scholarly journals The Role ofFoxp3-Expressing Regulatory T Cells and T Helpers in Immunopathogenesis of Multidrug Resistant Pulmonary Tuberculosis

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
E. G. Churina ◽  
O. I. Urazova ◽  
V. V. Novitskiy
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Pulmonary Tuberculosis ◽  
Immune Suppression ◽  
Protective Immunity ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Newly Diagnosed ◽  
Clinical Form ◽  
T Helpers

Subpopulation structure of regulatory T cells and T helpers of peripheral blood in patients with newly diagnosed pulmonary tuberculosis depending on the clinical form of disease and sensitivity ofMycobacterium tuberculosisto antituberculosis drugs has been analyzed in this work. It has been shown that the leading part in immune suppression at infiltrative, dissemination, and fibrosis-cavity pulmonary tuberculosis is played by natural regulatory CD4+CD25+Foxp3+-T lymphocytes. Thus we estimate increase of their number in blood by drug-resistance and drug-susceptible patients. It has been demonstrated that in patients with fibrocavernous and infiltrative form of the disease and drug-resistant pulmonary tuberculosis the number of CD4+CD25−Foxp3+-regulatory T cells was increasing. In patients with infiltrative pulmonary tuberculosis, including multidrug-resistantM. tuberculosis, an increased number of CD3+CD4+CD25−T helpers is determined by the pathogenic features of the development of the tuberculosis infection and is connected with the activation of Th1-dependent immune response. Reduction in the number of T-helpers in the blood of patients with dissemination and fibrosis-cavity pulmonary tuberculosis mediates inefficient implementation of cell-mediated protective immunity.

scholarly journals Subpopulation structure of regulatory Т-cells of blood in patients with multiple drugresistant pulmonary tuberculosis

2011 ◽  
Vol 10 (4) ◽  
pp. 183-187 ◽  
Author(s):  
Ye. G. Churina ◽  
V. V. Novitsky ◽  
O. I. Urazova ◽  
O. V. Voronkova ◽  
Yu. V. Kolobovnikova
Keyword(s):  
Drug Resistance ◽  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Lymphocytes ◽  
Regulatory T Cells ◽  
Pulmonary Tuberculosis ◽  
Immune Suppression ◽  
Peripheral Blood ◽  
Newly Diagnosed ◽  
Clinical Form

Subpopulation structure of regulatory T-cells of peripheral blood in patients with newly diagnosed pulmonary tuberculosis depending on the clinical form of disease and sensitivity of Mycobacterium tuberculosis to anti-tuberculosis drugs have been analyzed in this work. It has been shown that in formation immune suppression at infiltrative, dissemination and fibrosis-cavity pulmonary tuberculosis the leading part play natural regulatory CD4+ CD25+ Foxр3+ -T-lymphocytes. Thus increase of their number in blood at drug-resistance and drugsusceptible patients. It has been demonstrated that in patients with fibro-cavernous and infiltrative form of the disease and drug-resistance pulmonary tuberculosis the number of CD4+ CD25- Foxр3+ -regulatory T-cells were increasing.

scholarly journals Regulatory T Cells in γ Irradiation-Induced Immune Suppression

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. e39092 ◽  
Author(s):  
Hugh I. McFarland ◽  
Montserrat Puig ◽  
Lucja T. Grajkowska ◽  
Kazuhide Tsuji ◽  
Jay P. Lee ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Suppression ◽  
Γ Irradiation

scholarly journals Biological microchips for detection of multiple drug resistant M. tuberculosis strains isolated in Kyrgyz Republic

2008 ◽  
pp. 64-66
Author(s):  
J. T. Isakova ◽  
Z. K. Goncharova ◽  
A. A. Aldashev
Keyword(s):  
Drug Resistance ◽  
Pulmonary Tuberculosis ◽  
Gene Mutations ◽  
Rpob Gene ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Kyrgyz Republic ◽  
Newly Diagnosed ◽  
Single Drug ◽  
Multiple Drug Resistant

The aim of the study was to estimate spread of primary and secondary multiple drug resistant Mycobacterium tuberculosis (MBT) and to characterize rpoB, katG, inhA, and ahpC gene mutations of rifampicin (RIF) and isoniazid (INH) resistant MBT strains isolated from tuberculosis patients in Kyrgyz. We obtained 493 specimens from patients with pulmonary tuberculosis which were diagnosed based on clinical, X-ray, and bacteriological examination. Among them, newly diagnosed pulmonary tuberculosis was in 445 patients (90.2 %), and 48 of the patients (9.8 %) have already been treated for tuberculosis. Mutations of rpoB, KatG, inhA, and ahpC genes associated with RIF and INH resistance were detected by biological chip test. Sensitive MBT strains were detected in 47 % and resistant strains were in 53 % of the newly diagnosed patients. Single-drug resistance to RIF only was detected in 3 % of cases; resistance to INH was found in 20 %, resistance to both the drugs was detected in 30 % of the patients. In pre-treated patients single-drug resistance to RIF was defined in 4 % of cases, resistance to INH was in 8 %, resistance to both the drugs was estimated in 75 % of the patients. Therefore, we suppose that there is a high prevalence of multi-drug resistant MBT in Kyrgyz Republic: 30 % among newly diagnosed patients and 75 % among pre-treated patients. The main cause of RIF-resistance of MBT is Ser531→Leu mutation of rpoB gene, and the main cause of INHresistance is Ser315→Thr mutation of katG gene.

Immune suppression with complex III

2019 ◽  
Vol 12 (566) ◽  
pp. eaaw7886
Author(s):  
John F. Foley
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Suppression ◽  
Complex Iii ◽  
Suppressive Activity ◽  
Mitochondrial Complex

Loss of mitochondrial complex III in regulatory T cells reduces their suppressive activity without affecting their survival.

Mechanisms of Suppression Used by Regulatory T Cells in Patients Newly Diagnosed with Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2938-2938 ◽  
Author(s):  
Miroslaw J Szczepanski ◽  
Marta Szajnik ◽  
Malgorzata Czystowska ◽  
Magis Mandapathil ◽  
Ann Welsh ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Regulatory T Cells ◽  
Myeloid Leukemia ◽  
Neutralizing Antibodies ◽  
Hematologic Malignancies ◽  
Cell Contact ◽  
Newly Diagnosed ◽  
Acute Myeloid

Abstract An elevated frequency of CD4+CD25high regulatory T cells (Treg) has been reported in the peripheral blood in patients with various solid tumors and hematologic malignancies. Although the increase in Treg seems to be a characteristic feature of most tumors, the functional role of Treg and the mechanisms of suppression, especially in patients with hematologic malignancies, have been less well defined. We investigated Treg-mediated suppression and the responsible mechanisms in thirty newly diagnosed acute myeloid leukemia (AML) patients prior to any treatment and twenty five healthy donors (NC). The percentage of circulating CD4+ CD25high Treg was higher (p <0.0001) in the AML patients (4.5 ±0.2%, range 1.7–8.2%) compared to NC (1.5 ± 0.08%, range 0.9–3.1 %). To evaluate the suppressive function, CD4+CD25high T cells (S) were co-cultured with sorted, CFSE-labeled autologous CD4+CD25high T cells (R) at different S/R ratios. Suppression mediated by Treg co-incubated with proliferating autologous responders was significantly higher (p<0.001) in AML than that mediated by control Treg. To evaluate the role of cytokines produced by Treg in suppression and a need for cell-to- cell contact, transwell analysis of S/R co-cultures was performed. Co-incubation in the presence of transwell inserts (TRI) resulted in significant reduction of suppression (p<0.05), and the addition of neutralizing antibodies to IL-10 and TGF-β1 in the presence of TRI further decreased suppression mediated by Treg. These data suggest that both immunoinhibitory cytokine production and cell-to-cell contact are necessary for suppression. To explore other potential mechanisms of Treg suppression, we evaluated the expression by Treg of ectonucleotidases CD39 and CD73 and the capability of Treg to produce adenosine. CD4+CD25high T cells of AML patients had higher expression (p<0.01) of CD39 and more efficiently hydrolyzed ATP to adenosine relative to Treg in NC. These data indicate that various mechanisms of suppression may be utilized by Treg in patients with AML. The increase frequency of Treg mediating potent suppression by various mechanisms is likely to play a role in host anti-tumor immune responses. Therefore, modulation of the frequency and functions of Treg might provide new immunotherapeutic approaches in AML.

Phase I trial of drug resistant immunotherapy: A first-in-class combination of MGMT-modified γδ t cells and temozolomide chemotherapy in newly diagnosed glioblastoma multiforme.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3150-TPS3150
Author(s):  
Lawrence S. Lamb ◽  
Shirley Gibbs ◽  
Thriumaine Pillay ◽  
Melissa Beelen ◽  
William Ho ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Phase I ◽  
Phase I Trial ◽  
Γδ T Cells ◽  
Fixed Dose ◽  
Drug Resistant ◽  
Newly Diagnosed ◽  
Γδ T Cell

TPS3150 Background: Temozolomide (TMZ) transiently upregulates GBM-specific stress-induced NKG2D ligands that are targeted by innate immune effector cells. Leveraging this effect is problematic, however, due to the lymphodepleting effects of TMZ.Genetic modification of ex vivo expanded and activated with an MGMT-expressing lentivector allows simultaneous chemotherapy and γδ T cell therapy that targets the tumor when NKG2DL are maximally expressed. We have termed this Drug Resistant Immunotherapy (DRI). Patient-derived xenograft mouse models of both primary and recurrent GBM treated with DRI have shown a significant survival advantage that were otherwise impervious to either cell therapy or TMZ. These preclinical findings and associated safety data provide the rationale to initiate a Phase I trial of DRI in primary GBM. Methods: This first in human study will evaluate the safety and optimal dosing frequency of the DRI with TMZ (NCT04165941).Eligibility criteria include the following: GBM eligible for resection, ≥18y, adequate organ and marrow function, and KPS≥70. Six to 12patients with newly diagnosed GBM are being enrolled in a 3 + 3 design into 1 of 2 fixed dose levels (DL) of DRI. Following tumor resection and immediately prior to induction chemo/radiotherapy, an apheresis product is collected and γδ T cells expanded in Zoledronic Acid (Novartis) and rhIL-12 (Miltenyi) and transduced with a P140K-MGMT lentivector (Miltenyi Lentigen, Gaithersburg, MD), harvested, and cryopreserved. At initiation of maintenance phase TMZ therapy, patients receive 150mg/m2 intravenous TMZ concurrently with intracranial injection of 1 x 107 γδ T cells (DL1) delivered through a Rickham reservoir previously inserted into the tumor cavity at resection. The patient then receives 4 daily doses of oral TMZ followed by 24d rest. Treatment cycles escalate from 1 to 3 (DL2) DRI doses following a safety observation period and absence of dose limiting toxicity. Maintenance TMZ treatment will continue for 6 cycles. Safety evaluations consist of routine laboratory analyses, clinical measurements (physical exams, vital signs), neurological function and evidence DRI γδ T cell related toxicity. Peripheral blood will be obtained for comprehensive immuno-phenotyping and T cell function analysis. Clinical benefit of DRI will be characterized by evaluating responses (CR, PR, SD and PD) and determining progression-free, median, and overall survival. As of February 2020, enrollment into DL 1 is ongoing. Clinical trial information: NCT04165941 .

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