Targeting Deacetylase Sirt-1 Reprograms Treg Function in Immune Thrombocytopenia
Bibliographic record
Abstract
Introduction: Immune thrombocytopenia (ITP) is the most common acquired bleeding disorder dominated by loss of self-tolerance, where dysfunction of regulatory T cells (Tregs) claims its role. CD38 is a type II glycoprotein with exoenzymatic activities, widely expressed on the surface of antibody-secreting cells, activated T cells, natural killer cells, and myeloid cells. Clinical studies of anti-CD38 monoclonal antibodies in the treatment of autoimmune diseases are robust. Zhang et al. recently reported that anti-CD38 targeted therapy rapidly boosted platelet levels by clearing plasma cells and potentially altering CD4+ T cells in patients with ITP. However, the underlying mechanism of its long-term efficacy remains to be elucidated. It is suggested that deficiency of Sirtuin-1 (Sirt-1), a class III histone deacetylase, promoted Treg stability and enhanced Foxp3 acetylation in graft versus host disease. The objective of this study was to explore whether a sustained response of anti-CD38 targeted therapy is associated with Sirt-1-modulated Tregs in ITP. Methods: The proportion of Tregs in peripheral blood mononuclear cells (PBMCs) cultured with different concentration of CD38 monoclonal antibody were detected by flow cytometry. Immunosuppressive functions of Tregs on the proliferation of CFSE-labeled CD4+ CD25- effector T cells, and on CD8+ cytotoxic T lymphocyte-induced platelet apoptosis were assessed. The level of Sirt-1 in CD4+ T cells from ITP patients and healthy controls, as well as the intergroup differences in Sirt-1 levels treated with or without CD38 monoclonal antibody were analyzed by quantitative real-time PCR and western blot. Furthermore, EX527, a Sirt-1 inhibitor and SRT1720, a Sirt-1 agonist, as well as lentiviral interference of Sirt-1 in Tregs were used to verify the target of anti-CD38 therapy. Finally, a murine model of active ITP was established by intraperitoneal injection of C57BL/6 CD61-KO splenocytes immunized with CD61+ platelets to severe combined immunodeficient mice, aiming to investigate whether targeting Sirt-1 reprograms Treg function in ITP. Results: CD38 monoclonal antibody significantly increased the proportion of Tregs among PBMCs and CD4+ T cells, and enhanced the immunosuppressive functions of Tregs in vitro. The expression level of Sirt-1 in CD4+ T cells from ITP patients was significantly higher than that from healthy controls, and CD38 monoclonal antibody significantly decreased the expression of Sirt-1 in CD4+ T cells. An elevated frequency of Treg population was noticed when programming CD4+ T cells from ITP patients in the presence of Sirt-1 inhibitor, which mirrors anti-CD38 therapy; while a reduced frequency of Treg proportion was observed with Sirt-1 agonist. Tregs transfected with Sirt-1 shRNA had a significantly stronger immunosuppressive function, compared with those transfected with the control lentivirus. And Sirt-1 shRNA interference masked the effect of CD38 monoclonal antibody on Tregs. Moreover, a total of four treatment groups were established in the active ITP mice, among which the control solvent (Group A), inhibition of CD38 (Group B), inhibition of Sirt-1 (Group C), and inhibition of both CD38 and Sirt-1 (Group D) were administered intraperitoneally every other day. In both Group B and C, significantly ameliorated thrombocytopenia, increasedproportion of splenic Tregs, down-regulated Sirt-1 in Foxp3 positive frozen sections, and restoration of anti-/pro-inflammatory cytokine profiles was demonstrated, compared with Group A. Conclusion: In summary,CD38 monoclonal antibody potentially reprograms the immunosuppressive function of Tregs by inhibiting Sirt-1, which provides a novel target for the management of ITP. This study suggested versatile mechanisms of anti-CD38 therapy in autoimmune disorders and rationalized its long-term efficacy in patients with ITP.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".