Autologous hematopoietic SCT (AHSCT) has been investigated in the past as a therapeutic alternative for multiple sclerosis (MS). Despite advances in clinical management, knowledge about mechanisms involved with clinical remission post transplantation is still limited. Abnormal microRNA and gene expression patterns were described in MS and have been suggested as disease biomarkers and potential therapeutic targets. Here we assessed T- and B-cell reconstitution, microRNAs and immunoregulatory gene expression after AHSCT. Early immune reconstitution was mainly driven by peripheral homeostatic proliferation. AHSCT increased CD4⁺CD25^hiFoxP3⁺ regulatory T-cell counts and expression of CTLA-4 and GITR (glucocorticoid-induced TNFR) on CD4⁺CD25^hi T cells. We found transient increase in exhausted PD-1⁺ T cells and of suppressive CD8⁺CD28⁻CD57⁺ T cells. At baseline, CD4⁺ and CD8⁺ T cells from MS patients presented upregulated miR-16, miR-155 and miR-142-3p and downregulated FOXP3, FOXO1, PDCD1 and IRF2BP2. After transplantation, the expression of FOXP3, FOXO1, PDCD1 and IRF2BP2 increased, reaching control levels at 2 years. Expression of miR-16, miR-155 and miR-142-3p decreased towards normal levels at 6 months post therapy, remaining downregulated until the end of follow-up. These data strongly suggest that AHSCT normalizes microRNA and gene expression, thereby improving the immunoregulatory network. These mechanisms may be important for disease control in the early periods after AHSCT.

Key Points: Clinical response of SSc patients after AHSCT is associated with thymic and bone marrow rebounds. Responder patients showed higher Treg and Breg counts and lower pre-/post-AHSCT TCR repertoire overlap than nonresponder patients.

γδ T cells are clonotypically distinct in ascites and tumors of patients with ovarian cancer and their functionality correlates with clinical outcome.

Autologous hematopoietic stem cell transplantation (AHSCT) increases C-peptide levels and induces insulin-independence in patients with type 1 diabetes. This study aimed to investigate how clinical outcomes may associate with the immunological status, especially concerning the balance between immunoregulation and autoreactivity. Twenty-one type 1 diabetes patients were monitored after AHSCT, and assessed every six months for duration of insulin independence, C-peptide levels, frequencies of islet-specific autoreactive CD8+ T-cells, regulatory lymphocyte subsets, thymic function and T-cell repertoire diversity. In median follow-up of 78 (range 15-106) months, all patients became insulin-independent, resuming insulin after median of 43 (range 6-100) months. Patients were retrospectively divided into short- or prolonged-remission-groups, according to duration of insulin independence. For the entire follow-up, CD3+CD4+ T-cell numbers remained lower than baseline in both groups, whereas CD3+CD8+ T-cell levels did not change, resulting in a CD4/CD8 ratio inversion. Memory CD8+ T-cells comprehended most of T-cells detected on long-term follow-up of patients after AHSCT. B-cells reconstituted to baseline levels at 2-3 months post-AHSCT in both patient groups. In the prolonged-remission-group, baseline islet-specific T-cell autoreactivity persisted after transplantation, but regulatory T-cell counts increased. Patients with lower frequencies of autoreactive islet-specific T-cells remained insulin-free longer and presented greater C-peptide levels than those with lower frequencies of these cells. Therefore, immune monitoring identified a subgroup of patients with superior clinical outcome of AHSCT. Our study shows that improved immunoregulation may balance autoreactivity endorsing better metabolic outcomes in patients with lower frequencies of islet-specific T-cells. Development of new strategies of AHSCT is necessary to increase frequency and function of T and B regulatory cells and decrease efficiently autoreactive islet-specific T and B memory cells in type 1 diabetes patients undergoing transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) using αβ T-/B-cell–depleted grafts recently emerged as a transplant strategy and highlighted the potential role of γδ T cells on HSCT outcomes. Our aim was to scrutinize available evidence of γδ T-cell impact on relapse, infections, survival, and acute graft-versus-host disease (aGVHD). We performed a systematic review and meta-analysis of studies assessing γδ T cells in HSCT. We searched PubMed, Web of Science, Scopus, and conference abstracts from inception to March 2019 for relevant studies. We included all studies that assessed γδ T cells associated with HSCT. Data were extracted independently by 2 investigators based on strict selection criteria. A random-effects model was used to pool outcomes across studies. Primary outcome was disease relapse. We also assessed infections, survival, and aGVHD incidence. The review was registered with PROSPERO (CRD42019133344). Our search returned 2412 studies, of which 11 (919 patients) were eligible for meta-analysis. Median follow-up was 30 months (interquartile range, 22-32). High γδ T-cell values after HSCT were associated with less disease relapse (risk ratio [RR], 0.58; 95% confidence interval [95% CI], 0.40-0.84; P = .004; I² = 0%), fewer viral infections (RR, 0.59; 95% CI, 0.43-0.82; P = .002; I² = 0%) and higher overall (HR, 0.28; 95% CI, 0.18-0.44; P < .00001; I² = 0%) and disease-free survivals (HR 0.29; 95% CI, 0.18-0.48; P < .00001; I² = 0%). We found no association between high γδ T-cell values and aGVHD incidence (RR, 0.72; 95% CI, 0.41-1.27; P = .26; I² = 0%). In conclusion, high γδ T cells after HSCT is associated with a favorable clinical outcome but not with aGVHD development, suggesting that γδ T cells have a significant effect on the success of HSCT. This study was registered with PROSPERO as #CRD42019133344.

The determinants of clinical responses after autologous hematopoietic stem cell transplantation (aHSCT) in systemic sclerosis (SSc) are still unraveled. We analyzed long-term immune reconstitution (IR) and T cell receptor (TCR) repertoire diversity in 10 SSc patients, with at least 6 years simultaneous clinical and immunological follow-up after aHSCT. Patients were retrospectively classified as long-term responders (A, n = 5) or non-responders (B, n = 5), using modified Rodnan’s skin score (mRSS) and forced vital capacity (FVC%). All patients had similar severe SSc before aHSCT. Number of reinjected CD34+ cells was higher in group B versus A (P = 0.02). Long-term mRSS fall >25% was more pronounced in group A (P = 0.004), the only to improve long-term FVC% >10% (P = 0.026). There was an overall trend toward increased of T cell reconstitution in group B versus A. B cells had a positive linear regression slope in group A (LRS = 11.1) and negative in group B (LRS = −11.6). TCR repertoire was disturbed before aHSCT and the percentage of polyclonal families significantly increased at long-term (P = 0.046), with no difference between groups. Despite improved skin score after aHSCT in all SSc patients, pretransplant B cell clonal expansion and faster post-transplant T cell IR in long-term non-responder/relapsing patients call for new therapeutic protocols guided by IR analysis to improve their outcome.