Upregulation of TCRζ Chain Overcome T Cell Immunodeficiency in Patients with Chronic Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4719-4719
Author(s):  
Xianfeng Zha ◽  
Shaohua Chen ◽  
Lijian Yang ◽  
Bo Li ◽  
Yu Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Science ◽  
Myeloid Leukemia ◽  
Transfection Efficiency ◽  
Guangdong Province ◽  
Control Group ◽  
Control Vector ◽  
T Cell Immunodeficiency ◽  
And Control

Abstract Abstract 4719 TCRζ chain is the key molecular of TCR signaling, the defective TCRζ chain not only decreases the expression of TCR on the T cell surface and the quantity of circulation T cells, but also influences T cell activation and proliferation. Previous studies indicated that the obvious downregulation of TCRζ chain was one of main factors which caused T cell immunodeficiency in patients with chronic myeloid leukemia (CML), which lead to dysfunction of immune supervision to tumor. This study was undertaken to explore the possibility that forced expression of TCRζ chain may restored the T cell immune function. In present study, the freshly CD3 + T cells were isolated by MACS from de novo CML patients; freshly T cells were transfected with TCRζ chain recombinant vector (TCRζ-IRES-EGFP) and control vector (pIRES2-EGFP) by nucleoporation technique. The transfection efficiency was detected by FCM at 18 hours post-transfection, and TCRζ chain protein and its phosphorylation were detected by Western blotting after activation with OKT3 antibody for 1 minute. The supernatants and RNA were collected from transfected cells stimulated with OKT3 and anti-CD28 antibody, for analysis of IL-2 levels and the mRNA expression of ZAP70 and NF-κB. The results showed the transfection efficiency of TCRζ chain vector and control vector construct was 72.16±6.95% and 73.4±7.90% in CML T cells from different patients respectively. In T cells transfected with TCRζ chain, the expression of TCR chain was increased, the IL-2 production induced by OKT3 and anti-CD28 antibody in TCRζ chain transfected T cells (175.1±66.3pg/mL) were higher than that from control group (107.6±65.5pg/mL) (n=6, p=0.039). The bother expression levels of ZAP-70 and NF-κ B in the experimental group was higher than the control group (n = 4, p < 0.05), moreover the expression level between ZAP-70 and NF-κB showed linear correlation (n = 4, p = 0.013, r = 0.98). In conclusion, the results indicate that upregulation of deficient TCRζ chain may reverse the TCR/CD3-mediated signaling abnormalities, which may improve the T cell immune function in patients with CML. This study was supported by grant from the Key project of Natural Science Foundation of Guangdong Province, China (No. 9251063201000001). Disclosures: Zha: This study was supported by grant from the Key project of Natural Science Foundation of Guangdong Province, China (No. 9251063201000001): Research Funding. Li:the Key project of Natural Science Foundation of Guangdong Province: Research Funding.

scholarly journals Role of Adoptive T- Cell Therapy in Post Hematopoietic Stem Cells Transplant Viral Infections-: A Systemic Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-16
Author(s):  
Hassaan Imtiaz ◽  
Muhammad Saad Farooqi ◽  
Unaiza Faizan ◽  
Saad Ur Rehman ◽  
Muhammed Hamza Arshad ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Phase I ◽  
Viral Infections ◽  
Adoptive T Cell Therapy ◽  
Control Group ◽  
T Cell Therapy ◽  
And Control ◽  
Cmv Reactivation

Introduction Allogenic hematopoietic stem cell transplantation (Allo-HSCT) used for the treatment of multiple hematological malignancies requires immunosuppression, that can lead to the reactivation of viruses like EBV, CMV, adenovirus (AdV). These viruses pose a life-threatening risk to an individual like Graft vs Host Disease (GVHD) and other virus-specific complications. Adoptive T cell therapy (ATC) is an approach to treat refractory post-Allo-HSCT transplant viral infections. The aim of this study is to assess the efficacy of various ATCs being developed against various viruses. Methods A systematic search on PubMed, Embase, Clinicaltrials.gov, and Web of Science was performed for adoptive immunotherapy in viral infections after stem cell transplantation from inception to May 28, 2020. Out of 604 studies, 13 phase I and II clinical trials were selected for the systematic review. Results A total of 13 studies were included of which two studies included data on the pediatric population (n=13). A total of 335 patients (pts) were enrolled in 13 studies of which 264 were evaluable. CMV Perruccio et al. (2005) in a randomized controlled trial (RCT) assessed the efficacy of ATC against both Aspergillus and CMV after alloSCT. Median follow up (f/u) was six months. For Aspergillus (n=23), 90% and 54% achieved clearance, while for CMV (n=68) 92% and 9% didn't develop CMV reactivation in treatment and control group respectively. Overall Survival (OS) and progression-free survival (PFS) rate at two years were 92% and 80% respectively. Smith et al. (2018) (n=21) in a phase I trial studied the transfusion of virus-specific T cells (VST) (n=13) against CMV infection after undergoing alloSCT. After a median f/u of 28 weeks, overall response rate (ORR) was 85%. Bao et al. (2012) (n=10) conducted a study with VST transfusion against CMV infection (n=7). ORR was 85% of which 3 pts who were on immunosuppressive had shown reactivation. Miej et al. (2012) in phase I/II study (n=6) assessed the response of VST against refractory CMV with CR of 100% Neuenhahn et al. (2017) studied a phase I/II prospective trial (n=17) (CMV Seropositive graft donor (D+) 9/17 and CMV Seronegative graft donor (D-) 8/17) with CR of 62% in D+ group. In D- group only 37% developed T cells after Third-Party Donor transfer and only these achieved CR, while pts with no T cell detection in D- group (63%), only one achieved CR. Micklethwaite et al. (2008) did a phase I clinical trial (n=12) of CMV specific T cells given prophylactically. Only four pts showed CMV reactivation. Adenovirus Feucht et al. (2019) performed a phase I/II clinical trial (n=30) of VST against refractory AdV infection. 47% showed CR, 13% with negative blood AdV cleared virus from other sites, 10% showed PR. OS at six months was 71%. Winnie et al. (2018) (n=8) conducted phase I/II RCT among pediatric pts. Median f/u was six months. All patients have shown a decrease in AdV viral load. Qasim et al. (2013) conducted a prospective trial (n=5) among pediatric pts with CR of 60% until six weeks f/u. 20% died due to AdV viremia. Multi-virus CTLs Gerdemann et al. (2013) (n=36) did a clinical trial by infusing multi-virus cytotoxic T lymphocytes (CTLs) (n=10), reactive against CMV, EBV, and AdV. CR in 80% of the pts. Muranski et al. (2017) performed a phase I trial (n=9) and infused multi-virus CTLs prophylactically. No AdV, BK, or EBV related disease was observed in any pts while 11% pts had asymptomatic AdV viremia. Only those pts who received steroid therapy had CMV reactivation (44%). Ma et al. (2015) performed a phase I/II RCT with an intervention group (n=19, evaluable=10) and control group (n=33) with an infusion of multi-virus CTLs against CMV, EBV, AdV, and VZV after alloSCT, prophylactically. Pts in the intervention group had no reactivation of EBV, AdV, or VZV. 6 (60%) pts with CMV had reactivation; four before T cell therapy and two in the context of steroid therapy. OS at one year was 89% and 81% in the intervention and control group respectively. Third-Party Donor T-cells Tzannou et al. (2017) (n=37) in a phase II study demonstrated ORR of 92% (95% CI, 78.1% to 98.3%) in various viruses with ORR for BK virus 100%, CMV 94%, Adv 71%, EBV 100% and HHV-6 67%. Conclusion Adoptive T cell therapy for viral infections has shown efficacy in Post- allo-SCT pts who achieved complete clearance of infection in many cases, showed only minimal adverse events, and no major risk for GVHD related to this therapy was noted. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Characteristics of the TCR Vbeta Repertoire and Identical Clonally Expanded T Cells in Chronic Myeloid Leukemia Patients in Advanced Phase with ABL Mutations

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5136-5136
Author(s):  
Ling Xu ◽  
Yuhong Lu ◽  
Jing Lai ◽  
Wei Yu ◽  
Zhenyi Jin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Natural Science ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytotoxic Lymphocyte ◽  
Advanced Phase

Abstract Abstract Tumor specific or related antigen cytotoxic lymphocyte (CTL) have been identified in chronic myeloid leukemia patients, however, whether they are constituted by specific type of T cell receptor chains has not been illustrated so far. Previous studies have reported abnormal TCR repertoires and clonally expanded TCR Vβ T cells in chronic myeloid leukemia in chronic phase (CP-CML). In this study, we investigated the distribution and clonality of the TCR Vβ repertoire in 5 CML patients in blast crisis (BC-CML) and one in acceleration phase (AP-CML) with ABL kinase domain mutations (KDMs) including T315I, E255K, F317L+S417Y, Y-253F and L387M+T-315A. Examination of TCR Vβ expression and clonality was performed by reverse transcription-polymerase chain reaction (RT-PCR) combined with GeneScan analysis. Significantly skewed TCR Vβ repertoires were observed in those patients, and 4 to 8 oligoclonally expanded TCR Vβ subfamilies could be identified in each sample, which distributed in 15/24 different subfamilies (TCR Vβ4, Vβ5, Vβ6, β8, Vβ9, Vβ10, Vβ15, Vβ16, Vβ17, Vβ18, Vβ19, Vβ21, Vβ22, Vβ23, Vβ24). Intriguingly, a relatively highly expanded Vβ9 clone with the same length as CDR3 (139 bp) was found in all three CML patients in lymphoid blast crisis (LBC-CML) who had different KDMs, but the clone was not detected in the other two CML patient in myeloid blast crisis (MBC-CML) or the one CML patients in accelerated phase. In conclusion, restricted TCR Vβ repertoire expression and decreased clone complexity was a general phenomenon in the BC-CML patients with different KDMs, indicating the T-cell immunodeficiency status of these patients, and clonally expanded Vβ9 T cell clones may represent a specific immune response to leukemia-associated antigens in LBC-CML patients. Disclosures Li: The Foundation for High-level Talents in Higher Education of Guangdong, China ([2013]246-54),and the Guangzhou Science and Technology Project Foundation (201510010211): Research Funding; National Natural Science Foundation of China (81270604, U1301226, and 81400109), the Guangdong Natural Science Foundation (S2013040016151 and S2013020012863): Research Funding.

scholarly journals T-Cell Reconstitution after Unrelated Donor HSCT Using Immunotherapy with CD25/71 Allodepleted Donor T Cells: Results of the Randomised Icat Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1995-1995
Author(s):  
Karl S Peggs ◽  
Sarah J Albon ◽  
Catherine Irving ◽  
Rachel Richardson ◽  
Joan Casanovas-Company ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Count ◽  
Chronic Gvhd ◽  
Control Group ◽  
Unrelated Donor ◽  
Donor T Cells ◽  
The Mean ◽  
And Control ◽  
To Receive

Karl S Peggs and Sarah J Albon contributed equally to the work and are joint first author Introduction Alemtuzumab reduces the incidence of GVHD after unrelated donor stem cell transplant (MUD SCT) but delays immune reconstitution resulting in high morbidity/mortality from viral infections. Previous studies have suggested that adoptive transfer of allodepleted donor T cells (ADTs) improves immunity after SCT but this has never been tested in a randomised study. We developed a methodology for selective immunomagnetic depletion of alloreactive T-cells upregulating CD25 and CD71 after activation with host dendritic cells (DC) and showed that ADTs retain anti-viral responses with minimal host alloreactivity (Samarasinghe et al Blood 2010). We have now tested whether ADTs can safely be used to improve immune reconstitution after MUD SCT for haematological malignancies in a randomised Phase II multi-centre clinical study; ICAT (NCT01827579). Methods Patients undergoing Alemtuzumab-based peripheral blood SCT from a 9/10 or 10/10 MUD for haematological malignancy were randomised 2:1 to receive either the ATIMP (ADTs) or standard of care. Two weeks prior to SCT, patients randomised to ATIMP underwent a leucapheresis from which DCs were generated. Irradiated patient-derived DCs were then co-cultured with peripheral blood mononuclear cells (PBMC) from an unstimulated leucapheresis/500ml blood draw from the donor to activate alloreactive T cells. Four days later, the co-culture was depleted of CD25+ and CD71+ fractions by immunomagnetic depletion on the CliniMACs, sampled for residual alloreactivity and sterility, and cryopreserved. Patients randomised to the ATIMP were scheduled to receive 3 escalating doses of ADTs (0.1x106/Kg at day 30, 0.3x106/Kg at day 60 and 1x106/Kg at day 90 post-SCT) until either there was >grade 1 aGVHD or they had normal circulating T cells (>700/µL). The primary end-point of the study was circulating CD3+ T cell count at 4 months post-SCT with one-sided 15% significance level. Acute/chronic GVHD were graded using the Seattle/NIH criteria respectively. Results Twenty one patients were treated, 13 on the ATIMP arm and 8 on the control arm. The median age was 53 years and 67% (14) were male. 12 were AML/Myelodysplasia, 5 NHL, 3 CLL/CML and 1 HL. The median follow-up time is 14 months. Five of 13 ATIMP patients received 1 dose of ADTs, 4/13 2 doses and 4/13 all 3 doses. The incidence of acute and chronic GVHD was comparable between the arms. Overall, 7/13 ATIMP patients developed significant (>Grade 2) acute GVHD compared to 4/8 of the control arm (p>0.99). 3/13 patients in the ATIMP arm and 2/8 patients in the control arm developed severe aGVHD (all Grade 3). Three of 13 ATIMP cohort patients developed chronic GVHD (1 mild, 1 moderate, 1 severe), compared to 3/8 (all mild) in the control cohort. At 4 months, the circulating CD3+ T cell count mean was 730/µL (range 10-4080) in the ATIMP group and 212.5/µL (range 10-500) in the control group (1-sided p=0.11). However, the data was not normally distributed (Wilcoxon 1-sided p=0.18). Three ATIMP patients had high CD3+ T cell count at 4 months (>1000/µL). At 6 months, the mean circulating CD3+ T cell count was 833.6/µL (range 20-2690) and 327.5/µL (range 10-860). At month 4, the mean PHA stimulation index in the ATIMP arm was 16.8 (range 0.67- 73.1) vs 3.8 (range 1.1-8.2) in the control group. At 4 and 6 months post-SCT, spectratyping analysis showed no evidence of a difference in Vβ diversity between the 2 arms in both CD4+ and CD8+ cells. The 1-year survival rate in the ATIMP cohort is 92% vs 88% in the control, and 1-year disease free survival rate 67% in the ATIMP cohort vs 70% in the control. Conclusions These data suggest that adoptive transfer of ADTs improves T cell reconstitution in some patients after MUD SCT and that the GVHD rates were similar between ATIMP and control groups. Figure 1: Kinetics of T cell recovery after transplant in ATIMP (blue) and Control (red) patients. Mean +/- SEM shown. Figure 1 Disclosures Peggs: Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees. Ghorashian:UCLB: Patents & Royalties: UCLB; Celgene: Honoraria; novartis: Honoraria. Amrolia:UCLB: Patents & Royalties.

Dysexpression of TCRζ Related Genes in the Patients with Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4832-4832
Author(s):  
Xianfeng Zha ◽  
Xiaojuan Yan ◽  
Qi Shen ◽  
Xiuli Wu ◽  
Shaohua Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Expression Pattern ◽  
Natural Science ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Guangdong Province ◽  
Splicing Factor ◽  
Healthy Individuals ◽  
Expression Levels

Abstract Abstract 4832 T-cell immunodeficiency is a common feature in patients with chronic myeloid leukemia (CML), and deficiency in CD3 levels was detected in T cells from these patients, which may represent a characteristic that is related to lower T cell activation. Based on our previous finding that the expression level of the TCRζ chain gene was decreased significantly in CML, we further investigated the expression pattern of the TCRζ regulating factors. TCRζ 3′ untranslated region (3′-UTR) and the alternative splicing factor/splicing factor 2 (ASF/SF-2), to evaluate the regulating effect of ASF/SF-2 on the formation of TCRζ 3′-UTR. Moreover, the expression levels and the correlations of the FcεRIγ gene, which has a complementary to TCRζ, and the TCRζ downstream ZAP-70 gene, were analyzed. The TCRζ 3′-UTR were amplified from peripheral blood mononuclear cells (PBMCs) in 14 healthy individuals, 40 cases with CML and 22 cases with CML-CR by RT-PCR, and the splice variants of TCRζ 3′-UTR were identified. The expression levels of TCRζ, FcεRIγ, ASF/SF-2 gene and ZAP-70 gene were analyzed by real-time quantitative PCR. The results showed that two types of spliceosome: wild typed TCRζ 3′-UTR (906 bp) and alternative spliced TCRζ 3′-UTR (344 bp) could be detected in all healthy individuals. However, 35% of CML cases contained only the wild typed TCRζ 3′-UTR, which was significantly different from healthy individuals and CML-CR groups (p<0.001, p<0.001). The expression of TCRζ gene in CML group was significantly lower than healthy individuals and CML-CR groups (p=0.001,p<0.001), while significantly higher expression of FcεRIγ gene(p<0.001,p<0.001)and ASF/SF-2 (p=0.016,p<0.001) were found in CML group. According to the TCRζ 3′-UTR spliceosome feature, the CML patients were divided in two subgroups, patients who contained only the wild typed TCRζ 3′-UTR named as WT+AS− CML group, and patients who contained two types of TCRζ 3′-UTR named as WT+AS+ CML group. Significantly higher expression levels of ASF/SF-2 and FcεRIγ genes were found in WT+AS−CML group in comparison with WT+AS+ CML group (p=0.003,p=0.001), while the expression levels of TCRζ and ZAP-70 were decreased in WT+AS−CML group (Fig 1). In conclusions, the defective expression of TCRζ in CML might relate to the overexpression of ASF/SF2, which alternatively spliced the expression of TCRζ3′-UTR. The upregulation of FcεRIγ gene may overcome the defective status of TCRζ in a certain degree. Figure 1. Different expression pattern of ASF/SF-2, TCRζ, ZAP-70 and FcεRIγ genes in WT+AS-CML and WT+AS+CML. Figure 1. Different expression pattern of ASF/SF-2, TCRζ, ZAP-70 and FcεRIγ genes in WT+AS-CML and WT+AS+CML. Disclosures: Chen: Fundamental Research Funds for the Central Universities (No. 21611447, 21612116): Research Funding. Li:Fundamental Research Funds for the Central Universities (No. 21611447, 21612116): Research Funding; Natural Science Foundation of Guangdong Province, China (No. 9251063201000001): Research Funding; National Natural Science Foundation of China (No. 81100353): Research Funding; Medical Science Foundation of Guangdong Province (A2011325): Research Funding.

EFFECTS OF THYROXINE ON T-CELL COUNTS AND TUMOUR CELL REJECTION IN MICE

1976 ◽  
Vol 81 (1) ◽  
pp. 104-109 ◽  
Author(s):  
N. Aoki ◽  
G. Wakisaka ◽  
I. Nagata
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tritiated Thymidine ◽  
Cell Activity ◽  
Treated Group ◽  
Carcinoma Cells ◽  
Ehrlich Carcinoma ◽  
Control Group ◽  
Cell Counts ◽  
And Control

ABSTRACT In an attempt to study the effect of thyroxine on peripheral T-cell (thymus derived lymphocyte) counts or immunological functions, inbred C3H/He mice (8–10 weeks old) were injected subcutaneously with thyroxine for more than 3 months. After treatment for 3 months the mice were examined for peripheral T-cell counts, thymic incorporation of tritiated thymidine and rejection of tumour transplants. The number of T-cells was counted by the indirect immunoflourescence method using anti-ΘC3H serum after separation of lymphocytes on "Ficoll-Conray". It was revealed that the peripheral counts of both lymphocytes and T-cells were increased in the thyroxine treated group as compared with the control group, as was reported in the patients with Graves' disease. Thymic incorporation of tritiated thymidine was also found to be significantly increased in the thyroxine treated group. In addition, in order to study T-cell activity of the host, thyroxine treated and control mice were challenged with Ehrlich carcinoma cells at several concentrations (102, 104 and 2 × 106 per mouse). It was found that rejection of tumour transplants was significantly enhanced in the T-cell rich mice. Thus, it is possible that thyroxine affects peripheral T-cell counts and enhances immunological functions of the host.

scholarly journals Effects of therapeutic vaccination on the control of SIV in rhesus macaques with variable responsiveness to antiretroviral drugs

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253265
Author(s):  
Hillary Claire Tunggal ◽  
Paul Veness Munson ◽  
Megan Ashley O’Connor ◽  
Nika Hajari ◽  
Sandra Elizabeth Dross ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Rhesus Macaques ◽  
Treatment Interruption ◽  
Antiretroviral Drugs ◽  
Control Group ◽  
Viral Rebound ◽  
Significant Difference ◽  
And Control

A therapeutic vaccine that induces lasting control of HIV infection could eliminate the need for lifelong adherence to antiretroviral therapy. This study investigated a therapeutic DNA vaccine delivered with a single adjuvant or a novel combination of adjuvants to augment T cell immunity in the blood and gut-associated lymphoid tissue in SIV-infected rhesus macaques. Animals that received DNA vaccines expressing SIV proteins, combined with plasmids expressing adjuvants designed to increase peripheral and mucosal T cell responses, including the catalytic subunit of the E. coli heat-labile enterotoxin, IL-12, IL-33, retinaldehyde dehydrogenase 2, soluble PD-1 and soluble CD80, were compared to mock-vaccinated controls. Following treatment interruption, macaques exhibited variable levels of viral rebound, with four animals from the vaccinated groups and one animal from the control group controlling virus at median levels of 103 RNA copies/ml or lower (controllers) and nine animals, among all groups, exhibiting immediate viral rebound and median viral loads greater than 103 RNA copies/ml (non-controllers). Although there was no significant difference between the vaccinated and control groups in protection from viral rebound, the variable virological outcomes during treatment interruption enabled an examination of immune correlates of viral replication in controllers versus non-controllers regardless of vaccination status. Lower viral burden in controllers correlated with increased polyfunctional SIV-specific CD8+ T cells in mesenteric lymph nodes and blood prior to and during treatment interruption. Notably, higher frequencies of colonic CD4+ T cells and lower Th17/Treg ratios prior to infection in controllers correlated with improved responses to ART and control of viral rebound. These results indicate that mucosal immune responses, present prior to infection, can influence efficacy of antiretroviral therapy and the outcome of immunotherapeutic vaccination, suggesting that therapies capable of modulating host mucosal responses may be needed to achieve HIV cure.

Immunomodulatory Influence by Interferon alpha and Imatinib Mesylate in Chronic Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4534-4534
Author(s):  
Kazuaki Yokoyama ◽  
Tokiko Nagamura-Inoue ◽  
Shin Nakayama ◽  
Ikuo Ishige ◽  
Nobuhiro Ohno ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
T Cell Activation ◽  
Myeloid Leukemia ◽  
Cell Activation ◽  
Cell Function ◽  
Control Group ◽  
Immunological Parameters

Abstract Objectives: Imatinib mesylate (STI) is the first-line therapy for chronic myeloid leukemia in the chronic phase (CML-CP). However, STI as well as interferonα (IFN) has been reported to inhibit both T-cell activation and B cell function. To clarify the immunological differences by the type of therapy, we compared immunological parameters between CML patients in very good CyR to either STI or IFN as well as normal volunteers. We also studied the in vitro effects of STI on immune cell function. Patients and Methods: Each group comprised 14 subjects. The median treatment dose and duration were 6 MIU/week and 174 months for IFN, and 400 mg/day and 54 months for STI, respectively. Peripheral blood sample was used and subjected to multi-color flow cytometry (FCM) acquisition and analysis. For analysing TCR-mediated activation of T cells, we stained MNC with CFSE and stimulated those with anti-CD3/CD28 antibodies in the presence of STI at various concentrations for 4 days, followed by FCM. Results: The summary is shown in Table. WBC counts were well controlled at moderately lower levels than in the control group of normal volunteers: Hb levels were significantly reduced in the STI-group compared to the other two groups (P<0.0001), while platelet counts were lower in the IFN-group than in the control group (P<0.01). The number of T cells was significantly lower in both patient groups (P=0.0006), while the NK cell number was comparable among the three groups. Not only the absolute numbers of monocytes and B cells but also serum IgG and IgA titers were significantly lower in the STI- than IFN-group (P<0.0001). For T-cell subsets, the ratio of CD4/8 T cells was significantly lower, but that of CD26highCD4+ T cells was significantly higher in the IFN- than STI-group. TCR-triggered T cell proliferation was suppressed by STI in a dose dependent manner. Intriguingly, we also found that STI treatment resulted in significant down-regulation of CD4+CD26high T cell population which is considered as a subset of effector T cells. Collectively, our data imply that the two therapeutic agents induce a distinct immunological status in CML patients, and also raise the possibility that immunological surveillance of residual Ph clone may be somewhat defective in patients receiving STI for prolonged periods. In addition, STI revealed the inhibitory effect on TCR-mediated T cell activation in vitro. Finally, the periodic monitoring of immunological parameters is recommended for these patients. Control IFN STI No.of Subjects 14 14 14 Median age (range) 41 (30–63) 50 (39–73) 54 (29–65) Immune parameters Mean (SD) p value WBC (10^9/L) 5.50 (1.21) 4.81 (1.36) 3.95 (0.89) .0056 T cells (10^9/L) 1.02 (0.22) 0.63 (0.28) 0.59 (0.28) .0006 CD26high/CD4+T cells (%) 9.12 (5.19) 12.08 (5.01) 7.92 (3.65) .0407 Monocytes (10^8/L) 2.81 (0.53) 3.56 (1.52) 1.87 (1.10) .0003 B cells (10^8/L) 2.67 (1.34) 2.61 (1.67) 1.38 (0.94) .0201 Serum IgG (g/L) 15.63 (3.95) 10.32 (2.10) <.0001 Serum IgA (g/L) 3.70 (0.24) 2.32 (0.24) .0013

scholarly journals Early Use of Corticosteroid May Prolong SARS-CoV-2 Shedding in Non-Intensive Care Unit Patients with COVID-19 Pneumonia: A Multicenter, Single-Blind, Randomized Control Trial

Respiration ◽  
2021 ◽  
pp. 1-11
Author(s):  
Xiao Tang ◽  
Ying-Mei Feng ◽  
Ji-Xiang Ni ◽  
Jia-Ying Zhang ◽  
Li-Min Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Randomized Control Trial ◽  
Corticosteroid Treatment ◽  
Clinical Deterioration ◽  
Control Group ◽  
Number Of Patients ◽  
Early Use ◽  
Randomized Control ◽  
And Control ◽  
Single Blind

<b><i>Background:</i></b> There is still no clinical evidence available to support or to oppose corticosteroid treatment for coronavirus disease 2019 (COVID-19) pneumonia. <b><i>Objective:</i></b> To investigate the efficacy and safety of corticosteroid given to the hospitalized patients with COVID-19 pneumonia. <b><i>Methods:</i></b> This was a prospective, multicenter, single-blind, randomized control trial. Adult patients with COVID-19 pneumonia who were admitted to the general ward were randomly assigned to either receive methylprednisolone or not for 7 days. The primary end point was the incidence of clinical deterioration 14 days after randomization. <b><i>Results:</i></b> We terminated this trial early because the number of patients with COVID-19 pneumonia in all the centers decreased in late March. Finally, a total of 86 COVID-19 patients underwent randomization. There was no difference of the incidence of clinical deterioration between the methylprednisolone group and control group (4.8 vs. 4.8%, <i>p</i> = 1.000). The duration of throat viral RNA detectability in the methylprednisolone group was 11 days (interquartile range, 6–16 days), which was significantly longer than that in the control group (8 days [2–12 days], <i>p</i> = 0.030). There were no significant differences between the 2 groups in other secondary outcomes. Mass cytometry discovered CD3<sup>+</sup> T cells, CD8<sup>+</sup> T cells, and NK cells in the methylprednisolone group which were significantly lower than those in the control group after randomization (<i>p</i> &#x3c; 0.05). <b><i>Conclusions:</i></b> From this prematurely closed trial, we found that the short-term early use of corticosteroid could suppress the immune cells, which may prolong severe acute respiratory syndrome coronavirus 2 shedding in patients with COVID-19 pneumonia. <b><i>Trial Registration:</i></b> ClinicalTrials.gov, NCT04273321.

scholarly journals A modular and controllable T cell therapy platform for acute myeloid leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Mohamed-Reda Benmebarek ◽  
Bruno L. Cadilha ◽  
Monika Herrmann ◽  
Stefanie Lesch ◽  
Saskia Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Myeloid Leukemia ◽  
Tumor Antigens ◽  
Adoptive T Cell Therapy ◽  
Single Chain ◽  
T Cell Therapy ◽  
Acute Myeloid

AbstractTargeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.

Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2764-2771 ◽  
Author(s):  
Beth D. Harrison ◽  
Julie A. Adams ◽  
Mark Briggs ◽  
Michelle L. Brereton ◽  
John A. Liu Yin
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Dendritic Cells ◽  
T Cell ◽  
Myeloid Leukemia ◽  
T Cell Responses ◽  
Cell Responses ◽  
Antigen Presenting ◽  
Acute Myeloid ◽  
Stimulation Of

Abstract Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigen-presenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor α, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML.

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