Article Text
Abstract
Objective Here we looked for possible mechanisms regulating the progression of type 1 diabetes mellitus (T1DM). In this disease, autoaggressive T cells (T conventional cells, Tconvs) not properly controlled by T regulatory cells (Tregs) destroy pancreatic islets.
Research design and methods We compared the T-cell compartment of patients with newly diagnosed T1DM (NDT1DM) with long-duration T1DM (LDT1DM) ones. The third group consisted of patients with LDT1DM treated previously with polyclonal Tregs (LDT1DM with Tregs). We have also looked if the differences might be dependent on the antigen specificity of Tregs expanded for clinical use and autologous sentinel Tconvs.
Results Patients with LDT1DM were characterized by T-cell immunosenescence-like changes and expansion of similar vβ/T-cell receptor (TCR) clones in Tconvs and Tregs. The treatment with Tregs was associated with some inhibition of these effects. Patients with LDT1DM possessed an increased percentage of various proinsulin-specific T cells but not GAD65-specific ones. The percentages of all antigen-specific subsets were higher in the expansion cultures than in the peripheral blood. The proliferation was more intense in proinsulin-specific Tconvs than in specific Tregs but the levels of some proinsulin-specific Tregs were exceptionally high at baseline and remained higher in the expanded clinical product than the levels of respective Tconvs in sentinel cultures.
Conclusions T1DM is associated with immunosenescence-like changes and reduced diversity of T-cell clones. Preferential expansion of the same TCR families in both Tconvs and Tregs suggests a common trigger/autoantigen responsible. Interestingly, the therapy with polyclonal Tregs was associated with some inhibition of these effects. Proinsulin-specific Tregs appeared to be dominant in the immune responses in patients with T1DM and probably associated with better control over respective autoimmune Tconvs.
Trial registration number EudraCT 2014-004319-35.
- immunopathology of type 1 diabetes
- immune pathogenesis type 1 diabetes
- immune predictors type 1
- immune regulation
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Footnotes
MG and DI-G contributed equally.
Contributors MG and DIG contributed to the study design, protocol writing, cell preparation, data collection, analysis, interpretation, and writing and reviewing of the report. AWD, MT, MŻ, MH, HZ, JZD, and MZ contributed to lab assays, data collection and interpretation. AJC contributed to clinical assessment and data collection. RO, PJC, AB, AS, WM, NMT, GM, and JS contributed to data collection and interpretation and reviewed the report. AB contributed to data collection and interpretation and reviewed the report. MM was a clinical principal investigator, contributed to data collection, interpretation and reviewed the report. PT was a supervisor of the study who contributed to the study design, protocol writing, cell preparation, data collection, analysis, interpretation writing and reviewing of the report. PT is the guarantor of the study.
Funding This work was supported by the National Centre for Research and Development, Poland (grant numbers LIDER/160/L-6/14/NCBR/2015 and STRATEGMED1/233368/1/NCBR/2014).
Competing interests NMT, MM and PT are coinventors of patent related to presented content and stakeholders and advisors of POLTREG venture. The Medical University of Gdańsk received payment for the license to presented content.
Patient consent for publication Not required.
Ethics approval The studies in this report were conducted according to the protocols approved by the Ethics Committee of the Medical University of Gdańsk (no NKBBN/32/2015). Written informed consent was taken before starting the procedures from all the patients and they parents/legal representatives.
TregVAC1.0 study (http://www.controlled-trials.com/ISRCTN06128462) mentioned in the paper received approval from the Ethics Committee of the Medical University of Gdańsk no NKEBN/8/2010.
TregVAC2.0 study (EudraCT: 2014-004319-35) mentioned in the paper received approval from the Ethics Committee of the Medical University of Gdańsk NKBBN/374/2012 with amendment NKBBN/374-7/2014.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. The raw data are available upon request from corresponding author upon signing confidentiality agreement.