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Several mechanisms and cell types are involved in the regulation of the immune response. These include mostly regulatory T cells (Tregs), regulatory macrophages (Mregs), myeloid suppressor cells (MDSCs) and other regulatory cell types such as tolerogenic dendritic cells (tolDCs), regulatory B cells (Bregs), and mesenchymal stem cells (MSCs). These regulatory cells, known for their ability to suppress immune responses, can also suppress the anti-tumor immune response. The infiltration of many regulatory cells into tumor tissues is therefore associated with a poor prognosis. There is growing evidence that elimination of Tregs enhances anti-tumor immune responses. However, the systemic depletion of Treg cells can simultaneously cause deleterious autoimmunity. Furthermore, since regulatory cells are characterized by their high level of expression of immune checkpoints, it is also expected that immune checkpoint inhibitors perform part of their function by blocking these molecules and enhancing the immune response. This indicates that immunotherapy does not only act by activating specific effector T cells but can also directly or indirectly attenuate the suppressive activity of regulatory cells in tumor tissues. This review aims to draw together our current knowledge about the effect of immunotherapy on the various types of regulatory cells, and how these effects may be beneficial in the response to immunotherapy.

CMV infection is the most prevalent opportunistic infection following solid organ transplantation (SOT), significantly affecting both graft and patient survival. Effective control of viral replication is crucial to prevent CMV infection from progressing to end-organ disease. Despite its high prevalence, options for preventing CMV infection and end-organ disease are limited to a few antiviral drugs, which have severe side effects and may lead to resistance. In this context, measuring CMV-specific cell-mediated immunity (CMI) has proven to be a valuable tool, with high negative predictive value (NPV) for the absence of CMV viremia in patients with positive tests. This study aimed to evaluate the sensitivity and specificity of various cellular immune response assays and assess the feasibility of incorporating them into routine clinical practice for kidney transplant recipients (KTR). Conducted at the Hospital Universitari Germans Trias i Pujol (HGTP), the study analyzed 56 samples from KTR and 10 healthy controls (HC). Patients and controls were classified based on their pre-transplant serostatus, and CMI was measured using QuantiFERON-CMV ® ELISA, T cell proliferation assay (TCPA), activation-induced marker (AIM) assay, and an in-house ELISA. The AIM assay demonstrated that CD69 is a reliable activation marker for flow cytometry-based assays, as it consistently increased following polyclonal stimulation. Notably, among the total patient cohort with CD4 T cell reactivity, the CM subpopulation exhibited the most significant increase (p < 0.001). Comparative analysis revealed that both ELISAs had high sensitivity and specificity compared to other techniques. The consistency test results showed perfect and almost perfect agreement between the AIM (cut-off 0.2) and the QuantiFERON-CMV ® ELISA and in-house ELISA, respectively. The study also explored the feasibility of incorporating these tests into daily clinical practice, proposing an algorithm based on test results and cost-effectiveness. This algorithm involves testing patients using the QuantiFERON-CMV ® assay, followed by AIM testing in cases of indeterminate results or HLA mismatches. Incorporating these assays would help identify patients at the lowest risk of CMV infection after prophylaxis, enabling more selective and personalized prophylactic strategies.

Adoptive therapy with regulatory T cells or tolerance-inducing antigen (Ag)-presenting cells is innovative and promising therapeutic approach to control undesired and harmful activation of the immune system, as observed in autoimmune diseases, solid organ and bone marrow transplantation. One of the critical issues to elucidate the mechanisms responsible for success or failure of these therapies and define the specificity of the therapy is the evaluation of the Ag-specific T-cell responses. Several efforts have been made to develop suitable and reproducible assays. Here, we focus on dye-based proliferation assays. We highlight with practical examples the fundamental issues to take into consideration for implementation of an effective and sensitive dye-based proliferation assay to monitor Ag-specific responses in patients. The most critical points were used to design a road map to set up and analyze the optimal assay to assess Ag-specific T-cell responses in patients undergoing different treatments. This is the first step to optimize monitoring of tolerance induction, allowing comparison of outcomes of different clinical studies. The road map can also be applied to other therapeutic interventions, not limited to tolerance induction therapies, in which Ag-specific T-cell responses are relevant such as vaccination approaches and cancer immunotherapy.

Minimizing the risk of relapse is essential in multiple sclerosis (MS). As none of the treatments currently available are capable of completely preventing relapses, treatment of these episodes remains a cornerstone of MS care. The objective of this manuscript is to reduce uncertainty and improve quality of care of this neurological process. This article addresses definitions of key concepts, recommendations for clinical examination, classification criteria, magnetic resonance imaging, biomarkers, and specific therapeutic counsels including special populations such as pregnant and breastfeeding women, and children. An algorithm for treating MS relapses is also provided.

Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in peripheral blood samples from 66 RRMS patients under DMF (n=22) or fingolimod (n=44) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1CM cells (relapsed: 11.60±4.17%vs. nonrelapsed: 9.25±3.17%, p<0.05) and Th1Th17CM cells (relapsed: 15.65±6.15%vs. nonrelapsed: 10.14±4.05%, p<0.01) before initiating DMF or fingolimod treatment. Kaplan-Meier analysis revealed that patients with Th1Th17CM (CD4+CCR7+CD45RA-CCR6+CXCR3+) cells>11.48% had a 50% relapse-free survival compared to patients with Th1Th17CMcells<11.48% whose relapse-free survival was 88% (p=0.013, log-rank test). Additionally, a high percentage of Th1Th17CM cells was also found in patients with MRI activity (MRI activity: 14.02±5.87%vs. no MRI activity: 9.82±4.06%, p<0.01). Our results suggest that the percentage of Th1Th17CM lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment.

Aim Dimethyl fumarate (DMF) is one of the most promising therapies for relapsing‐remitting multiple sclerosis (RRMS) patients since it has shown immunomodulatory and neuroprotective effects. However, a percentage of RRMS patients do not exhibit an optimal response to DMF. The objective of this study was to identify early biomarkers of treatment response by analyzing changes in peripheral leukocyte subpopulations directly in whole blood samples. Methods A longitudinal and prospective study analyzing peripheral blood leukocyte subpopulations in 22 RRMS patients before initiating DMF treatment (baseline) and at 1, 3, 6, and 12 months of follow‐up was performed. Differences between no evidence of disease activity (NEDA) and ongoing disease activity (ODA) patients were analyzed. Results The beneficial effect of DMF was associated with a specific depletion of memory CD4+ and CD8+ T lymphocytes and B cells. Importantly, only NEDA patients showed (a) a shift from a pro‐ to an antiinflammatory profile, with an increase of Th2 cells and a decrease of Th1‐like Th17 lymphocytes; and (b) an increase of regulatory CD56bright NK cells. Conclusion The optimal response to DMF is mediated by a shift to antiinflammatory and immunoregulatory profile, which puts forward Th1‐like Th17 lymphocytes as a potential early biomarker of treatment response.

Autologous antigen-specific therapies based on tolerogenic dendritic cells (tolDC) offer the possibility to treat autoimmune diseases by restoring homeostasis and targeting specifically autoreactive responses. Here, we explore the hypothesis that systemic inflammation occurring in autoimmune diseases, such as multiple sclerosis (MS), can generate a disease-specific environment able to alter the functionality of tolDC. In this context in fact, a combined therapy of tolDC with an immunomodulatory treatment could potentiate the beneficial effect of this antigen-specific cell therapy. For this purpose, we analyzed the efficacy of a combined therapy based on the use of vitamin D3 (VitD3)-tolDC plus interferon beta (IFN-beta) in MS. VitD3-tolDC were generated from healthy donors and MS patients and co-cultured with allogeneic peripheral blood mononuclear cells, in the presence or absence of IFN-beta. In vitro, VitD3-tolDC treatment reduced the percentage of activated T cells and allogeneic proliferation, whereas VitD3-tolDC+IFN-beta treatment enhanced the suppressive ability of VitD3-tolDC and, additionally, induced a shift towards a Th2 profile. To determine the clinical benefit of the combined therapy, C57BL/6-experimental autoimmune encephalomyelitis (EAE)-induced mice were treated with antigen-specific VitD3-tolDC and/or IFN-beta. Treatment of EAE mice with combined therapy ameliorated the disease course compared to each monotherapy. These results suggest that a combined therapy based on antigen-specific VitD3-tolDC and IFN-beta may represent a promising strategy for MS patients.

While emerging evidence indicates that dendritic cells (DC) play a central role in the pathogenesis of multiple sclerosis (MS), their modulation with immunoregulatory agents provides prospect as disease-modifying therapy. Our observations reveal that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment of monocyte-derived DC results in a semimature phenotype and anti-inflammatory cytokine profile as compared to conventional DC, in both healthy controls and MS patients. Importantly, 1,25(OH)2D3-treated DC induce T cell hyporesponsiveness, as demonstrated in an allogeneic mixed leukocyte reaction. Next, following a freeze-thaw cycle, 1,25(OH)2D3-treated immature DC could be recovered with a 78% yield and 75% viability. Cryopreservation did not affect the expression of membrane markers by 1,25(OH)2D3-treated DC nor their capacity to induce T cell hyporesponsiveness. In addition, the T cell hyporesponsiveness induced by 1,25(OH)2D3-treated DC is antigen-specific and robust since T cells retain their capacity to respond to an unrelated antigen and do not reactivate upon rechallenge with fully mature conventional DC, respectively. These observations underline the clinical potential of tolerogenic DC (tolDC) to correct the immunological imbalance in MS. Furthermore, the feasibility to cryopreserve highly potent tolDC will, ultimately, contribute to the large-scale production and the widely applicable use of tolDC.

As the vaccination campaign against COVID-19 progresses, it becomes crucial to comprehend the lasting effects of vaccination on safeguarding against new infections or reinfections. This study aimed to assess the risk of new SARS-CoV-2 infections based on the number of vaccine doses, prior infections, and other clinical characteristics. We defined a cohort of 800 health care workers in a 24-month study (March 2020 to December 2022) in northern Barcelona to determine new infections by SARS-CoV-2. We used extended Cox models, specifically Andersen-Gill (AG) and Prentice-Williams-Peterson, and we examined the risk of new infections. The AG model incorporated variables such as sex, age, job title, number of chronic conditions, vaccine doses, and prior infections. Additionally, 2 Prentice-Williams-Peterson models were adjusted, one for those individuals with no or 1 infection and another for those with 2 or 3 infections, both with the same covariates as the AG model. The 800 participants (n=605, 75.6% women) received 1, 2, 3, and 4 doses of the vaccine. Compared to those who were unvaccinated, the number of vaccine doses significantly reduced (P<.001) the risk of infection by 66%, 81%, 89%, and 99%, respectively. Unit increase in the number of prior infections reduced the risk of infection by 75% (P<.001). When separating individuals by number of previous infections, risk was significantly reduced for those with no or 1 infection by 61% (P=.02), and by 88%, 93%, and 99% (P<.001) with 1, 2, 3, or 4 doses, respectively. In contrast, for those with 2 or 3 previous infections, the reduction was only significant with the fourth dose, at 98% (P<.001). The number of chronic diseases only increased the risk by 28%-31% (P<.001) for individuals with 0-1 previous infections. The study suggests that both prior infections and vaccination status significantly contribute to SARS-CoV-2 immunity, supporting vaccine effectiveness in reducing risk of reinfection for up to 24 months after follow-up from the onset of the pandemic. These insights contribute to our understanding of long-term immunity dynamics and inform strategies for mitigating the impact of COVID-19.

[This corrects the article on p. 1870 in vol. 8, PMID: 29312346.].