CD4+CD25high Foxp3+ Regulatory T-Cells Are Correlated with Different Risk Factors in Myelodysplastic Syndrome (MDS).

Abstract Regulatory T-cells (Tregs) are important in the immune surveillance of malignancies. In MDS Tregs may inhibit effective immune responses against the dysplastic clone thereby facilitating disease progression. We studied the number (CD4+ and CD8+), function and clonality of CD4+Tregs in the peripheral blood of 75 MDS patients with different subtypes of MDS and 9 healthy volunteers as controls. The number of Tregs was also compared between different cytogenetic abnormalities. The phenotype of the expanded Tregs was analysed by assessment of the naïve vs memory subpopulations (CD25highFoxp3+CD27+CD45RO− and CD25highFoxp3+CD27+CD45RO+ respectively) in low and high risk MDS. The absolute number of CD4+CD25highFoxp3+ and CD4+/CD8+CD25+Foxp3+ was calculated. The median number of CD4+CD25highFoxp3+ Tregs in 5q-syndrome was 0.7×107/l (range, 0.2–2.2x107), Refractory Anemia (RA) 0.7×107/l (range, 0.5–1.6x107), Refractory Cytopenia with Multilineage Dysplasia (RCMD) 1.3×107/l (range, 0.2–2.6x107), Refractory Anemia with Excess Blast (RAEB) 2.2×107/l (range, 0.6–7.0x107) and Myelodysplastic/Myeloproliferative Disease (MDS/MPD) 3.1×107/l (range, 0.8–5.0x107). CD4+Tregs were higher in patients with ≥5% BM blasts vs <5% BM blasts (p<0.001), in high vs low/intermediate IPSS (p<0.001), disease progression vs stable disease (p<0.001). CD4+ Tregs were lower in 5q- syndrome, RCMD and RA. However, these did not differ significantly from normal controls (p=0.6), whereas RAEB and MDS/MPD had higher CD4+ Tregs than normal donors (p<0.001, p=0.02). The number of Tregs has also been correlated with cytogenetic abnormalities (based on IPSS definition). In patients with isolated 5q- Tregs were significantly lower than those with complex (p=0.004) or intermediate risk karyotypes (p<0.001). There was no difference in the number of CD8+ Tregs between MDS subtypes (p=0.28), IPSS (p=0.19), or disease progression (p=0.19). The percentage of naïve Tregs was significantly higher in high risk patients compared with low risk and healthy volunteers (p=0.032). The ratio of naïve to memory Tregs was also significantly higher in the high risk than low risk (p=0.016) or control groups (p=0.032). The spectratype of CD4+CD25+ TCR amplicons showed a polyclonal pattern and the overall complexity of Vβ spectratypes was not different between low and high risk group (p=0.54). By contrast the spectratype of CD8+Tcells was skewed on average in 6/24 Vβ subfamilies indicating the clonal expansion of these cells. Functionality of the expanded Tregs was demonstrated by inhibition of IFN-γ secretion by effector T-cells, confirmed by both intracellular staining and ELISA. We demonstrate that expansion of Tregs occurs frequently in high risk MDS and disease progression. By contrast, in low risk MDS the Treg population tends to be lower, thereby permitting the emergence of autoimmune responses. Although the increased number of Tregs in high IPSS MDS is an important indication of immune suppression, Karyotype and bone marrow blast percentage can influence the number of Tregs independently.

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Expansion of Polyclonal CD4+CD25high Foxp3+ Regulatory T-Cells in High Risk Myelodysplastic Syndromes (MDS).

Blood ◽

10.1182/blood.v108.11.2641.2641 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2641-2641

Author(s):

Shahram Y. Kordasti ◽

Wendy Ingram ◽

Janet Hayden ◽

David Darling ◽

Linda Barber ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

High Risk ◽

Regulatory T Cells ◽

Autoimmune Diseases ◽

Immunosuppressive Therapy ◽

Absolute Number ◽

Low Risk ◽

Refractory Anaemia ◽

Bone Marrow Blasts

Abstract Foxp3+ regulatory T-cells(Tregs) play a central role in maintaining tolerance. A reduction in Tregs activity is a key feature of autoimmune diseases, whereas their expansion in malignant diseases leads to suppression of the host anti-tumour responses. Expansion of oligoclonal cytotoxic T cells, inhibition of MDS CD34+ progenitors proliferation and response to immunosuppressive therapy suggest that autoimmunity contributes to the pathophysiology of low risk MDS. However, this is not generally a feature of high risk MDS. We hypothesise that in high risk MDS patients an increased number of Tregs may suppress immune responses against the dysplastic clone. In early MDS, these cells may be reduced and or be associated with coexistent autoimmune diseases, an uncommon but recognised association of low risk MDS. We therefore studied CD4+ CD25high Foxp3+ and CD8+ CD25+Foxp3+ Tregs in peripheral blood of MDS patients and examined correlation with bone marrow blasts, cytogenetic Status, IPSS score and progression to AML. Clonality of CD4+CD25+ Tregs was assessed by TCR spectratype analysis of CDR3 size distribution and by CDR3 sequence analysis. 52 patients with MDS (30 male, 22 female) with a mean age of 62 years (range 40 to 82 years) were studied. According to WHO classification, 5/52 (10%) had a diagnosis of 5q− syndrome, 9/52(17%) refractory anaemia (RA), 18/52 (35%) refractory cytopenia with multilineage dysplasia (RCMD), 16/52 (31%) refractory anaemia with excess blasts (RAEB) and 4/52 (7%) patients MDS/MPD (one with JAK2 V617F Mutation). Cytogenetic study shows normal pattern in 57%, 5q- in 22%, stable cytogenetic in 10% and complex findings in 11%. All samples were taken at diagnosis prior to any treatment. In addition 5 samples were analyzed pre and post 5-Azacytidine therapy. The absolute number of CD4+CD25highFoxp3+ regulatory T cells in 5q- syndrome was 0.5±0.28×107/l, RA0.6±0.56×107/l, RCMD1.42±0.97×107/l, RAEB2.8±2.2×107/l and MDS/MPD 2.9±2×107/l. In cases with <5% bone marrow blasts (RA, 5q− & RCMD)absolute number and percentage of Tregs was significantly lower than those with ≥5% BM blasts (p=0.001). The mean number was also significantly lower at 0.73±0.57×107/l in low risk cases(IPSS 0) compared with 2±1.5×107/l in intermediate and high risk groups (p=0.008). CD8+ Tregs were not significantly different between the subtypes of MDS and between low and high risk IPSS subgroups. Tregs number did not differ significantly between various cytogenetic subgroups. The spectratype of CD4+CD25+ TCR amplicons, showed a polyclonal pattern and the overall complexity of Vβ subfamilies was not different between low risk and high risk MDS, suggesting that the expanded Tregs in high risk MDS are not clonal and likely to arise by peripheral expansion rather than an antigen-driven response. CD4+ CD25high Foxp3+ Tregs in five patients were studied pre and post 5-Azacytidine. The numbers were significantly decreased after treatment in the one patient who responded to treatment (p=0.001), whereas Treg numbers were unchanged or increased in non responsive cases. In 5 RCMD cases with concomitant autoimmune diseases the percentage of Tregs was lower than other patients within the same subgroup of MDS, however, this did not achieve statistical significance. The findings indicate Tregs are altered in MDS and may be important in the pathophysiology of MDS. Monitoring of Tregs numbers can be a useful indicator for disease progression and response to immunosuppressive therapy.

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New risk model is able to identify patients with a low risk of progression in systemic sclerosis

RMD Open ◽

10.1136/rmdopen-2020-001524 ◽

2021 ◽

Vol 7 (2) ◽

pp. e001524

Author(s):

Nina Marijn van Leeuwen ◽

Marc Maurits ◽

Sophie Liem ◽

Jacopo Ciaffi ◽

Nina Ajmone Marsan ◽

...

Keyword(s):

Machine Learning ◽

Systemic Sclerosis ◽

High Risk ◽

Disease Progression ◽

Risk Model ◽

Immunosuppressive Drugs ◽

Low Risk ◽

Expert Assessment ◽

Risk Of Progression

ObjectivesTo develop a prediction model to guide annual assessment of systemic sclerosis (SSc) patients tailored in accordance to disease activity.MethodsA machine learning approach was used to develop a model that can identify patients without disease progression. SSc patients included in the prospective Leiden SSc cohort and fulfilling the ACR/EULAR 2013 criteria were included. Disease progression was defined as progression in ≥1 organ system, and/or start of immunosuppression or death. Using elastic-net-regularisation, and including 90 independent clinical variables (100% complete), we trained the model on 75% and validated it on 25% of the patients, optimising on negative predictive value (NPV) to minimise the likelihood of missing progression. Probability cutoffs were identified for low and high risk for disease progression by expert assessment.ResultsOf the 492 SSc patients (follow-up range: 2–10 years), disease progression during follow-up was observed in 52% (median time 4.9 years). Performance of the model in the test set showed an AUC-ROC of 0.66. Probability score cutoffs were defined: low risk for disease progression (<0.197, NPV:1.0; 29% of patients), intermediate risk (0.197–0.223, NPV:0.82; 27%) and high risk (>0.223, NPV:0.78; 44%). The relevant variables for the model were: previous use of cyclophosphamide or corticosteroids, start with immunosuppressive drugs, previous gastrointestinal progression, previous cardiovascular event, pulmonary arterial hypertension, modified Rodnan Skin Score, creatine kinase and diffusing capacity for carbon monoxide.ConclusionOur machine-learning-assisted model for progression enabled us to classify 29% of SSc patients as ‘low risk’. In this group, annual assessment programmes could be less extensive than indicated by international guidelines.

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Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

Journal of Virology ◽

10.1128/jvi.01165-12 ◽

2012 ◽

Vol 86 (18) ◽

pp. 9802-9816 ◽

Cited By ~ 17

Author(s):

Melissa M. Norström ◽

Marcus Buggert ◽

Johanna Tauriainen ◽

Wendy Hartogensis ◽

Mattia C. Prosperi ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

High Resolution ◽

Disease Progression ◽

T Cell Responses ◽

Low Risk ◽

Early Infection ◽

Cell Responses ◽

Cell Counts ◽

Hiv 1

HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although rates can vary within this group. Underlying mechanisms are not fully understood but likely involve both immunological and virological dynamics. The present study investigated HIV-1in vivoevolution and epitope-specific CD8+T cell responses in six HLA-B*5701 patients who had not received antiretroviral treatment, monitored from early infection for up to 7 years. The subjects were classified as high-risk progressors (HRPs) or low-risk progressors (LRPs) based on baseline CD4+T cell counts. Dynamics of HIV-1 Gag p24 evolution and multifunctional CD8+T cell responses were evaluated by high-resolution phylogenetic analysis and polychromatic flow cytometry, respectively. In all subjects, substitutions occurred more frequently in flanking regions than in HLA-B*5701-restricted epitopes. In LRPs, p24 sequence diversity was significantly lower; sequences exhibited a higher degree of homoplasy and more constrained mutational patterns than HRPs. The HIV-1 intrahost evolutionary rate was also lower in LRPs and followed a strict molecular clock, suggesting neutral genetic drift rather than positive selection. Additionally, polyfunctional CD8+T cell responses, particularly to TW10 and QW9 epitopes, were more robust in LRPs, who also showed significantly higher interleukin-2 (IL-2) production in early infection. Overall, the findings indicate that HLA-B*5701 patients with higher CD4 counts at baseline have a lower risk of HIV-1 disease progression because of the interplay between specific HLA-linked immune responses and the rate and mode of viral evolution. The study highlights the power of a multidisciplinary approach, integrating high-resolution evolutionary and immunological data, to understand mechanisms underlying HIV-1 pathogenesis.

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Regulatory T cells delay disease progression in a murine model of Alzheimer�s disease

Frontiers in Immunology ◽

10.3389/conf.fimmu.2013.02.00305 ◽

2013 ◽

Vol 4 ◽

Cited By ~ 1

Author(s):

DANSOKHO CIRA ◽

A�d Saba ◽

Chaingneau Thomas ◽

Holzenberger Martin ◽

Aucouturier Pierre ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Disease Progression ◽

Murine Model ◽

Delay Disease Progression

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Cooperation between Cancer Cells and Regulatory T Cells to Promote Immune-escape through Integrin αvβ8-Mediated TGF-β Activation

10.21203/rs.3.rs-208701/v1 ◽

2021 ◽

Author(s):

Alexandra Laine ◽

Ossama Labiad ◽

Hector Hernandez-Vargas ◽

Sebastien This ◽

Amélien Sanlaville ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Regulatory T Cells ◽

Cancer Cells ◽

Immune Escape ◽

Antibody Treatment ◽

Inactive Form ◽

Treg Population ◽

Cytotoxic Function ◽

Made In

Abstract Among the strategies allowing cancer cells to escape the immune system, the presence of TGF-b in the tumor micro-environment is one of the most potent. However, TGF-b is secreted in an inactive form and mechanisms responsible for its activation within the tumor remain unknown. Here, we demonstrate that regulatory T cells (Tregs) compose the main cells expressing the b8 chain of avb8 integrin (Itgb8) in the tumors and that the Itgb8pos Treg population activates TGF-b produced by the cancer cells and stored in the tumor micro-environment. Itgb8 ablation in Tregs impaired TGF-b signaling in T lymphocytes present in the tumor but not in the tumor draining lymph nodes. The cytotoxic function of CD8pos T lymphocytes infiltrating the tumors was subsequently exacerbated leading to an efficient control of the tumor growth. Similar observations were made in patient tumors after anti-Itgb8 antibody treatment. Thus, this study reveals that Tregs work in concert with cancer cells to produce bioactive-TGF-b and create a powerful-immunosuppressive micro-environment.

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Abstract T MP18: In Vivo Expansion of Regulatory T cells with Interleukin-2/Interleukin-2-antibody Complex Protects against Transient Ischemic Stroke

Stroke ◽

10.1161/str.46.suppl_1.tmp18 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Haiyue Zhang ◽

Peiying Li ◽

Yanqin Gao ◽

Jun Chen ◽

Xiaoming Hu

Keyword(s):

T Cells ◽

Ischemic Stroke ◽

Brain Injury ◽

Regulatory T Cells ◽

Interleukin 2 ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Treg Population ◽

Antibody Complex

Background and Purpose: Our previous work documents the transfer of regulatory T cells (Tregs) in rodent models of ischemic stroke protects acute ischemic brain injury by regulating poststroke inflammatory response and thereby ameliorating BBB disruption. However, the low number of Tregs restricts the clinical feasibility of Treg transfer. Recently, in vivo expansion of Tregs with IL-2/IL-2-antibody complex (IL-2/IL-2Ab) was validated protective in autoimmune diseases model,renal ischemia reperfusion model and atherosclerosis. Here we investigate the beneficial effect of IL-2/IL-2Ab on ischemic stroke and decipher the underlying mechanisms. Methods: IL-2/IL-2Ab or isotype IgG was ip injected into C57/BL6 mice for 3 consecutive days. The mice are then subjected to 60-minute middle cerebral artery occlusion (MCAO) or sham operation. Brain infarction, inflammation and neurological performance was assessed up to 7 days after reperfusion. Results: Flow cytometry analysis reveals a marked increase of CD4+CD25+Foxp3+ Tregs in the blood, lymph nodes and spleens collected from IL-2/IL-2Ab-treated mice as compared to those from isotype-treated controls. Such Treg elevation could be observed since 3 days after IL-2/IL-2Ab injection and lasts until 7 days after MCAO. Immunochemistry staining confirms the increased number of Foxp3+ cells in the spleen at 3 days after MCAO in IL-2/IL-2Ab-treated mice. IL-2/IL-2Ab promotes function recovery up to 7 days after stroke, as revealed by significantly improved performance in corner test (n=6-9, ***p<0.001), rotarod test (n=8, **p<0.01), cylinder test (n=8, **p<0.01) and adhesive removal test (n=3, *p<0.05). Quantification of TTC staining and microtubule-associated protein (MAP2) staining shows reductions in brain infarct volume at 3 days (n=5-9,*p<0.05) and 7 days (n=7-9,*p<0.01), respectively, after MCAO. Meanwhile, we observed reduced infiltration of peripheral immune cells (CD3+ T cells, MPO+ neutrophils and F4/80+ macrophages) into the ischemic brain. Conclusions: Our finding suggests that IL-2/IL-2Ab treatment is a novel and clinical feasible immune therapy to expand Treg population in vivo, reduce post-stroke inflammatory responses and protect against ischemic brain injury.

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Mass Cytometry Identifies Distinct Subsets of Regulatory T Cells and Natural Killer Cells Associated With High Risk for Type 1 Diabetes

Frontiers in Immunology ◽

10.3389/fimmu.2019.00982 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 7

Author(s):

Hugo Barcenilla ◽

Linda Åkerman ◽

Mikael Pihl ◽

Johnny Ludvigsson ◽

Rosaura Casas

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

High Risk ◽

Natural Killer Cells ◽

Regulatory T Cells ◽

Natural Killer ◽

Mass Cytometry ◽

Killer Cells

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CD25 regulatory T cells determine secondary but not primary remission in EAE: Impact on long-term disease progression☆

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2005.11.003 ◽

2006 ◽

Vol 172 (1-2) ◽

pp. 73-84 ◽

Cited By ~ 46

Author(s):

D GARTNER ◽

H HOFF ◽

U GIMSA ◽

G BURMESTER ◽

M BRUNNERWEINZIERL

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Disease Progression

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Quantification of Regulatory T Cells Enables the Identification of High-Risk Breast Cancer Patients and Those at Risk of Late Relapse

Journal of Clinical Oncology ◽

10.1200/jco.2006.05.9584 ◽

2006 ◽

Vol 24 (34) ◽

pp. 5373-5380 ◽

Cited By ~ 705

Author(s):

Gaynor J. Bates ◽

Stephen B. Fox ◽

Cheng Han ◽

Russell D. Leek ◽

José F. Garcia ◽

...

Keyword(s):

Breast Cancer ◽

At Risk ◽

T Cells ◽

High Risk ◽

Regulatory T Cells ◽

Cancer Patients ◽

Late Relapse ◽

Breast Cancer Patients ◽

Risk Of Relapse

Purpose To assess the clinical significance of tumor-infiltrating FOXP3-positive regulatory T cells (TR) in breast cancer patients with long-term follow-up. Patients and Methods FOXP3-positive TR were detected by immunohistochemistry with our new, extensively characterized FOXP3 monoclonal antibody, 236A/E7. Numbers of FOXP3-positive lymphocytes in tissue microarray cores from pure ductal carcinoma in situ (DCIS; n = 62), invasive breast cancer (n = 237) or from comparable areas of normal terminal duct lobular breast tissue (n = 10) were determined. A median cutoff of ≥ 15 defined patients with high numbers of TR. Results TR numbers were significantly higher in in situ and invasive breast carcinomas than in normal breast; invasive tumors have significantly higher numbers than DCIS (P = .001). High numbers of FOXP3-positive TR identified patients with DCIS at increased risk of relapse (P = .04) and patients with invasive tumors with both shorter relapse-free (P = .004) and overall survival (P = .007). High TR numbers were present in high-grade tumors (P ≤ .001), in patients with lymph node involvement (P = .01), and in estrogen receptor (ER) –negative tumors (P = .001). Importantly, high numbers of TR within ER-positive tumors identified high-risk patients (P = .005). Unlike conventional clinicopathologic factors, high numbers of FOXP3-positive TR can identify patients at risk of relapse after 5 years. Conclusion These findings indicate that quantification of FOXP3-positive TR in breast tumors is valuable for assessing disease prognosis and progression, and that TR are an important therapeutic target for breast cancer. FOXP3-positive TR represent a novel marker for identifying late-relapse patients who may benefit from aromatase therapy after standard tamoxifen treatment.

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