improve understanding of clinical trial outcomes.
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