scholarly journals MP3: ROLE OF HISTONE DEACTYLASE (HDAC) INHIBITORS IN ADULT T-CELL LYMPHOMA/LEUKEMIA (ATL)

2016 ◽  
Vol 64 (3) ◽  
pp. 805.2-805 ◽  
Author(s):  
N Mukhi ◽  
G Sidhu ◽  
J Gonsky ◽  
I Shapira
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
Progressive Disease ◽  
Hdac Inhibitors ◽  
Disease Patient ◽  
Disease Process ◽  
Viral Reactivation ◽  
Hbv Reactivation ◽  
Human T Cell

Purpose of StudyATL is a peripheral T-cell neoplasm(PTCL) associated with human T-cell lymphotropic virus-1 (HTLV-1) infection. Currently there is no established therapy for relapsed/refractory disease. Initial in-vitro studies of HDAC inhibitors showed selective apoptosis of HTLV-1 infected T cell lines. In phase II trial for relapsed/refractory PTCL, 2 patients had EBV and 1 patient had HBV reactivation. It was unclear if this was from HDAC induced immunosuppression or direct promotion of viral replication or underlying disease process. All HDAC inhibitors trials in last 6 years excluded ATL patients although they are approved for this disease. We here describe our experience of 3 patients with relapsed/refractory ATL treated with HDAC inhibitor romidepsin.Methods UsedChart review of patients with relapsed/refractory ATL treated with romidepsin at King's County Hospital.Summary of ResultsCase 1: 43 year old male with acute ATL who progressed on EPOCH after 4 cycles. Romidepsin was started at 14 mg/m2 IV Day 1, 8, 15 Q28 days. He tolerated cycle 1 well but continued to have progressive disease. Patient died 40 days after initiation of therapy from infection.Case 2: 37 year old male with acute ATL who had disease progression on EPOCH×2 cycles. He was started on romidepsin 10 mg/m2 IV (dose reduced due to T. bili 3.5 gm/dl). After first dose, his platelets dropped to to 20 k/mm3 necessitating treatment delay and dose reduction to 6 mg/m2. He had temporary response as evidenced by reduction in WBC count from 103 kmm3 to 5 k/mm3 and improvement in liver function. He only received 1 cycle and died on Day 50 from disease progression.Case 3: 47 year old male with ATL lymphoma intially treated with CHOP×6 cycles and relapsed after 1 year with peripheral lymphocytosis to 57 k/mm3 and diffuse lymphadenopathy. He received ICE×2 cycles with progressive disease. He was started on romidepsin 14 mg/m2. He received 1 dose and had Grade IV anemia/thrombocytopenia. He developed urosepsis and expired on Day 20.ConclusionsIn our small experience of romidepsin in relapsed/refractory ATL, patients appear to have modest response rates and higher rate of cytopenias when compared to other PTCL subtypes in clinical trials. Given the concerns for viral reactivation and lack of data for use of romidepsin in ATL, it should be used cautiously.

scholarly journals DL4-μbeads induce T cell lineage differentiation from stem cells in a stromal cell-free system

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ashton C. Trotman-Grant ◽  
Mahmood Mohtashami ◽  
Joshua De Sousa Casal ◽  
Elisa C. Martinez ◽  
Dylan Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
T Cell ◽  
Stromal Cell ◽  
Hematopoietic Stem ◽  
Free System ◽  
Cell Therapies ◽  
Immunodeficient Mice ◽  
Human T Cell

AbstractT cells are pivotal effectors of the immune system and can be harnessed as therapeutics for regenerative medicine and cancer immunotherapy. An unmet challenge in the field is the development of a clinically relevant system that is readily scalable to generate large numbers of T-lineage cells from hematopoietic stem/progenitor cells (HSPCs). Here, we report a stromal cell-free, microbead-based approach that supports the efficient in vitro development of both human progenitor T (proT) cells and T-lineage cells from CD34+cells sourced from cord blood, GCSF-mobilized peripheral blood, and pluripotent stem cells (PSCs). DL4-μbeads, along with lymphopoietic cytokines, induce an ordered sequence of differentiation from CD34+ cells to CD34+CD7+CD5+ proT cells to CD3+αβ T cells. Single-cell RNA sequencing of human PSC-derived proT cells reveals a transcriptional profile similar to the earliest thymocytes found in the embryonic and fetal thymus. Furthermore, the adoptive transfer of CD34+CD7+ proT cells into immunodeficient mice demonstrates efficient thymic engraftment and functional maturation of peripheral T cells. DL4-μbeads provide a simple and robust platform to both study human T cell development and facilitate the development of engineered T cell therapies from renewable sources.

scholarly journals Biochemical Characterization, Specificity and Inhibition Studies of HTLV-1, HTLV-2, and HTLV-3 Proteases

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 127
Author(s):  
Norbert Kassay ◽  
János András Mótyán ◽  
Krisztina Matúz ◽  
Mária Golda ◽  
József Tőzsér
Keyword(s):  
T Cell ◽  
Biochemical Characterization ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

The human T-lymphotropic viruses (HTLVs) are causative agents of severe diseases including adult T-cell leukemia. Similar to human immunodeficiency viruses (HIVs), the viral protease (PR) plays a crucial role in the viral life-cycle via the processing of the viral polyproteins. Thus, it is a potential target of anti-retroviral therapies. In this study, we performed in vitro comparative analysis of human T-cell leukemia virus type 1, 2, and 3 (HTLV-1, -2, and -3) proteases. Amino acid preferences of S4 to S1′ subsites were studied by using a series of synthetic oligopeptide substrates representing the natural and modified cleavage site sequences of the proteases. Biochemical characteristics of the different PRs were also determined, including catalytic efficiencies and dependence of activity on pH, temperature, and ionic strength. We investigated the effects of different HIV-1 PR inhibitors (atazanavir, darunavir, DMP-323, indinavir, ritonavir, and saquinavir) on enzyme activities, and inhibitory potentials of IB-268 and IB-269 inhibitors that were previously designed against HTLV-1 PR. Comparative biochemical analysis of HTLV-1, -2, and -3 PRs may help understand the characteristic similarities and differences between these enzymes in order to estimate the potential of the appearance of drug-resistance against specific HTLV-1 PR inhibitors.

scholarly journals Histone/protein deacetylases and T-cell immune responses

Blood ◽  
2012 ◽  
Vol 119 (11) ◽  
pp. 2443-2451 ◽  
Author(s):  
Tatiana Akimova ◽  
Ulf H. Beier ◽  
Yujie Liu ◽  
Liqing Wang ◽  
Wayne W. Hancock
Keyword(s):  
T Cell ◽  
Cell Biology ◽  
T Regulatory Cells ◽  
Hdac Inhibitors ◽  
Experimental Studies ◽  
Cell Subset ◽  
Histone Protein ◽  
Anti Inflammatory

Abstract Clinical and experimental studies show that inhibition of histone/protein deacetylases (HDAC) can have important anti-neoplastic effects through cytotoxic and proapoptotic mechanisms. There are also increasing data from nononcologic settings that HDAC inhibitors (HDACi) can exhibit useful anti-inflammatory effects in vitro and in vivo, unrelated to cytotoxicity or apoptosis. These effects can be cell-, tissue-, or context-dependent and can involve modulation of specific inflammatory signaling pathways as well as epigenetic mechanisms. We review recent advances in the understanding of how HDACi alter immune and inflammatory processes, with a particular focus on the effects of HDACi on T-cell biology, including the activation and functions of conventional T cells and the unique T-cell subset, composed of Foxp3+ T-regulatory cells. Although studies are still needed to tease out details of the various biologic roles of individual HDAC isoforms and their corresponding selective inhibitors, the anti-inflammatory effects of HDACi are already promising and may lead to new therapeutic avenues in transplantation and autoimmune diseases.

Wogonin preferentially kills malignant lymphocytes and suppresses T-cell tumor growth by inducing PLCγ1- and Ca2+-dependent apoptosis

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2354-2363 ◽  
Author(s):  
Sven Baumann ◽  
Stefanie C. Fas ◽  
Marco Giaisi ◽  
Wolfgang W. Müller ◽  
Anette Merling ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Therapeutic Potential ◽  
Human T Cell ◽  
Voltage Dependent ◽  
Ca2 Channels ◽  
Malignant T Cells

Herbs have successfully been used in traditional Chinese medicine for centuries. However, their curative mechanisms remain largely unknown. In this study, we show that Wogonin, derived from the traditional Chinese medicine Huang-Qin (Scutellaria baicalensis Georgi), induces apoptosis in malignant T cells in vitro and suppresses growth of human T-cell leukemia xenografts in vivo. Importantly, Wogonin shows almost no toxicity on T lymphocytes from healthy donors. Wogonin induces prolonged activation of PLCγ1 via H2O2 signaling in malignant T cells, which leads to sustained elevation of cytosolic Ca2+ in malignant but not normal T cells. Subsequently, a Ca2+ overload leads to disruption of the mitochondrial membrane. The selective effect of Wogonin is due to its differential regulation of the redox status of malignant versus normal T cells. In addition, we show that the L-type voltage-dependent Ca2+ channels are involved in the intracellular Ca2+ mobilization in T cells. Furthermore, we show that malignant T cells possess elevated amounts of voltage-dependent Ca2+ channels compared with normal T cells, which further enhance the cytotoxicity of Wogonin for malignant T cells. Taken together, our data show a therapeutic potential of Wogonin for the treatment of hematologic malignancies.

scholarly journals Lipid Microbubble–Conjugated Anti-CD3 and Anti-CD28 Antibodies (Microbubble-Based Human T Cell Activator) Offer Superior Long-Term Expansion of Human Naive T Cells In Vitro

2020 ◽  
Vol 4 (8) ◽  
pp. 475-484
Author(s):  
Ana Lustig ◽  
Ty’Keemi Manor ◽  
Guixin Shi ◽  
Jiangyuan Li ◽  
Ying-Ting Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Human T Cell ◽  
Cell Activator

scholarly journals Tax and Overlapping Rex Sequences Do Not Confer the Distinct Transformation Tropisms of Human T-Cell Leukemia Virus Types 1 and 2

2003 ◽  
Vol 77 (14) ◽  
pp. 7728-7735 ◽  
Author(s):  
Jianxin Ye ◽  
Li Xie ◽  
Patrick L. Green
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Human T Cell ◽  
T Cell Leukemia Virus

ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are distinct oncogenic retroviruses that infect several cell types but display their biological and pathogenic activity only in T cells. Previous studies have indicated that in vivo HTLV-1 has a preferential tropism for CD4+ T cells, whereas HTLV-2 in vivo tropism is less clear but appears to favor CD8+ T cells. Both CD4+ and CD8+ T cells are susceptible to HTLV-1 and HTLV-2 infection in vitro, and HTLV-1 has a preferential immortalization and transformation tropism of CD4+ T cells, whereas HTLV-2 immortalizes and transforms primarily CD8+ T cells. The molecular mechanism that determines this tropism of HTLV-1 and HTLV-2 has not been determined. HTLV-1 and HTLV-2 carry the tax and rex transregulatory genes in separate but partially overlapping reading frames. Since Tax has been shown to be critical for cellular transformation in vitro and interacts with numerous cellular processes, we hypothesized that the viral determinant of transformation tropism is encoded by tax. Using molecular clones of HTLV-1 (Ach) and HTLV-2 (pH6neo), we constructed recombinants in which tax and overlapping rex genes of the two viruses were exchanged. p19 Gag expression from proviral clones transfected into 293T cells indicated that both recombinants contained functional Tax and Rex but with significantly altered activity compared to the wild-type clones. Stable transfectants expressing recombinant viruses were established, irradiated, and cocultured with peripheral blood mononuclear cells. Both recombinants were competent to transform T lymphocytes with an efficiency similar to that of the parental viruses. Flow cytometry analysis indicated that HTLV-1 and HTLV-1/TR2 had a preferential tropism for CD4+ T cells and that HTLV-2 and HTLV-2/TR1 had a preferential tropism for CD8+ T cells. Our results indicate that tax/rex in different genetic backgrounds display altered functional activity but ultimately do not contribute to the different in vitro transformation tropisms. This first study with recombinants between HTLV-1 and HTLV-2 is the initial step in elucidating the different pathobiologies of HTLV-1 and HTLV-2.

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