scholarly journals Antiviral Therapy with Entecavir following Antituberculosis Therapy Alleviates Liver Injury and Restores Innate Immunity in Tuberculosis Patients Coinfected with Hepatitis B Virus

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Xiaojing Huang ◽  
Xiao Zheng ◽  
Chenyang Shen
Keyword(s):  
Innate Immunity ◽  
T Cells ◽  
Antiviral Therapy ◽  
Cd8 T Cells ◽  
Intestinal Microflora ◽  
Antituberculosis Therapy ◽  
Tnf Α ◽  
Significant Difference ◽  
Ifn Γ ◽  
Negative Conversion

Objective. Coinfection of tuberculosis (TB) and viral hepatitis may increase the risk of antituberculosis treatment-induced hepatotoxicity, which is regarded as a common cause of termination of the first-line antituberculosis drugs. The study aimed at investigating the protective effects of antiviral therapy on the liver and innate immunity in patients with TB-HBV coinfection. Methods. A total of 100 patients with TB-HBV coinfection were recruited and split into antituberculosis and antiviral groups, 50 per group, according to odd or even date of hospital admission from December 2019 to October 2020. The patients in the anti-TB group received antituberculosis therapy, and those in the antiviral group received antiviral therapy. The clinical effectiveness; HBV-DNA negative conversion rate; liver function assessment involving alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL); immune function evaluation including CD4+, CD8+, CD4+/CD8+, and CD3+ T cells; inflammatory cytokines containing tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ); and intestinal microflora including bifidobacterium, lactobacillus, enterobacterium, enterococcus, and clostridium were main outcome measures after treatment. Results. It was found that the total response rate in the antiviral group was significantly higher than the anti-TB group after treatment (χ2 = 3.157, P = 0.017 ). There was a significant difference in HBV-DNA negative conversion rates between the antiviral group and anti-TB group (82% vs. 58%, χ2 = 6.384, P = 0.001 ). The ALT, AST, and TBIL in the two groups were all increased after treatment ( P < 0.05 ), but the antiviral group indicated a rise of the above indices compared to the anti-TB group ( P < 0.05 ). The two groups showed a rise on the concentration of CD3+, CD4+, and CD4+/CD8+ T cells and a decline on the CD8+ T cells after treatment ( P < 0.05 ), but these changes in the antiviral group were more evident to those in the anti-TB group ( P < 0.05 ). There was an increase on the IFN-γ level and decrease on the TNF-α and IL-6 levels in both groups after treatment ( P < 0.05 ), but the antiviral group revealed a higher level of IFN-γ with lower levels of TNF-α and IL-6 compared to the anti-TB group ( P < 0.05 ). After treatment, the number of bifidobacteria and lactobacilli was increased, and the number of enterobacteria, enterococci, and clostridium were decreased in the two groups ( P < 0.05 ), while these changes in the antiviral group were more remarkable compared to the anti-TB group ( P < 0.05 ). There was no significant difference in the incidence of adverse reactions between the two groups (χ2 = 0.267, P = 0.731 ). Conclusion. Antiviral therapy for tuberculosis-HBV coinfected patients could inhibit HBV replication, providing protection against liver damage, improving innate immunity, and balancing intestinal microflora.

scholarly journals The Immunomodulatory Effect of Triptolide on Mesenchymal Stem Cells in Vitro

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5011-5011
Author(s):  
Haiping He ◽  
Atsuko Takahashi ◽  
Yuki Yamamoto ◽  
Akiko Hori ◽  
Yuta Miharu ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Complete Medium ◽  
Surface Markers ◽  
Rt Pcr ◽  
Tnf Α ◽  
Ifn Γ

Background: Mesenchymal stromal cells (MSC) are known to have the immunosuppressive ability and have been applied in clinic to treat acute graft-versus-host disease (GVHD), as one of severe complications after hematopoietic stem cells transplantation (HSCT) in Japan. However, MSC are activated to suppress the immune system only upon the stimulation of inflammatory cytokines and the clinical results of MSC therapies for acute GVHD are varied. It is ideal that MSC are primed to be activated and ready to suppress the immunity (=priming) before administration in vivo. Triptolide (TPL) is a diterpene triepoxide purified from a Chinese herb - Tripterygium Wilfordii Hook F (TWHF). It has been shown to possess anti-inflammatory and immunosuppressive properties in vitro. In this study, we aim to use TPL as the activator for umbilical cord-derived MSC (UC-MSC) to entry stronger immunosuppressive status. Methods: The proliferation of UC-MSC with TPL at the indicated concentrations for different time of 24, 48, 72, and 96 hours. Cell counting kit-8(CCK-8) was added in the culture medium to detect cell toxicity and the absorbance was measured using microplate reader. Flow cytometry was used to identify the MSC surface markers expression. TPL-primed UC-MSC were once replaced with fresh medium and co-culture with mixed lymphocyte reaction (MLR) consisted with mononuclear cells (MNCs) stained with CFSE and irradiated allogenic dendritic cell line (PMDC05) in RPMI 1640 medium supplemented with 10 % FBS (complete medium). IDO-1, SOD1, and TGF-β gene expression in TPL-primed UC-MSC and UC-MSC induced by 10 ng/ml IFN-γ and/or 15 ng/ml TNF-α were evaluated by RT-PCR. PDL1 and PDL2 expression in TPL-primed UC-MSC and UC-MSC in response to IFN-γ and/or TNF-α were checked by Flowjo. Results: Exposure of TPL for UC-MSC for 72hour at the concentration above 0.1 μM resulted in the cell damage significantly. Therefore, we added TPL in UC-MSC at 0.01μM of TPL for up to 48 hours, then washed thourouphly for the following culture for experiments. To evaluate the influence of TPL on the surface markers of UC-MSC, we cultured UC-MSC for 4 hours in complete medium following culture with 0.01μM of TPL for 20 hours (TPL-primed UC-MSC). TPL-primed UC-MSC revealed positive for CD105, CD73, and CD90, negative for CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR surface molecules as same as the non-primed UC-MSC. In MLR suppression by UC-MSC, the TPL-primed UC-MSC activity revealed stronger anti-proliferative effect on the CD4+ and CD8+ T cells activated by allogeneic DC than those of non-primed UC-MSC in MLR. Furthermore, the TPL-primed UC-MSC promoted the expression of IDO-1, SOD1 and TGF-β in response to IFN-γ+/-TNF-α by RT-PCR and enhanced the expression of PD-L1 by FACS analysis. Discussion:In this study, we found the TPL-primed UC-MSC showed stronger antiproliferative potency on CD4+ and CD8+ T cells compared with non-primed UC-MSC. TPL-primed UC-MSC promoted the expression of IDO-1, SOD1 and TGF-β stimulated by IFN-γ+/-TNF-α, although TPL alone did not induce these factors. Furthermore, we found that the PD1 ligand (PD-L1) was induced in TPL-primed UC-MSC, likely IFN-γ enhanced the PD-L1 expression, evaluated by flowcytometry. These results suggested that TPL-primed UC-MSC seemed more sensitive to be activated as the immunosuppressant. Here, we firstly report the new function of TPL to induce the upregulation of immunosuppressive effect, although the mechanisms of TPL inhibition to MSC need to be explore. Conclusively, TPL-primed UC-MSC might be applied for the immunosuppressive inducer of MSC. Figure Disclosures He: SASAGAWA Medical Scholarship: Research Funding; IMSUT Joint Research Project: Research Funding. Nagamura:AMED: Research Funding. Tojo:AMED: Research Funding; Torii Pharmaceutical: Research Funding. Nagamura-Inoue:AMED: Research Funding.

scholarly journals Complementary Dendritic Cell–activating Function of CD8+ and CD4+ T Cells

2002 ◽  
Vol 195 (4) ◽  
pp. 473-483 ◽  
Author(s):  
Robbie B. Mailliard ◽  
Shinichi Egawa ◽  
Quan Cai ◽  
Anna Kalinska ◽  
Svetlana N. Bykovskaya ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Class I ◽  
Chronic Infections ◽  
Cd40 Ligation ◽  
Activation Level ◽  
Tnf Α ◽  
Ifn Γ

Dendritic cells (DCs) activated by CD40L-expressing CD4+ T cells act as mediators of “T helper (Th)” signals for CD8+ T lymphocytes, inducing their cytotoxic function and supporting their long-term activity. Here, we show that the optimal activation of DCs, their ability to produce high levels of bioactive interleukin (IL)-12p70 and to induce Th1-type CD4+ T cells, is supported by the complementary DC-activating signals from both CD4+ and CD8+ T cells. Cord blood– or peripheral blood–isolated naive CD8+ T cells do not express CD40L, but, in contrast to naive CD4+ T cells, they are efficient producers of IFN-γ at the earliest stages of the interaction with DCs. Naive CD8+ T cells cooperate with CD40L-expressing naive CD4+ T cells in the induction of IL-12p70 in DCs, promoting the development of primary Th1-type CD4+ T cell responses. Moreover, the recognition of major histocompatibility complex class I–presented epitopes by antigen-specific CD8+ T cells results in the TNF-α– and IFN-γ–dependent increase in the activation level of DCs and in the induction of type-1 polarized mature DCs capable of producing high levels of IL-12p70 upon a subsequent CD40 ligation. The ability of class I–restricted CD8+ T cells to coactivate and polarize DCs may support the induction of Th1-type responses against class I–presented epitopes of intracellular pathogens and contact allergens, and may have therapeutical implications in cancer and chronic infections.

scholarly journals The Level of Viral Antigen Presented by Hepatocytes Influences CD8 T-Cell Function

2007 ◽  
Vol 81 (6) ◽  
pp. 2940-2949 ◽  
Author(s):  
Adam J. Gehring ◽  
Dianxing Sun ◽  
Patrick T. F. Kennedy ◽  
Esther Nolte-'t Hoen ◽  
Seng Gee Lim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Antigen ◽  
Cell Function ◽  
Cd8 T Cell ◽  
T Cell Function ◽  
Tnf Α ◽  
Antiviral Function ◽  
Ifn Γ

ABSTRACT CD8 T cells exert their antiviral function through cytokines and lysis of infected cells. Because hepatocytes are susceptible to noncytolytic mechanisms of viral clearance, CD8 T-cell antiviral efficiency against hepatotropic viruses has been linked to their capacity to produce gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). On the other hand, intrahepatic cytokine production triggers the recruitment of mononuclear cells, which sustain acute and chronic liver damage. Using virus-specific CD8 T cells and human hepatocytes, we analyzed the modulation of virus-specific CD8 T-cell function after recognition peptide-pulsed or virally infected hepatocytes. We observed that hepatocyte antigen presentation was generally inefficient, and the quantity of viral antigen strongly influenced CD8 T-cell antiviral function. High levels of hepatitis B virus production induced robust IFN-γ and TNF-α production in virus-specific CD8 T cells, while limiting amounts of viral antigen, both in hepatocyte-like cells and naturally infected human hepatocytes, preferentially stimulated CD8 T-cell degranulation. Our data document a mechanism where virus-specific CD8 T-cell function is influenced by the quantity of virus produced within hepatocytes.

Prophylactic Amotosalen-Treated Donor T-Cells Prevent Late CMV Infection in Allogeneic Bone Marrow Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3024-3024
Author(s):  
Mohammad S. Hossain ◽  
John D. Robak ◽  
Edmund K. Waller
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Immune Reconstitution ◽  
Chronic Gvhd ◽  
Mcmv Infection ◽  
Tnf Α ◽  
Donor T Cells ◽  
Ifn Γ

Abstract A major problem in allogeneic BMT is post transplant immunodeficiency leading to opportunistic infection and relapse. Previously we showed that amotosalen-treated allogeneic donor T cells given at the time of BMT and experimental murine cytomegalovirus (MCMV) infection could prevent lethal MCMV disease without producing GvHD. In this study we have focused on a more clinically applicable model where prophylactic amotosalen-treated allogeneic donor splenocytes are given at the time of BMT, followed by MCMV infection 100 days later. We observed that amotosalen-treated donor T-cells significantly expanded and responded well in presence of viral infection without inducing any GvHD, protected recipients against viral disease, and were associated with significantly improved hematopoietic engraftment and immune reconstitution. Methods: Using a parent to F1 mouse BMT model, splenocytes (3x106 untreated or 10x106 amotosalen-treated) from MCMV immunized C57BL/6 donors were transplanted along with 5x106 T-cell depleted bone marrow (TCD BM) from naïve congeneic mice into lethally irradiated (11Gy) CB6F1 recipients (C57BL/6 x Balb/C). Recipient mice were infected i.p. with a sublethal dose (5x104 pfu per mouse) of MCMV 100 days or more after transplant. Clinical chronic GvHD was monitored by weight loss, hair loss, ruffled fur, diarrhea, and decreased activity. Flow cytometry was used to quantitate T cell chimerism (in recipient PBMC, spleen, liver and thymus) and MCMV-peptide specific CD8+ T-cells (tetramer+ and IFN-γ producing). Serum IFN-γ and TNF-α were determined by ELISA. Liver and spleen viral loads were determined by counting PFU in tissue homogenates plated onto 3T3 confluent monolayers. Results: Recipients of untreated control donor splenocytes suffered from chronic GvHD within 100 days of transplant, while those that received amotosalen-treated splenocytes experienced no GvHD. In response to MCMV infection at 100 days post transplant, residual amotosalen-treated donor T-cells rapidly expanded over 25-fold within 10 days, but did not cause lethality or detectable GvHD. Expanded amotosalen-treated T-cells showed activated anti-viral responses and developed a memory phenotype at late phases of viral infection. PBMC, spleen and liver showed elevated levels of MCMV specific tetramer+, IFN-γ+, and TNF-α+ CD8+ T-cells that were associated with accelerated viral clearance within day 3 after viral infection. While expansion and generation of amotosalen-treated donor T-cells mostly occurred in the liver, the generation of donor bone marrow-derived new T-cells occurred through both the thymus and the liver. In contrast, recipients of untreated donor splenocytes had reduced thymic function, resulting in severely impaired immune reconstitution and decreased anti-viral immunity. Conclusion: Prophylactically administered amotosalen-treated allogeneic donor T cells 1) were almost completely devoid of GvHD activity, 2) promoted hematopoietic engraftment and improved immune reconstitution, and 3) persisted long-term (&gt;100 days) and successfully protected recipients from sublethal MCMV infection. Thus, infusion of amotosalen-treated donor T-cells at the time of transplantation is a clinically-attractive approach to adoptive anti-viral immunotherapy without chronic GvHD following hematopoietic progenitor cell transplantation.

scholarly journals Itacitinib, a JAK1 Selective Inhibitor Preserves Graft-Versus-Leukemia (GVL), Enhances Survival and Is Highly Efficacious in a MHC-Mismatched Mouse Model of Acute GvHD

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4522-4522 ◽  
Author(s):  
Ashish Juvekar ◽  
Bruce Ruggeri ◽  
Sindy Condon ◽  
Andrew Borkowski ◽  
Reid Huber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Inflammatory Cytokine ◽  
Acute Gvhd ◽  
Colon Tissue ◽  
Graft Versus Leukemia ◽  
Tnf Α ◽  
Dosing Regimens ◽  
Ifn Γ

Abstract Introduction: Graft-versus-host disease (GvHD) is a severe complication arising in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Potent and selective modulation of JAK1/STAT-mediated signaling is an attractive therapeutic strategy for the management of acute GvHD and is currently being evaluated in clinical trials (GRAVITAS-301: NCT03139604; GRAVITAS-119: NCT03320642). Methods: Acute GvHD was induced in BALB/c mice using the established MHC-mismatched mouse model. BALB/c (H-2Kd) recipients were given an intravenous injection of a combination of splenocytes and T cell depleted bone marrow cells from allogeneic cell transfer from donor C57BL/6 (H-2Kb) mice. Animals were dosed orally with vehicle or the selective JAK1 inhibitor, itacitinib (60 mg/kg or 120 mg/kg twice daily). Engraftment was analyzed for the proportion of donor and host leukocytes (CD45+, H-2Kb, and H-2Kd). GvHD clinical scores were assessed by standard methods and inflammatory cytokine profiles in blood and colon quantified by multiplex analysis. Colon samples were sectioned and stained with the following immunohistochemical (IHC) markers: CD4, CD8, phosphoSTAT3 and CD3+phosphoSTAT3 (dual staining) for pharmacodynamic assessment of JAK/STAT pathway activity in colon and infiltrating T-cells. Effects of itacitinib on preservation of Graft-versus-Leukemia (GVL) were evaluated by injecting BALB/c mice with A20 lymphoma cells that are of H-2Kd phenotype along with combination of splenocytes and T cell depleted bone marrow from C57BL/6 (H-2Kb) mice. Results: Itacitinib administration was highly effective in both prophylactic (from day −3) and therapeutic (from day 14) dosing regimens in ameliorating body weight loss and improving GvHD scores. Itacitinib did not significantly impact donor engraftment as determined by CD45+/H-2Kb quantification by flow cytometry. Similar efficacy was observed with 60 mg/kg versus 120 mg/kg twice daily dosing regimens. Oral itacitinib administration achieved JAK1 IC50 coverage for 4 h and 12 h at 60 mg/kg twice daily and 120 mg/kg twice daily, respectively. Associated with GvHD progression, maximal upregulation of inflammatory cytokines were observed in peripheral blood on day 17 (IFN-γ, TNF-α, IL-6, IL-13) and in colon on day 28 (IFN-γ, TNF-α, IL-1β). Itacitinib (120 mg/kg twice daily) treatment significantly reduced the inflammatory cytokine milieu at these disease stages. No differences were observed in absolute number of CD4+ T cells and CD8+ T cells in blood and spleen with itacitinib treatment, but significant reductions were detected in CD4+ T cells and CD8+ T cells in the inflamed colon tissue along with significant JAK1/STAT3 inhibition as measured by reductions in normalized pSTAT3 in T cells and colonic epithelial cells. Itacitinib treatment did not negatively impact GVL responses, as evidence by T cell mediated reduction of tumor burden. Furthermore, itacitinib treatment enhanced the survival of the recipient BALB/c mice in comparison to the vehicle treated animals. Conclusions: Itacitinib, a selective JAK1 inhibitor ameliorated GvHD severity when administered prophylactically or therapeutically and had no detrimental effects on engraftment and preservation of GVL. Furthermore, itacitinib inhibited JAK1/STAT3 activation in diseased colon tissue and infiltrating T-cells, and reduced disease burden and improved survival by modulating levels of inflammatory cytokines important in the pathophysiology of acute GvHD. Disclosures Juvekar: Incyte Corporation: Employment. Ruggeri:Incyte Corporation: Employment. Condon:Incyte Corporation: Employment. Borkowski:Biomodels LLC: Employment. Huber:Incyte Corporation: Employment. Smith:Incyte Corporation: Employment.

scholarly journals The Role of β-Catenin in Th1 Immune Response against Tuberculosis and Profiles of Expression in Patients with Pulmonary Tuberculosis

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Kunlong Xiong ◽  
Jinxia Niu ◽  
Ruijuan Zheng ◽  
Zhonghua Liu ◽  
Yanzheng Song ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Cd4 T Cell ◽  
Cell Frequency ◽  
Tnf Α ◽  
Ifn Γ

β-Catenin is a key molecule of canonical Wnt/β-catenin pathway. Its roles and expression profiles in T cells of tuberculosis (TB) remain unclear. The aim of this study was to explore the role of β-catenin in CD4+ T cells and its expression characteristics in patients with pulmonary tuberculosis (PTB). In this study, CD4+ T cell-specific β-catenin conditional knockout mice (β-CAT-cKO mice) were aerosol infected with Mycobacteria tuberculosis (Mtb) H37RV with wild-type mice as controls. Four weeks after infection, the mRNA expression of IFN-γ, TNF-α, and TCF-7 in the lungs of mice was measured. CD4, CD8, β-catenin, IFN-γ, and TNF-α in mononuclear cells from the lungs and spleens were measured by flow cytometry, and the pathological changes of lungs were also observed. Patients with PTB were enrolled, with blood samples collected and PBMCs isolated. The expressions of β-catenin, IFN-γ, TNF-α, and PD-1 in CD4+ and CD8+ T cells were measured by flow cytometry. Results showed a decreased frequency of and reduced IFN-γ/TNF-α mRNA expression and secretion by CD4+ T cells in the lungs of infected β-CAT-cKO mice compared with infected wild-type controls, and only slightly more inflammatory changes were observed in the lungs. β-catenin expressions in CD4+ and CD8+ T cells were significantly decreased in blood cells of patients with severe PTB compared with those in mild PTB. The stimulation of peripheral blood mononuclear cells (PBMCs) with lithium chloride (LiCl), a stimulant of β-catenin, resulted in the increase in CD4+ T cell frequency, as well as their secretion of IFN-γ and TNF-α. β-Catenin demonstrated a moderately positive correlation with PD-1 in CD4+ T cells. β-Catenin along with PD-1 and IFN-γ in CD4+ T cells had a high correlation with those in CD8+ T cells. In conclusion, β-catenin may be involved in the regulation of Th1 response and CD4+ T cell frequency in TB.

scholarly journals Circulating cytokines and lymphocyte subsets in patients who have recovered from COVID-19

2020 ◽  
Author(s):  
Hasi Chaolu ◽  
Xinri Zhang ◽  
Xin Li ◽  
Xin Li ◽  
Dongyan Li
Keyword(s):  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Lymphocyte Subsets ◽  
Healthy Controls ◽  
Tnf Α ◽  
Ifn Γ ◽  
Circulating Cytokines

To investigate the immune status of people who previously had COVID-19 infections, we recruited patients 2 weeks post-recovery and analyzed circulating cytokines and lymphocyte subsets. We measured levels of total lymphocytes, CD4+ T cells, CD8+ T cells, CD19+ B cells, CD56+ NK cells, and the serum concentrations of interleukin (IL)-1, IL-4, IL-6, IL-8, IL-10, transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) by flow cytometry. We found that in most post-recovery patients, levels of total lymphocytes (66.67%), CD3+ T cells (54.55%), CD4+ T cells (54.55%), CD8 + T cells (81.82%), CD19+ B cells (69.70%), and CD56+ NK cells(51.52%) remained lower than normal, whereas most patients showed normal levels of IL-2 (100%), IL-4 (80.88%), IL-6 (79.41%), IL-10 (98.53%), TNF-α (89.71%), IFN-γ (100%) and IL-17 (97.06%). Compared to healthy controls, 2-week post-recovery patients had significantly lower absolute numbers of total lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK cells, along with significantly higher levels of IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ and IL-17. Among post-recovery patients, T cells, particularly CD4+ T cells, were positively correlated with CD19+ B cell counts. Additionally, CD8+ T cells positively correlated with CD4+ T cells and IL-2 levels, and IL-6 positively correlated with TNF-α and IFN-γ. These correlations were not observed in healthy controls. By ROC curve analysis, post-recovery decreases in lymphocyte subsets and increases in cytokines were identified as independent predictors of rehabilitation efficacy. These findings indicate that the immune system has gradually recovered following COVID-19 infection; however, the sustained hyper-inflammatory response for more than 14 days suggests a need to continue medical observation following discharge from the hospital. Longitudinal studies of a larger cohort of recovered patients are needed to fully understand the consequences of the infection.

Impact of Donor Serostatus on CMV Reactivation and Reconstitution of Multi-Function CMV-Specific T Cells in CMV-Positive Transplant Recipients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4339-4339
Author(s):  
Wendi Zhou ◽  
Jeff Longmate ◽  
Simon F Lacey ◽  
Joycelynne Palmer ◽  
Ghislaine Gallez-Hawkins ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Donor Group ◽  
Functional Profile ◽  
Tnf Α ◽  
Ifn Γ ◽  
Cmv Reactivation

Abstract CMV reactivation remains a significant cause of morbidity and mortality due to the extended period of immunodeficiency after allogeneic hematopoietic stem cell transplantation (HCT), despite great strides in management of the infection in the past two decades. Reconstitution of cytomegalovirus (CMV)-specific CD8+ T cells is essential to control of CMV infection in CMV-seropositive recipients (R+) after HCT. The CMV serologic status of the recipient before HCT has a strong influence on outcome. Key questions addressed in this study are the impact of donor CMV serostatus on the reconstitution of effective CMV immunity or risk of CMV reactivation and GCV usage in CMV R+ recipients. Betts and colleagues have reported that HIV-specific CD8+ T-cells which simultaneously degranulated and produced IFN-γ, TNF-α, MIP-1β and IL2 were associated with lower viral load and HIV long term non-progressor status. These findings in the context of HIV infection motivated us to investigate whether levels of multi-functional CMV-specific CD8+ T-cells in HCT recipients correlated with the CMV serostatus of the donor and the differentiation state of transferred CMV-specific memory T-cells. We hypothesize that a mature CD8+ T-cell functional profile leads to a lower incidence of CMV viremia in R+ recipients of T-cell replete HCT with a D+ donor. A total of 183 R+ HCT recipients were enrolled. CMV reactivation was defined as any positive CMV blood culture or plasma PCR obtained during a monitoring period that began at d40 post-HCT and continued thereafter twice weekly until d100. After d100, CMV in plasma was monitored in patients at high risk because of GVHD or immunosuppressive medication. Peripheral blood mononuclear cells from R+ HCT recipients were collected at intervals between d90 and d360 post-HCT. A subset (n=123) of the subjects limited only by sample availability were evaluated for CMV-specific CD8+ T-cells producing IFN-g (IFN-γ-CD8+). We used a well-described pp65 peptide library as a stimulatory antigen to evaluate the ex vivo functional profile of pp65-specific CD8+ T-cells from R+ recipients either receiving CMV seropositive (D+/R+) or seronegative (D−/R+) T-cell replete donor grafts. D+ status was associated with higher IFN-γ-CD8+ during the sampling time-course by fitting linear generalized estimating equation models on a logarithmic scale (p=0.0004). A significant interaction was found between prior CMV reactivation and donor serostatus on IFN-γ-CD8+ levels (p=0.0001). Comparing the subset of IFN-γ-CD8+ measurements prior to reactivation, the D− donor group produced lower levels of IFN-γ-CD8+ than the D+ donor group (p=0.0002), although both donor groups have similar levels of IFN-γ-CD8+ post-reactivation. Similar results were obtained when adjusting for the 9 pre-transplant covariates, and none were associated with IFN-γ-CD8+ levels, except donor serostatus and its interaction with CMV reactivation. Six-color flow cytometry was used to assess the functional profile of CMV-specific CD8+ T-cells in 62 of 183 HCT recipients prospectively followed for CMV reactivation. R+ recipients receiving grafts from D− donors (D−/R+) reconstituted fewer multi-functional CD8+ T-cells expressing IFN-γ, TNF-α, MIP-1β and CD107 compared to D+/R+ recipients. Unlike mono-functional CD8+ T-cells secreting IFN-g, which were abundantly generated during CMV reactivation in D−/R+, the relative lack of multi-functional CD8+ T-cells persisted until at least one year post-HCT. In addition, D−/R+ recipients had more CMV reactivation than D+/R+ recipients. D+/R+ transplants have elevated levels of multi-functional CD8+ T cell levels and lower hazard for CMV reactivation. Virologic and immunologic outcomes were robust to adjustment for pre-transplant factors affecting HCT, including donor type, stem cell source, recipient age, and preparative regimen. Statistical modeling to account for pre- and post-transplant factors including GVHD and its treatment by steroids had minimal effect on the contribution of serostatus to the risk of CMV reactivation and differences in multi-functional CD8+ T cell levels.

scholarly journals HIV-Specific Cd8+ T Cells Produce Antiviral Cytokines but Are Impaired in Cytolytic Function

2000 ◽  
Vol 192 (1) ◽  
pp. 63-76 ◽  
Author(s):  
Victor Appay ◽  
Douglas F. Nixon ◽  
Sean M. Donahoe ◽  
Geraldine M.A. Gillespie ◽  
Tao Dong ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Ex Vivo ◽  
Hla Class I ◽  
Cytolytic Activity ◽  
Specific Lysis ◽  
Exact Function ◽  
Tnf Α ◽  
Ifn Γ

The use of peptide–human histocompatibility leukocyte antigen (HLA) class I tetrameric complexes to identify antigen-specific CD8+ T cells has provided a major development in our understanding of their role in controlling viral infections. However, questions remain about the exact function of these cells, particularly in HIV infection. Virus-specific cytotoxic T lymphocytes exert much of their activity by secreting soluble factors such as cytokines and chemokines. We describe here a method that combines the use of tetramers and intracellular staining to examine the functional heterogeneity of antigen-specific CD8+ T cells ex vivo. After stimulation by specific peptide antigen, secretion of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-1β, and perforin is analyzed by FACS® within the tetramer-positive population in peripheral blood. Using this method, we have assessed the functional phenotype of HIV-specific CD8+ T cells compared with cytomegalovirus (CMV)-specific CD8+ T cells in HIV chronic infection. We show that the majority of circulating CD8+ T cells specific for CMV and HIV antigens are functionally active with regards to the secretion of antiviral cytokines in response to antigen, although a subset of tetramer-staining cells was identified that secretes IFN-γ and MIP-1β but not TNF-α. However, a striking finding is that HIV-specific CD8+ T cells express significantly lower levels of perforin than CMV-specific CD8+ T cells. This lack of perforin is linked with persistent CD27 expression on HIV-specific cells, suggesting impaired maturation, and specific lysis ex vivo is lower for HIV-specific compared with CMV-specific cells from the same donor. Thus, HIV-specific CD8+ T cells are impaired in cytolytic activity.

scholarly journals Association among cytokine profiles of innate and adaptive immune responses and clinical-virological features in untreated patients with chronic hepatitis B

2019 ◽  
Author(s):  
Yurong Gu ◽  
Yifan Lian ◽  
Qiaolan Zheng ◽  
Zexuan Huang ◽  
Lin Gu ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Natural Killer ◽  
Chronic Hepatitis B ◽  
Cd8 T Cells ◽  
Nkt Cells ◽  
Adaptive Immune ◽  
Tnf Α ◽  
Ifn Γ

Abstract Background Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune system. This study aimed to identify the relationship between antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. Methods We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells in a cohort of chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. Results IFN-γ+ and TNF-α+ by CD4+ and CD8+ T cells were significantly higher in immune active (IA) than other phases. Immune tolerant (IT) patients showed the least expression of IFN-γ+ by NK and NKT cells, and TNF-α+ by NK cells. IFN-γ+, TNF-α+ and IL-2+ by CD4+ and CD8+ T cells were comparable between IA and gray zones (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differ from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ+ and TNF-α+, but not IL-2+, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ+ by NKT cells was associated with HBV DNA, while IFN-γ+ by CD4+ and CD8+ T cells had correlation with age. Conclusion HBV clinical phases are characterized by distinct cytokines signatures, which showed little relationship to viral features at a single time point in these untreated CHB patients.

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