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Immune Reconstitution after Hematopoietic Stem Cell Transplantation
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Andreas Thiel, Tobias Alexander, Christian A. Schmidt, Falk Hiepe, Renate Arnold, Andreas Radbruch, Larissa Verda, Richard K. Burt
CD4+CD25+ T cells contain the high affinity interleukin-2 receptor alpha (IL-2Rα) also known as CD25, a T cell activation marker.54-55 From experiments with thymectomized mice, CD4+CD25+ T cells are thymic-derived.56 Once activated via their TCR, CD4+CD25+ cells exert an antigen independent inhibition of IL-2 production and promote cell cycle arrest.57 CD4+CD25+ T cells have been reported to inhibit by means of IL-10 and/or TGF-β.58-59 However, this remains controversial and while the mechanism CD4+CD25+ T cell suppression is unclear, the effect requires cell-cell contact.60-61 CD4+CD25+ T cells have been shown to be important in preventing several animal autoimmune disorders.62-64
Clinical Studies In Acute and Chronic Inflammation
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
The IL-2 receptor (CD25) is expressed on activated T cells. IL-2 receptor bearing cells and soluble-IL-2 receptors are elevated in patients at risk for transplant rejection (Deng et al., 1995; Chang et al., 1996). Anti-IL-2 receptor therapy has been evaluated as prophylaxis in cardiac, hepatic and renal transplant patients and in the prophylaxis and treatment of GVHD. Results are encouraging, particularly with prophylaxis against transplant rejection, where anti-IL-2 therapy was found to be at least as effective as anti-thymocyte globulin (ATG) and anti-CD3 therapy.
Parachuting Stress: Effects on Endocrine and Immune Functions
Published in Alan J. Husband, Psychoimmunology CNS-Immune Interactions, 2019
M. Schedlowski, R. Jacobs, T. Flüge, J. Aiker, F. Pröhl, G. Stratmann, S. Richter, A. Hädicke, T.O.F. Wagner, R.E. Schmidt, U. Tewes
White blood cell counts (WBC) were done by using standard methods. Peripheral blood mononuclear cells were isolated on a Ficoll Hypaque gradient and stained by using monoclonal antibodies for indirect immunofluorescence analysis.22 CD2 antibody detects T and NK cells, CD3 characterizes all T cells while CD4 and CD8 antibodies recognize T helper and T suppressor/cytotoxic subsets. CD 16 antibodies are specific for the low affinity Fc receptor for IgG (FCγ RIII) and thereby for NK cells. CD56 antigen is expressed on NK cells. p75 is the ß-chain of the IL-2 receptor in peripheral blood expressed mainly on NK cells. CD25 identifies the a-chain of the IL-2 receptor; antibodies against CD2R and CD26 characterize activation structures. 10,000 cells were analyzed per sample on a FACScan (Becton Dickinson, Heidelberg, Germany). The staining procedure has been described in detail previously.23 The absolute numbers were obtained from the white blood cell count in differentials performed in parallel on these samples.
Immunosuppressive tumor microenvironment modulation by chemotherapies and targeted therapies to enhance immunotherapy effectiveness
Published in OncoImmunology, 2022
Robby Barnestein, Loïck Galland, Laura Kalfeist, François Ghiringhelli, Sylvain Ladoire, Emeric Limagne
To continue on the subject of pancreatic cancer, CSF-1, also known as M-CSF, is involved in chemoattraction of myeloid subsets including TAM2, promoting tumor progression and propensity to metastasize.175 By targeting the CSF1/CSF1R axis, Mitchem et al. showed that anti-CSF1Rs are able to limit gemcitabine-induced pro-tumoral TAM infiltration in pancreatic ductal adenocarcinoma. This combotherapy also increased tumor infiltration of CTLs and depleted Treg subsets.176 C-X-C motif Chemokine receptor type 2 (CCR2) is a CCL2 receptor also expressed by myeloid cells. Again with the goal of modulating the TME, adding a CCR2 inhibitor to standard FOLFIRINOX chemotherapy has an antitumor immune tendency by decreasing TAM and Treg subsets and promoting CD8+, CD4+ T cells in patients with borderline resectable or locally advanced pancreatic cancer.177 Interestingly, with a mathematical model, Shafiekhani et al. combined 5-FU chemotherapy and anti-CD25 immunotherapy to improve clinical outcome and therapeutic efficacy.178 Indeed, anti-CD25 could decrease the abundance of tumor infiltrating regulatory T cells.
Cholangiocarcinoma: what are the most valuable therapeutic targets – cancer-associated fibroblasts, immune cells, or beyond T cells?
Published in Expert Opinion on Therapeutic Targets, 2021
Juan Wang, Emilien Loeuillard, Gregory J. Gores, Sumera I. Ilyas
Regulatory T cells (Treg) are another major immunosuppressive element in the tumor immune microenvironment, contributing to tumor immune escape and resistance to immunotherapy. An elevated intratumoral Treg denstity is associated with poor overall survival in several malignancies including CCA [47,48]. Thus, targeting Tregs has the potential to restore and enhance the antitumor immune response. In addition to their lineage marker Foxp3, Treg express several surface marker including CD25 and cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4). Tumor-infiltrating Tregs have high CD25 expression. CD25, also known as the IL-2 receptor alpha subunit (IL-2Rα), has been proposed as a target for cancer immunotherapy as it can be selectively targeted to deplete Tregs. In preclinical models of cancer, anti-CD25 antibody depleted Tregs in the tumor immune microenvironment and synergized with anti-PD-1 to reduce tumor burden [49]. However, in human clinical trials, anti-CD25 antibodies have failed likely due to off-target effects on IL-2 receptor signaling on effector CD8+ T cells [50,51]. An optimized human anti-CD25 clone (RG6292) demonstrated efficient Treg depletion without any overt off-target effects on effector T cells [50]. A multi-center, phase I clinical trial of human anti-CD25 monoclonal antibody is currently under investigation in solid tumors (NCT04158583) [50]. Although there is limited evidence to-date on therapeutic targeting of Tregs in CCA, the existing body of literature in tumor immunology suggests that Tregs depletion has therapeutic potential in CCA.
Overproduction of IL-2 by Cbl-b deficient CD4+ T cells provides resistance against regulatory T cells
Published in OncoImmunology, 2020
SeongJun Han, Douglas C. Chung, Michael St. Paul, Zhe Qi Liu, Carlos Garcia-Batres, Alisha R. Elford, Charles W. Tran, Laurence Chapatte, Pamela S. Ohashi
Previous reports suggested that TCR signaling is enhanced in the absence of Cbl-b, and that T cell activation is independent of CD28 signaling.38,44,45,53 This augmented TCR signaling may explain the higher expression of CD25 on T cells. Therefore, we examined whether the upregulation of CD25 expression was relative to the strength of the TCR signal. Overall, a substantial increase in CD25 expression is observed by increasing TCR signaling using graded anti-CD3 concentrations or increased duration of stimulation (Figure 3d,e). However, Cbl-b KO CD4+ T cells required less TCR signal to induce a high level of CD25 expression, suggesting a link with TCR sensitivity and upregulation of CD25 (Figure 3d,e). Lastly, when stimulated without Treg cells, Cbl-b deficiency or exogenous IL-2 supplementation specifically enhanced CD25 expression while CD122 and CD132 surface expression were kept at basal expression (figure 3f). This observation can be explained by previous studies demonstrating that high-affinity IL-2 receptors (consisting of CD25, CD122 and CD132) are internalized upon IL-2 ligation, whereas CD122 and CD132 are degraded while CD25 is recycled back to the plasma membrane.54–56 In summary, hyper-secretion of IL-2 is correlated with the upregulation of IL-2 receptors on Cbl-b KO CD4+ T cells and may play an important role in rendering T cells refractory to Treg suppression.