187 research outputs found
APC-targeted proinsulin expression inactivates insulin-specific memory CD8+ T cells in NOD mice
Type 1 diabetes (T1D) results from T-cell-mediated autoimmune destruction of pancreatic ÎČ cells. Effector T-cell responses emerge early in disease development and expand as disease progresses. Following ÎČ-cell destruction, a long-lived T-cell memory is generated that represents a barrier to islet transplantation and other cellular insulin-replacement therapies. Development of effective immunotherapies that control or ablate ÎČ-cell destructive effector and memory T-cell responses has the potential to prevent disease progression and recurrence. Targeting antigen expression to antigen-presenting cells inactivates cognate CD8+ effector and memory T-cell responses and has therapeutic potential. Here we investigated this in the context of insulin-specific responses in the non-obese diabetic mouse where genetic immune tolerance defects could impact on therapeutic tolerance induction. Insulin-specific CD8+ memory T cells transferred to mice expressing proinsulin in antigen-presenting cells proliferated in response to transgenically expressed proinsulin and the majority were rapidly deleted. A small proportion of transferred insulin-specific Tmem remained undeleted and these were antigen-unresponsive, exhibited reduced T cell receptor (TCR) expression and H-2Kd/insB15-23 tetramer binding and expressed co-inhibitory molecules. Expression of proinsulin in antigen-presenting cells also abolished the diabetogenic capacity of CD8+ effector T cells. Therefore, destructive insulin-specific CD8+ T cells are effectively inactivated by enforced proinsulin expression despite tolerance defects that exist in diabetes-prone NOD mice. These findings have important implications in developing immunotherapeutic approaches to T1D and other T-cell-mediated autoimmune diseases
Early-life exposure to gut microbiota from disease protected mice does not impact disease outcome in type 1 diabetes susceptible NOD mice
The microbial community making up the gut microbiota can profoundly influence intestinal homeostasis and immune system development, and is believed to influence the development of complex diseases including type 1 diabetes (T1D). T1D susceptible non-obese diabetic (NOD) mice have been shown to harbour a distinct microbiota to disease protected mice. We hypothesised that the T1D susceptible genetic background of NOD mice would be resistant to the introduction of a C57BL/6 derived microbiota. NOD and C57BL/6 mice were cohoused either continually from birth, from birth until weaning or from weaning onwards, allowing transfer of microbiota between the mice. Cohousing NOD with C57BL/6 mice from before birth, resulted in moderate changes to the gut microbiota, whereas initiating co-housing at weaning only led to minimal changes. Terminating cohousing at weaning reduced the changes in the microbiota composition. However, diabetes onset was not significantly delayed and there was no reduction in intestinal inflammation or the proportion of regulatory T cells in the co-housed NOD mice. However, insulin but not IGRP-specific CD8+ T cells were reduced by co-housing suggesting an epitope-specific modulation of the autoreactive response by the gut microbiota. These results suggest that the T1D susceptible genetic background of the NOD mouse was resistant to the introduction of a C57BL/6 derived microbiota. This article is protected by copyright. All rights reserved
Idd9.2 and Idd9.3 Protective Alleles Function in CD4+ T-Cells and Nonlymphoid Cells to Prevent Expansion of Pathogenic Islet-Specific CD8+ T-Cells
OBJECTIVE - Multiple type 1 diabetes susceptibility genes have now been identified in both humans and mice, yet mechanistic understanding of how they impact disease pathogenesis is still minimal. We have sought to dissect the cellular basis for how the highly protective mouse Idd9 region limits the expansion of autoreactive CD8 T-cells, a key cell type in destruction of the islets. RESEARCH DESIGN AND METHODS - We assess the endogenous CD8 T-cell repertoire for reactivity to the islet antigen glucose-6-phosphatase-related protein (IGRP). Through the use of adoptively transferred T-cells, bone marrow chimeras, and reconstituted severe combined immunodeficient mice, we identify the protective cell types involved. RESULTS - IGRP-specific CD8 T-cells are present at low frequency in the insulitic lesions of Idd9 mice and could not be recalled in the periphery by viral expansion. We show that Idd9 genes act extrinsically to the CD8 T-cell to prevent the massive expansion of pathogenic effectors near the time of disease onset that occurs in NOD mice. The subregions Idd9.2 and Idd9.3 mediated this effect. Interestingly, the Idd9.1 region, which provides significant protection from disease, did not prevent the expansion of autoreactive CD8 T-cells. Expression of Idd9 genes was required by both CD4 T-cells and a nonlymphoid cell to induce optimal tolerance. CONCLUSIONS - Idd9 protective alleles are associated with reduced expansion of IGRP-specific CD8 T-cells. Intrinsic expression of protective Idd9 alleles in CD4 T-cells and nonlymphoid cells is required to achieve an optimal level of tolerance. Protective alleles in the Idd9.2 congenic subregion are required for the maximal reduction of islet-specific CD8 T-cells
Should we screen for intracranial aneurysms (IAs) in systemic hypertension at the time of cardiac magnetic resonance (CMR)?
Isletâspecific CD8+ T cells gain effector function in the gut lymphoid tissues via bystander activation not molecular mimicry
Type 1 diabetes (T1D) is caused by aberrant activation of autoreactive T cells specific for the islet beta cells. How isletâspecific T cells evade tolerance to become effector T cells is unknown, but it is believed that an altered gut microbiota plays a role. Possible mechanisms include bystander activation of autoreactive T cells in the gut or âmolecular mimicryâ from crossâreactivity between gut microbiotaâderived peptides and isletâderived epitopes. To investigate these mechanisms, we use two isletâspecific CD8+ T cell clones and the nonâobese diabetic mouse model of type 1 diabetes. Both insulinâspecific G9C8 cells and IGRPâspecific 8.3 cells underwent early activation and proliferation in the pancreatic draining lymph nodes but not in the Peyer's patches or mesenteric lymph nodes. Mutation of the endogenous epitope for G9C8 cells abolished their CD69 upregulation and proliferation, ruling out G9C8 cell activation by a gut microbiota derived peptide and molecular mimicry. However, previously activated isletâspecific effector memory cells but not naĂŻve cells migrated into the Peyer's patches where they increased their cytotoxic function. Oral delivery of butyrate, a microbiota derived antiâinflammatory metabolite, reduced IGRPâspecific cytotoxic function. Thus, while initial activation of isletâspecific CD8+ T cells occurred in the pancreatic lymph nodes, activated cells trafficked through the gut lymphoid tissues where they gained additional effector function via nonâspecific bystander activation influenced by the gut microbiota
Antibody levels following vaccination against SARS-CoV-2: associations with post-vaccination infection and risk factors
SARS-CoV-2 antibody levels can be used to assess humoral immune responses following SARS-CoV-2 infection or vaccination, and may predict risk of future infection. From cross-sectional antibody testing of 9,361 individuals from TwinsUK and ALSPAC UK population-based longitudinal studies (jointly in April-May 2021, and TwinsUK only in November 2021-January 2022), we tested associations between antibody levels following vaccination and: (1) SARS-CoV-2 infection following vaccination(s); (2) health, socio-demographic, SARS-CoV-2 infection and SARS-CoV-2 vaccination variables. Within TwinsUK, single-vaccinated individuals with the lowest 20% of anti-Spike antibody levels at initial testing had 3-fold greater odds of SARS-CoV-2 infection over the next six to nine months, compared to the top 20%. In TwinsUK and ALSPAC, individuals identified as at increased risk of COVID-19 complication through the UK "Shielded Patient List" had consistently greater odds (2 to 4-fold) of having antibody levels in the lowest 10%. Third vaccination increased absolute antibody levels for almost all individuals, and reduced relative disparities compared with earlier vaccinations. These findings quantify the association between antibody level and risk of subsequent infection, and support a policy of triple vaccination for the generation of protective antibodies
Rheumatoid arthritis - treatment: 180. Utility of Body Weight Classified Low-Dose Leflunomide in Japanese Rheumatoid Arthritis
Background: In Japan, more than 20 rheumatoid arthritis (RA) patients died of interstitial pneumonia (IP) caused by leflunomide (LEF) were reported, but many of them were considered as the victims of opportunistic infection currently. In this paper, efficacy and safety of low-dose LEF classified by body weight (BW) were studied. Methods: Fifty-nine RA patients were started to administrate LEF from July 2007 to July 2009. Among them, 25 patients were excluded because of the combination with tacrolimus, and medication modification within 3 months before LEF. Remaining 34 RA patients administered 20 to 50âmg/week of LEF were followed up for 1 year and enrolled in this study. Dose of LEF was classified by BW (50âmg/week for over 50âkg, 40âmg/week for 40 to 50âkg and 20 to 30âmg/week for under 40âkg). The average age and RA duration of enrolled patients were 55.5 years old and 10.2 years. Prednisolone (PSL), methotrexate (MTX) and etanercept were used in 23, 28 and 2 patients, respectively. In case of insufficient response or adverse effect, dosage change or discontinuance of LEF were considered. Failure was defined as dosages up of PSL and MTX, or dosages down or discontinuance of LEF. Last observation carried forward method was used for the evaluation of failed patients at 1 year. Results: At 1 year after LEF start, good/ moderate/ no response assessed by the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score, including a 28-joint count (DAS28)-C reactive protein (CRP) were showed in 14/ 10/ 10 patients, respectively. The dosage changes of LEF at 1 year were dosage up: 10, same dosage: 5, dosage down: 8 and discontinuance: 11 patients. The survival rate of patients in this study was 23.5% (24 patients failed) but actual LEF continuous rate was 67.6% (11 patients discontinued) at 1 year. The major reason of failure was liver dysfunction, and pneumocystis pneumonia was occurred in 1 patient resulted in full recovery. One patient died of sepsis caused by decubitus ulcer infection. DAS28-CRP score was decreased from 3.9 to 2.7 significantly. Although CRP was decreased from 1.50 to 0.93âmg/dl, it wasn't significant. Matrix metalloproteinase (MMP)-3 was decreased from 220.0 to 174.2âng/ml significantly. Glutamate pyruvate transaminase (GPT) was increased from 19 to 35 U/l and number of leukocyte was decreased from 7832 to 6271 significantly. DAS28-CRP, CRP, and MMP-3 were improved significantly with MTX, although they weren't without MTX. Increase of GPT and leukopenia were seen significantly with MTX, although they weren't without MTX. Conclusions: It was reported that the risks of IP caused by LEF in Japanese RA patients were past IP history, loading dose administration and low BW. Addition of low-dose LEF is a potent safe alternative for the patients showing unsatisfactory response to current medicines, but need to pay attention for liver function and infection caused by leukopenia, especially with MTX. Disclosure statement: The authors have declared no conflicts of interes
Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.
Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant
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