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Treg, autoimmunity, leukemia

Katelyn E Brown
Pediatric acute lymphoblastic leukemia (ALL) represents the most common pediatric cancer diagnosis, with numbers rising gradually every year. This paper proposes a novel therapeutic agent for pediatric ALL on the basis of a failed clinical drug trial in 2006. TGN1412 was a promising therapeutic agent that yielded outstanding results in both in vitro studies and animal trials. It is a CD28 superagonist monoclonal antibody that activates T regulatory (TReg ) cells in the absence of costimulation of the T cell receptor (TCR) by an antigen-presenting cell...
May 19, 2018: Diseases (Basel)
Xue Li, Dong Li, Xiaoyang Huang, Panpan Zhou, Qing Shi, Bing Zhang, Xiuli Ju
Regulatory T cells (Tregs) characterized by the transcription factor forkhead box P3 (FoxP3) are crucial for maintaining immune tolerance and preventing autoimmunity. However, FoxP3 does not function alone and Helios is considered a potential candidate for defining Treg subsets. In this study, we investigated the expression and function of Helios for identifying Tregs in childhood precursor B-cell acute lymphoblastic leukemia (pre-B ALL). Our results demonstrated that patients with pre-B ALL had a higher percentage of Helios+ FoxP3+ CD4+ Tregs...
April 2018: Leukemia Research
Y Wang, S Sedimbi, L Löfbom, A K Singh, S A Porcelli, S L Cardell
CD1d-restricted invariant natural killer T (iNKT) cells are known as potent early regulatory cells of immune responses. Besides the established roles in the regulation of inflammation and autoimmune disease, studies have shown that iNKT cells have important roles in tumor surveillance and the control of tumor metastasis. Here we found that the absence of iNKT cells markedly decreased the total number of intestinal polyps in APCMin/+ mice, a model for colorectal cancer. Polyp iNKT cells were enriched for interleukin-10 (IL-10)- and IL-17-producing cells, showed a distinct phenotype being CD4+ , NK1...
January 2018: Mucosal Immunology
Hiroshi Ureshino, Takero Shindo, Hiroyoshi Nishikawa, Nobukazu Watanabe, Eri Watanabe, Natsuko Satoh, Kazutaka Kitaura, Hiroaki Kitamura, Kazuko Doi, Kotaro Nagase, Hiromi Kimura, Makoto Samukawa, Susumu Kusunoki, Masaharu Miyahara, Tadasu Shin-I, Ryuji Suzuki, Shimon Sakaguchi, Shinya Kimura
The regulatory T cells (Treg) with the most potent immunosuppressive activity are the effector Tregs (eTreg) with a CD45RA(-)Foxp3(++)CCR4(+) phenotype. Adult T-cell leukemia (ATL) cells often share the Treg phenotype and also express CCR4. Although mogamulizumab, a monoclonal antibody to CCR4, shows marked antitumor effects against ATL and peripheral T-cell lymphoma, concerns have been raised that it may induce severe autoimmune immunopathology by depleting eTregs. Here, we present case reports for two patients with ATL who responded to mogamulizumab but developed a severe skin rash and autoimmune brainstem encephalitis...
August 2016: Cancer Immunology Research
Mehdi Yousefi, Ali Akbar Movassaghpour, Karim Shamsasenjan, Ghasem Ghalamfarsa, Sanam Sadreddini, Farhad Jadidi-Niaragh, Mohammad Hojjat-Farsangi
While Tregs maintain self-tolerance and inhibit antitumor responses, T helper (Th)17 cells may enhance inflammatory and antitumor responses. The balance between these two important T-cell subsets has been skewed in many immunopathologic conditions such as autoimmune and cancer diseases. B-cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the western world and is characterized with monoclonal expansion of B lymphocytes. There is evidence which implies that the progression of CLL is associated with expansion of Treg and downregulation of Th17 cells...
2015: Future Oncology
M Levite
Dopamine, a principal neurotransmitter, deserves upgrading to 'NeuroImmunotransmitter' thanks to its multiple, direct and powerful effects on most/all immune cells. Dopamine by itself is a potent activator of resting effector T cells (Teffs), via two independent ways: direct Teffs activation, and indirect Teffs activation by suppression of regulatory T cells (Tregs). The review covers the following findings: (i) T cells express functional dopamine receptors (DRs) D1R-D5R, but their level and function are dynamic and context-sensitive, (ii) DR membranal protein levels do not necessarily correlate with DR mRNA levels, (iii) different T cell types/subtypes have different DR levels and composition and different responses to dopamine, (iv) autoimmune and pro-inflammatory T cells and T cell leukaemia/lymphoma also express functional DRs, (v) dopamine (~10(-8) M) activates resting/naive Teffs (CD8(+) >CD4(+) ), (vi) dopamine affects Th1/Th2/Th17 differentiation, (vii) dopamine inhibits already activated Teffs (i...
January 2016: Acta Physiologica
Kris Janssens, Chris Van den Haute, Veerle Baekelandt, Sophie Lucas, Jack van Horssen, Veerle Somers, Bart Van Wijmeersch, Piet Stinissen, Jerome J A Hendriks, Helena Slaets, Niels Hellings
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), for which current treatments are unable to prevent disease progression. Based on its neuroprotective and neuroregenerating properties, leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is proposed as a novel candidate for MS therapy. However, its effect on the autoimmune response remains unclear. In this study, we determined how LIF modulates T cell responses that play a crucial role in the pathogenesis of MS...
March 2015: Brain, Behavior, and Immunity
Thorsten Braun, Pierre Fenaux
Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) are frequently associated with clinical manifestations of autoimmune disorders (AD) and inflammatory response of the immune system. AD accompanying MDS and CMML include vasculitis, seronegative polyarthritis and neutrophilic dermatosis. Rare AD including relapsing polychondritis is strongly associated with MDS as in a high proportion of those patients MDS is diagnosed during disease course. Antinuclear antibodies (ANA) are frequently found among MDS patients without clinical manifestation of AD...
December 2013: Best Practice & Research. Clinical Haematology
Iwona Hus, Agnieszka Bojarska-Junak, Sylwia Chocholska, Waldemar Tomczak, Justyna Woś, Anna Dmoszyńska, Jacek Roliński
Th17 cells, a recently discovered subset of T helper cells that secrete IL-17A, can affect the inflammation process autoimmune and cancer diseases development. The purpose of this study was to evaluate the role of Th17 cells and IL17A in biology of CLL. The study group included 294 untreated CLL patients in different clinical stages. Here, we show that higher Th17 and IL-17A values were associated with less advanced clinical stage of CLL. Th17 cells' percentages in PB were lower in patients who died due to CLL during follow-up due to CLL (as compared to surviving patients) and in patients responding to first-line therapy with fludarabine-based regimens (as compared to non-responders)...
2013: PloS One
Wim Pierson, Bénédicte Cauwe, Antonia Policheni, Susan M Schlenner, Dean Franckaert, Julien Berges, Stephanie Humblet-Baron, Susann Schönefeldt, Marco J Herold, David Hildeman, Andreas Strasser, Philippe Bouillet, Li-Fan Lu, Patrick Matthys, Antonio A Freitas, Rita J Luther, Casey T Weaver, James Dooley, Daniel H D Gray, Adrian Liston
Foxp3⁺ regulatory T (Treg) cells are a crucial immunosuppressive population of CD4⁺ T cells, yet the homeostatic processes and survival programs that maintain the Treg cell pool are poorly understood. Here we report that peripheral Treg cells markedly alter their proliferative and apoptotic rates to rapidly restore numerical deficit through an interleukin 2-dependent and costimulation-dependent process. By contrast, excess Treg cells are removed by attrition, dependent on the Bim-initiated Bak- and Bax-dependent intrinsic apoptotic pathway...
September 2013: Nature Immunology
Farhad Jadidi-Niaragh, Ghasem Ghalamfarsa, Mehdi Yousefi, Mina Hajifaraj Tabrizi, Fazel Shokri
Identification of regulatory T cells (Tregs) has led to breaking the dichotomy of the Th1/Th2 axis in the immunopathology of several diseases such as autoimmune diseases and cancer. Despite the presence of extensive information about immunobiology of Tregs in pathogenesis of autoimmune diseases, little is known about the frequency and function of these cells in hematologic malignancies, particularly chronic lymphocytic leukemia (CLL). Recent data have demonstrated increased frequency and intact functional capacity of CD4(+) Tregs in CLL patients...
August 2013: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Deepesh P Lad, Subhash Varma, Neelam Varma, Man Updesh Singh Sachdeva, Parveen Bose, Pankaj Malhotra
Regulatory T-cells (Tregs) have been shown to be important for the balance of autoimmunity and oncogenesis. Tregs have a protective role in autoimmune diseases and conversely promote oncogenesis. Chronic lymphocytic leukemia (CLL) is unique in being at the cross-roads of oncogenesis and autoimmunity. We studied Tregs, defined as CD4+CD25(high)CD127(low)FOXP3+, in 32 treatment-naive patients with CLL. Our study shows that patients with CLL had a higher absolute Treg count than the control group (p < 0.001)...
May 2013: Leukemia & Lymphoma
Giovanni D'Arena, Giovanni Rossi, Barbara Vannata, Silvia Deaglio, Giovanna Mansueto, Fiorella D'Auria, Teodora Statuto, Vittorio Simeon, Laura De Martino, Aurelio Marandino, Giovanni Del Poeta8, Vincenzo De Feo, Pellegrino Musto
Regulatory T-cells (Tregs) constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL). Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosus, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis...
2012: Mediterranean Journal of Hematology and Infectious Diseases
Adam W Mailloux, Chiharu Sugimori, Rami S Komrokji, Lili Yang, Jaroslaw P Maciejewski, Mikkael A Sekeres, Ronald Paquette, Thomas P Loughran, Alan F List, Pearlie K Epling-Burnette
Myelodysplastic syndromes are premalignant diseases characterized by cytopenias, myeloid dysplasia, immune dysregulation with association to autoimmunity, and variable risk for acute myeloid leukemia transformation. Studies of FOXP3(+) regulatory T cells (Tregs) indicate that the number and/or activation state may influence cancer progression in these patients. Focusing on patients with a lower risk for leukemia transformation, 18 (34.6%) of 52 patients studied displayed an altered Treg compartment compared with age-matched controls...
September 15, 2012: Journal of Immunology: Official Journal of the American Association of Immunologists
Hao Wu, Peng Li, Na Shao, Jingjing Ma, Min Ji, Xiulian Sun, Daoxin Ma, Chunyan Ji
Acute myeloid leukemia (AML) is the most common hematological malignancy in adults, characterized by distorted proliferation and the development of myeloid cells and their precursors in the blood and bone marrow. Interleukin 35 (IL-35), a novel inhibitory cytokine secreted by regulatory T (Treg) cells is a novel potential target used for the therapeutic manipulation of Treg activity in order to treat cancer and autoimmune diseases. To investigate the role and imbalance of Treg-related cytokines in the pathogenesis of AML, we measured the plasma concentration of three Treg-associated cytokines [IL-35, IL-10 and transforming growth factor-β (TGF-β)] and evaluated their clinical relevance...
May 2012: Oncology Letters
Su M Metcalfe, Tarek M Fahmy
Nanotechnology permits the design of therapeutic devices with defined structure and molecular composition. Modular designs employing surface-bound ligands provide specific homing devices for loaded cargo, and biocompatible and biodegradable constructs provide surrogate temporary microenvironments. We first present a case for developing 'smart' modular constructs as immunogenic vaccines to prime immune memory against specific pathogens where current vaccines fail. Second, we argue that nanotherapeutic intervention can harness pivotal molecular pathways recently discovered to regulate lineage development between pathogenic TH17 cells associated with autoimmune disease, versus tolerogenic regulatory T cells (Treg)...
February 2012: Trends in Molecular Medicine
Camilla A Lindqvist, Angelica S I Loskog
It is well established that T regulatory (Treg) cells counteract tumour immunity. However, conflicting results describing the role of Treg cells in haematological tumours warrant further investigations to clarify the interactions between Treg cells and the tumour. B-cell malignancy derives from different stages of B-cell development and differentiation in which T cells play a profound role. The transformed B cell may still be in need of T-cell help to thrive but simultaneously they may be recognized and destroyed by cytotoxic lymphocytes...
April 2012: Immunology
Hee-Won Moon, Bo Hyun Kim, Chul Min Park, Mina Hur, Yeo-Min Yun, Sung-Yong Kim, Mark Hong Lee
BACKGROUND: CD4+CD25+ regulatory T-cells (Tregs) play a critical role in immune responses. We explored the status of Tregs in neoplastic and autoimmune hematologic diseases. We also evaluated the technical aspects of Treg measurement in terms of sample type and detection markers. METHODS: A total of 68 subjects were enrolled: 11 with AML, 8 with MDS, 10 with autoimmune diseases, and 39 controls. Tregs were analyzed in peripheral blood (PB) and bone marrow (BM) samples from each subject...
October 2011: Korean Journal of Laboratory Medicine
Joseph G Sinkovics
In leukemic mice, the native host's explicit and well-defined immune reactions to the leukemia virus (a strong exogenous antigen) and to leukemia cells (pretending in their native hosts to be protected "self" elements) are extinguished and replaced in GvHD (graft-versus-host disease) by those of the immunocompetent donor cells. In many cases, the GvHD-inducer donors display genetically encoded resistance to the leukemia virus. In human patients only antileukemia and anti-tumor cell immune reactions are mobilized; thus, patients are deprived of immune reactions to a strong exogenous antigen (the elusive human leukemia-sarcoma retroviruses)...
December 2010: Acta Microbiologica et Immunologica Hungarica
Jason Park, Wenda Gao, Roy Whiston, Terry B Strom, Su Metcalfe, Tarek M Fahmy
Within the immune system there is an exquisite ability to discriminate between "self" and "non-self" that is orchestrated by antigen-specific T lymphocytes. Genomic plasticity enables differentiation of naive CD4+ T lymphocytes into either regulatory cells (Treg) that express the transcription factor Foxp3 and actively prevent autoimmune self-destruction or effector cells (Teff) that attack and destroy their cognate target. An example of such plasticity is our recent discovery that leukemia inhibitory factor (LIF) supports Treg maturation in contrast to IL-6, which drives development of the pathogenic Th17 effector phenotype...
February 7, 2011: Molecular Pharmaceutics
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