Regulatory T (Treg) cells expressing the FOXP3 transcription factor are presently under investigation by many teams globally as a cellular therapy to induce tolerance in transplantation. This is ...primarily due to their immunosuppressive and homeostatic functions. Depending on the type of allograft, Treg cells will need to infiltrate and function in metabolically diverse microenvironments. This means that any resident and circulating Treg cells need to differentially adapt to counter acute or chronic allograft rejection. However, the links between Treg cell metabolism and function are still not entirely delineated. Current data suggest that Treg cells and their effector counterparts have different metabolite dependencies and metabolic programs. These properties could be exploited to optimize intragraft Treg cell function. In this review, we discuss the current paradigms regarding Treg cell metabolism and outline critical intracellular axes that link metabolism and function. Finally, we discuss how this knowledge could be clinically translated for the benefit of transplant patients.
Forkhead box protein 3–positive regulatory T (Treg) cells are indispensable for the maintenance of self-tolerance and immune homeostasis. They can also be exploited for the treatment of immunologic ...diseases, including autoimmune diseases and allergy, by way of activating and expanding antigen-specific Treg cells in vivo . Cell therapy with in vitro activated and expanded Treg cells can be another therapeutic modality. The feasibility of such Treg cell–based therapeutic strategies is discussed based on recent advances in our understanding of the molecular and cellular basis of Treg cell development and function.
Natural FOXP3+ CD25+ CD4+ regulatory T cells (Tregs) actively suppress pathological and physiological immune responses, contributing to the maintenance of immunological self-tolerance and immune ...homeostasis. Various molecular and cellular events have been described to explain the mechanism(s) of Treg-mediated suppression. However, none of the proposed mechanisms can explain all aspects of suppression. It is probable that various combinations of several mechanisms are operating, depending on the milieu and the type of immune responses, although there might be a single key mechanism that has a predominant role. Further studies of suppression and search for Treg-specific cell surface molecules are required for potential clinical application to treat and prevent immunological diseases and to control immune responses for the benefit of the host.
Erdheim-Chester disease (ECD) is a rare histiocytosis, considered to be an inflammatory myeloid neoplasm. Tropism for specific involvements of the disease remains unexplained. Vascular endothelial ...growth factor-A (VEGF) is implicated in cancer pathophysiology and mutations of the RAS oncogene have been shown to induce upregulation of VEGF gene expression. We therefore hypothesized that VEGF might play a particular role in ECD pathophysiology. We conducted a retrospective, single-center study to assess serum VEGF (sVEGF) concentrations and determine whether they were associated with the characteristics of ECD patients, and to determine whether VEGF was expressed by histiocytes. We evaluated 247 ECD patients, 53.4% of whom had sVEGF levels above the normal range (>500 pg/mL). Patients with high sVEGF levels more frequently had cardiac and vascular involvement (58.3% vs. 41.4%, P=0.008 and 70.5% vs. 48.3%, P=0.0004, respectively). In treatment-naïve patients (n=135), the association of C-reactive protein >5 mg/L and sVEGF >500 pg/mL was strongly associated with vascular involvement (odds ratio=5.54 95% confidence interval: 2.39-13.62, P<0.001), and independently associated with cardiac involvement (odds ratio=3.18 95% confidence interval: 1.34-7.83, P=0.010) after adjustment for the presence of the BRAF V600E mutation. Changes in sVEGF concentration on treatment were associated with a response of cardiac involvement on consecutive cardiac magnetic resonance images. All histological samples analyzed (n=24) displayed histiocytes with intracytoplasmic expression of VEGF, which was moderate to high in more than 90% of cases. Our study suggests a role for VEGF in cardiac and vascular involvement in ECD.
A slight increase in the proportion of circulating regulatory T (Treg) cells has been reported in systemic lupus erythematosus (SLE) patients taking oral prednisone. The effects of intravenous (IV) ...high dose methylprednisolone (MP) on Tregs have not yet been described, especially in active SLE.
We prospectively analyzed the proportion of circulating CD4+ Treg cell subsets defined as follows: (1) naïve Treg (nTreg) FoxP3lowCD45RA+ cells; (2) effector Treg (eTreg) FoxP3highCD45RA- cells; and (3) non-suppressive FoxP3lowCD45RA- cells (non-regulatory Foxp3low T cells). Peripheral blood mononuclear cells of patients with active SLE were analyzed before the first infusion of IV high dose MP (day 0) and the following days (day 1, day 2, ±day 3 and ±day 8). The activity of SLE was assessed by the SLEDAI score.
Seventeen patients were included. Following MP infusions, the median (range) percentage of eTregs significantly increased from 1.62% (0.53-8.43) at day 0 to 2.80% (0.83-14.60) at day 1 (p = 0.003 versus day 0), 4.64% (0.50-12.40) at day 2 (p = 0.06 versus day 1) and 7.50% (1.02-20.70) at day 3 (p = 0.008 versus day 2), and declined to baseline values at day 8. Expanding eTreg cells were actively proliferating, as they expressed Ki-67. The frequency of non-regulatory FoxP3low T cells decreased from 6.39% (3.20-17.70) at day 0 to 4.74% (1.03-9.72) at day 2 (p = 0.005); nTreg frequency did not change. All patients clinically improved immediately after MP pulses. The absence of flare after one year of follow up was associated with a higher frequency of eTregs at day 2.
IV high dose MP induces a rapid, dramatic and transient increase in circulating regulatory T cells. This increase may participate in the preventive effect of MP on subsequent flares in SLE.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A novel technology, photonic ring immunoassay (PRI), for detecting 12 autoantibodies simultaneously in whole blood in less than 15 minutes was evaluated by comparing results from 235 clinically ...diagnosed patients with standard laboratory tests. The overall agreement was greater than 91% for 10 of the 12 assays, with positive percent agreement greater than 89% for 9 of the assays and negative percent agreement greater than 91% for 10 of them. Thus, the clinical sensitivities and specificities were similar for the 2 methods. In addition, 199 normal blood donors were tested on the ANA 12 PRI, yielding specificities greater than 97.5% for all assays. This proof of concept study shows that this new system is suitable for point of care testing for clinically useful autoantibodies, allowing the doctor to have test results in minutes rather than days.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The SARS-CoV-2 pandemic still represents a threat for immunosuppressed and hematological malignancy (HM) bearing patients, causing increased morbidity and mortality. Given the low anti-SARSCoV-2 IgG ...titers post-vaccination, the COVID-19 threat prompted the prophylactic use of engineered anti-SARS-CoV-2 monoclonal antibodies. In addition, potential clinical significance of T cell responses has been overlooked during the first waves of the pandemic, calling for additional in-depth studies. We reported that the polarity and the repertoire of T cell immune responses govern the susceptibility to SARS-CoV-2 infection in health care workers and solid cancer patients. Here, we longitudinally analyzed humoral and cellular immune responses at each BNT162b2 mRNA vaccine injection in 47 HM patients under therapy. Only one-third of HM, mostly multiple myeloma (MM) bearing patients, could mount S1-RBD-specific IgG responses following BNT162b2 mRNA vaccines. This vaccine elicited a S1-RBD-specific Th1 immune response in about 20% patients, mostly in MM and Hodgkin lymphoma, while exacerbating Th2 responses in the 10% cases that presented this recognition pattern at baseline (mostly rituximab-treated patients). Performing a third booster barely improved the percentage of patients developing an S1-RBD-specific Th1 immunity and failed to seroconvert additional HM patients. Finally, 16 patients were infected with SARS-CoV-2, of whom 6 developed a severe infection. Only S1-RBD-specific Th1 responses were associated with protection against SARS-CoV2 infection, while Th2 responses or anti-S1-RBD IgG titers failed to correlate with protection. These findings herald the paramount relevance of vaccine-induced Th1 immune responses in hematological malignancies.
Background
Lymphopenia and the neutrophil/lymphocyte ratio may have prognostic value in COVID-19 severity.
Objective
We investigated neutrophil subsets and functions in blood and bronchoalveolar ...lavage (BAL) of COVID-19 patients on the basis of patients’ clinical characteristics.
Methods
We used a multiparametric cytometry profiling based to mature and immature neutrophil markers in 146 critical or severe COVID-19 patients.
Results
The Discovery study (38 patients, first pandemic wave) showed that 80% of Intensive Care Unit (ICU) patients develop strong myelemia with CD10
−
CD64
+
immature neutrophils (ImNs). Cellular profiling revealed three distinct neutrophil subsets expressing either the lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1), the interleukin-3 receptor alpha (CD123), or programmed death-ligand 1 (PD-L1) overrepresented in ICU patients compared to non-ICU patients. The proportion of LOX-1- or CD123-expressing ImNs is positively correlated with clinical severity, cytokine storm (IL-1β, IL-6, IL-8, TNFα), acute respiratory distress syndrome (ARDS), and thrombosis. BALs of patients with ARDS were highly enriched in LOX-1-expressing ImN subsets and in antimicrobial neutrophil factors. A validation study (118 patients, second pandemic wave) confirmed and strengthened the association of the proportion of ImN subsets with disease severity, invasive ventilation, and death. Only high proportions of LOX-1-expressing ImNs remained strongly associated with a high risk of severe thrombosis independently of the plasma antimicrobial neutrophil factors, suggesting an independent association of ImN markers with their functions.
Conclusion
LOX-1-expressing ImNs may help identifying COVID-19 patients at high risk of severity and thrombosis complications.
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