Soluble Interleukin-2 Receptors Inhibit Interleukin 2-Dependent Proliferation and Cytotoxicity: Explanation for Diminished Natural Killer Cell Activity in Cutaneous T-Cell Lymphomas In Vivo?

Dummer, Reinhard; Posseckert, Gerhard; Nestle, Frank O.; Witzgall, Ralph; Burger, M. C.; Becker, Jürgen C.; Schäfer, E.; Wiede, Johannes; Sebald, Walter; Burg, Günter

doi:10.1111/1523-1747.ep12494223

Cited by 48 publications

(12 citation statements)

References 25 publications

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“…Besides a lack of Foxp3, other mechanisms might contribute to the observed functional dysregulation of CD4+CD25+ T cells in the non-suppressive patients. As survival and function of CD4+CD25+ T cells is highly dependent on the production of IL-2 by neighboring T cells (Malek and Bayer, 2004), a low level of IL-2, as reported in CTCL patients (Dummer et al ., 1992) might trigger apoptosis of CD4+CD25+ T cells (Taams et al ., 2001). Notably, we did observe a high percentage of non-viable CD4+CD25+ T cells (30-50%, as measured by trypan blue stain, data not shown) in three out of the four non-suppressive CTCL patients, a feature that was found in only one out of six suppressive patients.…”

Section: Discussionmentioning

confidence: 85%

Lack of Suppressive CD4+CD25+FOXP3+ T Cells in Advanced Stages of Primary Cutaneous T-Cell Lymphoma

Tiemessen

Mitchell

Hendry

et al. 2006

Journal of Investigative Dermatology

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Mycosis fungoides and its leukemic variant, Sezary syndrome, are the most common primary cutaneous T-cell lymphomas (CTCLs). In an ex vivo study, we investigated the percentage, phenotype, and suppressive function of CD4+CD25+ regulatory T cells (Tregs) from peripheral blood of CTCL patients. The percentage of Tregs did not differ significantly between patients and controls. Functional assays demonstrated a dichotomy in Treg function: in four out of 10 patients CD4+CD25+ T cells were incapable of suppressing autologous CD4+CD25- T-cell proliferation, whereas suppressive function was intact in the other six patients. Suppressive activity of Tregs inversely correlated with the peripheral blood tumor burden. T-plastin gene expression, used as a Sezary cell marker, confirmed that Sezary cells were heterogeneous for CD25 expression. Mixed lymphocyte reactions demonstrated that CD4+CD25- T cells from patients who lacked functional Tregs were susceptible to suppression by Tregs from healthy controls, and had not become suppressive themselves. Furthermore, we found reduced expression of Foxp3 in the CD4+CD25+ Tregs of these patients relative to the other six CTCL patients and controls. Our findings thus indicate a dysfunction of peripheral Tregs in certain CTCL patients, which correlates with tumor burden.

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Section: Discussionmentioning

confidence: 85%

Lack of Suppressive CD4+CD25+FOXP3+ T Cells in Advanced Stages of Primary Cutaneous T-Cell Lymphoma

Tiemessen

Mitchell

Hendry

et al. 2006

Journal of Investigative Dermatology

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“…Of particular interest was the presence and degree of amplification in sIL-2R␣ in HCs versus GR and HCs versus int/PR ( Table 3) in this study. High levels of sIL-2R␣ are known to have an immunomodulatory effect, reported to predict for an unfavorable prognosis in a variety of hematologic malignan- cies, including FL [25], cutaneous T cell lymphoma [26], hairy cell leukemia [27], and CLL [28]. The immunomodulatory role of sIL-2R␣ appears to be pleiotropic depending on the disease state.…”

Section: Discussionmentioning

confidence: 99%

Aggressive disease defined by cytogenetics is associated with cytokine dysregulation in CLL/SLL patients

Karmali

Paganessi

Frank

et al. 2013

Journal of Leukocyte Biology

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Early treatment of CLL/SLL does not impact survival-reflecting limitations in detecting progression early and identifying asymptomatic patients likely to benefit from early treatment. Improved understanding of CLL/SLL biology would identify better prognostic/predictive markers. This study attempts to address these issues by determining the relationship between cytokine aberrations and poor clinical outcomes in CLL/SLL in the context of a genetic-based prognostic model. Fifty-nine serum cytokines/chemokines were measured in 28 untreated CLL/SLL patients. Patients were stratified as GR or int/PR using cytogenetics. Comparison of CLL/SLL with 28 HCs revealed increased expression of Th2 cytokines (IL-10, IL-5, sIL-2Rα; P≤0.01) and decreased levels of Th1 cytokines (IL-17, IL-23, IFN-γ; P≤0.003). In a multivariate analysis of GR versus int/PR groups, differential expression of sIL-2Rα maintained significance with increased expression in int/PR CLL/SLL. With median follow-up of 54.3 months after diagnosis, four patients incurred disease progression, with an IL-17/sIL-2Rα model predicting need for treatment in all cases. In summary, specific cytokine signatures are associated with genetically defined aggressive disease and predict need for therapy. This suggests utility in detecting disease progression early, identifying those likely to incur a survival advantage with early treatment, and directing future therapy.

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“…An increase in sIL-2R serum level in lymphomas is an early predictive marker for an imminent relapse [15, 16]. In CTCL a high sIL-2R level coincides with a decreased IL-2 serum level and could therefore be a reason for the diminished NK cell activity due to reduced activation by IL-2 [17, 18]. This study showed that sIL-2R is also a good candidate to distinguish between T cell inflammatory diseases, Sézary syndrome and non-leukemic CTCL.…”

Section: Discussionmentioning

confidence: 99%

Serological Immunomarkers in Cutaneous T Cell Lymphoma

Hassel¹,

Meier²,

Joller‐Jemelka

et al. 2004

Dermatology

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Introduction: As serological immunomarkers like neopterin, β₂-microglobulin, soluble IL-2 receptor (sIL-2R) and IL-6 have been described to be elevated in various malignancies, the aim of this study was to investigate whether they would be of diagnostic and prognostic value for leukemic and non-leukemic cutaneous T cell lymphoma (CTCL). Patients and Methods: Forty-one CTCL patients from the lymphoma clinics of the Department of Dermatology, University of Zürich, were tested for the serum levels of the above-mentioned immunomarkers at several time points, and clinical status and clinical outcome were recorded. Thirty-nine patients with CBCL and T cell inflammatory diseases served as controls. Results: The study revealed that neopterin, β₂-MG and sIL-2R are significantly elevated in Sézary syndrome, whereby sIL-2R seemed to be the most sensitive marker and is typically increased in Sézary syndrome. Moreover, there is a correlation between tumor burden index values and serum parameters. Concerning the outcome of the disease (progression versus non-progression), only neopterin showed a significant prognostic value in non-leukemic CTCL patients. Conclusion: Serological immunomarkers are helpful tools in determining the tumor burden in CTCL and thus might be useful for disease monitoring during treatment. They may have prognostic value for predicting the clinical course.

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Soluble Interleukin-2 Receptors Inhibit Interleukin 2-Dependent Proliferation and Cytotoxicity: Explanation for Diminished Natural Killer Cell Activity in Cutaneous T-Cell Lymphomas In Vivo?

Cited by 48 publications

References 25 publications

Lack of Suppressive CD4+CD25+FOXP3+ T Cells in Advanced Stages of Primary Cutaneous T-Cell Lymphoma

Lack of Suppressive CD4+CD25+FOXP3+ T Cells in Advanced Stages of Primary Cutaneous T-Cell Lymphoma

Aggressive disease defined by cytogenetics is associated with cytokine dysregulation in CLL/SLL patients

Serological Immunomarkers in Cutaneous T Cell Lymphoma

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