scholarly journals A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes

2021 ◽  
Author(s):  
Ashish K Marwaha ◽  
Samuel Chow ◽  
Anne M Pesenacker ◽  
Laura Cook ◽  
Annika Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Immune Cell ◽  
Dose Finding ◽  
Mechanistic Study ◽  
Open Label ◽  
C Peptide ◽  
Label Dose ◽  
Ifn Γ

Abstract Aim We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (<100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia. Methods We sequentially enrolled 20 participants into four subcutaneous dosing cohorts: i) 45mg loading-weeks 0/4/16, ii) 45mg maintenance-weeks 0/4/16/28/40, iii) 90mg loading-weeks 0/4/16 and iv) 90mg maintenance-weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses. Results Although several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90mg maintenance dosing cohort had the smallest mean decline in C-peptide AUC (0.1pmol/mL). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1 and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A. Conclusion Ustekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response.

scholarly journals Rationale and study design of the Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D): a non-randomised, open label, adaptive dose finding trial

BMJ Open ◽  
2014 ◽  
Vol 4 (6) ◽  
pp. e005559-e005559 ◽  
Author(s):  
F. Waldron-Lynch ◽  
P. Kareclas ◽  
K. Irons ◽  
N. M. Walker ◽  
A. Mander ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Study Design ◽  
Dose Finding ◽  
Open Label

scholarly journals Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

PLoS Medicine ◽  
2016 ◽  
Vol 13 (10) ◽  
pp. e1002139 ◽  
Author(s):  
John A. Todd ◽  
Marina Evangelou ◽  
Antony J. Cutler ◽  
Marcin L. Pekalski ◽  
Neil M. Walker ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Single Dose ◽  
T Cell ◽  
Regulatory T Cell ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Dose Finding ◽  
Open Label ◽  
Cell Responses

scholarly journals Targeting regulatory T cells with Interleukin-2 treatment in type 1 diabetes: a response-adaptive, non-randomised, open-label trial of repeat doses of Aldesleukin (DILfrequency)

2017 ◽  
Author(s):  
Eleonora Seelig ◽  
James Howlett ◽  
Linsey Porter ◽  
Lucy Truman ◽  
James Heywood ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Steady State ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
Dose Frequency ◽  
Open Label ◽  
Adaptive Trial ◽  
Optimal Regimen

SummaryBackgroundType 1 diabetes (T1D) results from loss of immune regulation leading to the development of autoimmunity to pancreatic beta-cells, involving autoreactive T effector cells (Teffs). Regulatory T cells (Tregs), that prevent autoimmunity, require Interleukin-2 (IL-2) for maintenance of immunosuppressive functions and, alterations in the IL-2 pathway predispose to T1D. Using an adaptive trial design we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of autoreactive Teffs.MethodsDILfrequency is a single-center, non-randomised, open-label, response-adaptive study of participants aged 18 to 70 years with T1D. The initial learning phase allocated 12 participants to six different predefined dose-frequency regimens. Then, three cohorts of 8 participants were sequentially allocated dose-frequencies, based on repeated interim analyses of all accumulated trial data. The co-primary endpoints were percentage change in Tregs, Teffs and, CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. Trial registration ISRCTN40319192 and ClinicalTrials.gov (NCT02265809).Findings115 participants were assessed between November 17th 2014 and May 22nd 2016, 38 participants were enrolled with 36 completing treatment. The optimal regimen to maintain a steady state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 × 106 IU/m2 (95% CI (−0.007 to 0.485)) every 3 days (1.3 to 4.4). Tregs and CD25 were dose-frequency responsive, while Teffs were not. The commonest adverse event was injection site reaction (464/694 events), with a single participant developing transient eosinophilia at the highest dose (0.47 × 106 IU/m2).InterpretationThis response-adaptive trial defined a well-tolerated aldesleukin regimen that specifically induces Treg expansion that can now be trialled to treat T1D.FundingSir Jules Thorn Trust, Wellcome, JDRF, SNSF, NIHR

The CYP27B1 polymorphism and the IFN-γ production of T-cells in type 1 diabetes

2014 ◽  
Vol 122 (03) ◽  
Author(s):  
Y Morán-Auth ◽  
M Penna-Martinez ◽  
K Lasotha ◽  
V Harant ◽  
K Badenhoop
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Ifn Γ

scholarly journals Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes

2017 ◽  
Vol 9 (402) ◽  
pp. eaaf7779 ◽  
Author(s):  
Mohammad Alhadj Ali ◽  
Yuk-Fun Liu ◽  
Sefina Arif ◽  
Danijela Tatovic ◽  
Hina Shariff ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Immune Modulation ◽  
Cell Function ◽  
Human Leukocyte ◽  
Foxp3 Expression ◽  
Interleukin 10 ◽  
Β Cell ◽  
C Peptide

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen–DR4(DRB1*0401)–restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group’s daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell–specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.

scholarly journals B Quiet: Autoantigen-Specific Strategies to Silence Raucous B Lymphocytes and Halt Cross-Talk with T Cells in Type 1 Diabetes

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 42
Author(s):  
Jamie L. Felton ◽  
Holly Conway ◽  
Rachel H. Bonami
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cell ◽  
B Lymphocytes ◽  
Cell Function ◽  
Immune Cell ◽  
Disease Risk ◽  
Significant Risk

Islet autoantibodies are the primary biomarkers used to predict type 1 diabetes (T1D) disease risk. They signal immune tolerance breach by islet autoantigen-specific B lymphocytes. T-B lymphocyte interactions that lead to expansion of pathogenic T cells underlie T1D development. Promising strategies to broadly prevent this T-B crosstalk include T cell elimination (anti-CD3, teplizumab), B cell elimination (anti-CD20, rituximab), and disruption of T cell costimulation/activation (CTLA-4/Fc fusion, abatacept). However, global disruption or depletion of immune cell subsets is associated with significant risk, particularly in children. Therefore, antigen-specific therapy is an area of active investigation for T1D prevention. We provide an overview of strategies to eliminate antigen-specific B lymphocytes as a means to limit pathogenic T cell expansion to prevent beta cell attack in T1D. Such approaches could be used to prevent T1D in at-risk individuals. Patients with established T1D would also benefit from such targeted therapies if endogenous beta cell function can be recovered or islet transplant becomes clinically feasible for T1D treatment.

scholarly journals Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes

2020 ◽  
Author(s):  
C.C. Robertson ◽  
J.R.J. Inshaw ◽  
S. Onengut-Gumuscu ◽  
W.M. Chen ◽  
D. Flores Santa Cruz ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Protein Interactions ◽  
Drug Targets ◽  
Immune Cell ◽  
Causal Variant ◽  
Chromatin Accessibility ◽  
High Yield ◽  
Causal Variants

AbstractWe report the largest and most ancestrally diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 152 regions associated to false discovery rate < 0.01, including 36 regions associated to genome-wide significance for the first time. Credible sets of disease-associated variants are specifically enriched in immune cell accessible chromatin, particularly in CD4+ effector T cells. Colocalization with chromatin accessibility quantitative trait loci (QTL) in CD4+ T cells identified five regions where differences in T1D risk and chromatin accessibility are potentially driven by the same causal variant. Allele-specific chromatin accessibility further refined the set of putative causal variants with functional relevance in CD4+ T cells and integration of whole blood expression QTLs identified candidate T1D genes, providing high-yield targets for mechanistic follow-up. We highlight rs72938038 in BACH2 as a candidate causal T1D variant, where the T1D risk allele leads to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritise potential drug targets by integrating genetic evidence, functional genomic maps, and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D, including proposed genetic regulatory mechanisms of T1D-associated variants and genetic support for therapeutic targets for immune intervention.

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