scholarly journals Propranolol Suppresses the T-Helper Cell Depletion-Related Immune Dysfunction in Cirrhotic Mice

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 604 ◽  
Author(s):  
Hung-Cheng Tsai ◽  
Chien-Fu Hsu ◽  
Chia-Chang Huang ◽  
Shiang-Fen Huang ◽  
Tzu-Hao Li ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Adrenergic Receptors ◽  
Immune Dysfunction ◽  
Cell Depletion ◽  
Percentage Increase ◽  
T Helper ◽  
Th Cells ◽  
Duct Ligation ◽  
Treg Subset ◽  
Propranolol Treatment

Bacterial translocation (BT) and splenomegaly contribute to cirrhosis-associated immune dysfunction (CAID) including T cell depletion, infection, and chronic inflammation. β-blockers have been reported to decrease BT and improve splenomegaly. This study explores the modulation of β1 and β2 adrenergic receptors (ADRB1/ADRB2) by propranolol treatment on the peripheral and splenic immune dysfunction of cirrhotic mice. In vivo experiments were performed in bile duct ligation (BDL)- and thioacetamide (TAA)-cirrhotic mice receiving two weeks of propranolol treatment. Acute effects of propranolol were evaluated in T-helper (Th) cells isolated from spleen of cirrhotic mice. Over-expression of β1 and β2 adrenergic receptors (ADRB1/ADRB2) in spleen and T lymphocytes was associated with high peripheral/splenic lipopolysaccharide binding protein levels. Moreover, a decrease in Th cells percentage, increase in Treg subset, and cytokines were accompanied by increased apoptosis, proliferation, and reduced white pulp hyperplasia in cirrhotic mice, which were counteracted by propranolol treatment. The Th-cell depletion, systemic inflammation, BT, and infection were improved by chronic propranolol treatment. Acute propranolol treatment inhibited apoptosis, Treg-conditioned differentiation, and promoted Th2-conditioned differentiation through ADRB-cyclic adenosine monophosphate (cAMP) signals in cirrhotic mice. In conclusion, suppression of ADRB1 and ADRB2 expressions in spleen and splenic T lymphocytes by acute and chronic propranolol treatment ameliorate systemic and splenic immune dysfunction in cirrhosis.

scholarly journals Development of Autologous, Oligoclonal, Poorly Functioning T Lymphocytes in a Patient With Autosomal Recessive Severe Combined Immunodeficiency Caused by Defects of the Jak3 Tyrosine Kinase

Blood ◽  
1998 ◽  
Vol 91 (3) ◽  
pp. 949-955 ◽  
Author(s):  
Duilio Brugnoni ◽  
Luigi D. Notarangelo ◽  
Alessandra Sottini ◽  
Paolo Airò ◽  
Marta Pennacchio ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Tyrosine Kinase ◽  
Cd4 T Cells ◽  
Severe Combined Immunodeficiency ◽  
Combined Immunodeficiency ◽  
T Helper ◽  
T Helper 1 ◽  
In Vitro Susceptibility ◽  
And Function

Abstract Defects of the common gamma chain subunit of the cytokine receptors (γc) or of Jak3, a tyrosine kinase required for γc signal transduction, result in T−B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (>3,000/μL) of autologous CD3+CD4+ T cells. These cells showed a primed/activated phenotype (CD45R0+ Fas+HLA-DR+ CD62Llo), defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in γc-/y and in Jak3−/−mice, in which a population of activated, anergic T cells (predominantly CD4+) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4+ T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8+ T cells, nor do they fully restore the functional properties of CD4+ T lymphocytes.

scholarly journals T cell regulation of b cell activation. Cloned Lyt-1+2-T suppressor cells inhibit the major histocompatibility complex-restricted interaction of T helper cells with B cells and/or accessory cells.

1983 ◽  
Vol 158 (4) ◽  
pp. 1178-1190 ◽  
Author(s):  
Y Asano ◽  
R J Hodes
Keyword(s):  
Major Histocompatibility Complex ◽  
B Cells ◽  
Cell Activation ◽  
Suppressor Cells ◽  
Major Histocompatibility ◽  
T Helper ◽  
Th Cells ◽  
Effector Cells ◽  
Histocompatibility Complex ◽  
Accessory Cells

The present studies have identified cloned Lyt-1+2- T suppressor (Ts) cells that are both antigen specific and major histocompatibility complex (MHC) restricted in their activation requirements and that function to regulate the MHC-restricted activation of B cells by T helper (Th) cells. ParentA-restricted Ts clones suppressed, in antigen-specific fashion, the responses generated by (A X B)F1 Th cells cooperating with parentA (B plus accessory) cells, but did not suppress responses by the same (A X B)F1 Th cell population cooperating with parentB (B plus accessory) cells. Moreover, responses of (A X B)F1 leads to parentA Th cells and (A X B)F1 (B plus accessory) cells were suppressed by parentA-restricted Ts clones but not by parentB-restricted Ts clones. Thus, these findings suggest that the cloned Ts cells that have been characterized here function by specifically inhibiting the MHC-restricted interaction between Th cells and B and/or accessory cells. It was further demonstrated in experiments using cloned Th and Ts populations that these Lyt-1+2-Ts cells act not simply as inducers of suppressor but rather function in a restricted fashion as effector cells in the suppressor pathway.

IMMU-49. DYNAMIC CHANGES AND PROGNOSTIC VALUE OF PERIPHERAL BLOOD LYMPHOCYTE SUBSETS IN INTRACRANIAL GERM CELL TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi103-vi104
Author(s):  
Hairong Wang ◽  
Cheng-Cheng Guo ◽  
Hongyu Chen ◽  
Yang Qun-ying ◽  
Zhong-ping Chen
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Germ Cell ◽  
Peripheral Blood ◽  
B Lymphocyte ◽  
Germ Cell Tumors ◽  
T Helper ◽  
Tumor Treatment ◽  
Dynamic Changes ◽  
Intracranial Germ Cell Tumors

Abstract OBJECTIVE This study was designed to retrospectively analyze the dynamic changes of peripheral blood lymphocyte subsets and prognosis among patients with intracranial germ cell tumors. METHODS A total of 150 intracranial germ cell tumors patients diagnosed between June 2011 till November 2019 were retrospectively investigated. Peripheral blood total T lymphocytes (CD3+) percentage, T helper/inducible lymphocytes(CD3+CD4+)percentage, T inhibitory/toxic lymphocytes (CD3+CD8+) percentage, B lymphocyte (CD19+) percentage, NK lymphocyte (CD3/CD16+CD56+) percentage, regulatory T cells (CD4+CD25+,CD8+CD25+), and T helper/toxic lymphocyte ratio (CD4+/CD8+ ratio) were quantified by flow cytometry analysis. Clinical information was extracted from the database in Sun Yat-sen University Cancer Center and survival data was confirmed through outpatient visits and telephone follow-up. RESULTS T lymphocytes population was increased after anti-tumor treatment, with significant difference of total T lymphocytes (CD3+), inhibitory/toxic T cells (CD3+CD8+) and regulatory T cells (CD4+CD25+ and CD8+CD25+), (p=0.008, p=0.000, p=0.008 and p=0.001 respectively), while B lymphocytes(CD19+) decreased after chemotherapy(p=0.003). The dynamic levels of T lymphocyte and B lymphocyte subpopulation after chemotherapy did not present significant differences between gender, age, and locations of tumors (p >0.05), except CD4+CD25+ T cells in younger children (age< 16 years older) increased significantly than the elder (age >16), p=0.04. Patients with increased CD19+ B cells presented significant suboptimal outcomes compared with the no increased (p=0.024). Similarly, increased CD3+ T cells, CD3+CD8+ T cells, CD4+CD25+ T cells reduced the risk of death (p=0.006, p=0.019, p=0.042 respectively). Multivariate Cox Regression analysis showed: increased CD19+ B cells, p=0.04, HR=1.688, 95%CI=1.025-2.779. CONCLUSION After anti-tumor treatment, cell-mediated immunity activated, enhanced, and dominated in anti-tumor response. An increased level of CD19+ subsets was an independent predictor for inferior overall survival. Systemic circulating T cells immunity played an important role and mediating antitumor responses may pave the road for new immunity strategies.

scholarly journals A Signal Transducer and Activator of  Transcription (Stat)4-independent Pathway for the Development of  T Helper Type 1 Cells

1998 ◽  
Vol 188 (6) ◽  
pp. 1191-1196 ◽  
Author(s):  
Mark H. Kaplan ◽  
Andrea L. Wurster ◽  
Michael J. Grusby
Keyword(s):  
Delayed Type Hypersensitivity ◽  
Th2 Cells ◽  
Signal Transducer ◽  
T Helper ◽  
Th1 Cell ◽  
Th Cells ◽  
Th Cell ◽  
Ifn Γ

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6−/− lymphocytes fail to differentiate into interleukin (IL)-4–secreting Th2 cells. However, in contrast to Stat4−/− lymphocytes, T cells from Stat4, Stat6−/− mice produce significant amounts of interferon (IFN)-γ when activated in vitro. Although Stat4, Stat6−/− lymphocytes produce less IFN-γ than IL-12–stimulated control lymphocytes, equivalent numbers of IFN-γ–secreting cells can be generated from cultures of Stat4, Stat6−/− lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell–promoting conditions. Moreover, Stat4, Stat6−/− mice are able to mount an in vivo Th1 cell–mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

scholarly journals Impact of T Helper Cell Subtype on CAR-T Cell Therapy Efficacy

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Ibrahim M. Khan, BS BA ◽  
Andrew S. Nelson, PhD ◽  
Mark H. Kaplan, PhD
Keyword(s):  
T Cells ◽  
B Cell ◽  
Culture Conditions ◽  
Cell Killing ◽  
T Helper ◽  
Th Cells ◽  
Car T Cells ◽  
Th9 Cells ◽  
Tnf Α ◽  
Car T

Background and Hypothesis: Chimeric antigen receptors (CARs) are recombinant receptors with high affinity for the target antigen. Used for tumor therapy, CARs are transduced into patient T cells. CAR-T cells specific for CD19 are used to treat B cell acute lymphoblastic leukemia (B-ALL). Cancerous B cells are destroyed by CAR-T cells in an antigen-specific manner. Currently being used in conjunction with radiation and other cancer therapies to prohibit relapse, Dr. Marco Davila of the Moffitt Cancer Center, has shown that CAR-T therapy induces long term remission and B cell aplasia. Experimental Design: In this experiment the CAR vector obtained from Dr. Davila was transduced into T helper cells cultured under varying conditions (Th0, Th9, and ThGranzyme A). B cell killing and longevity of transduced CAR-Th cells were monitored as part of the criteria for determining the most effective Th subtype for the CAR-T therapy. The target cell killing-mechanism was analyzed at the RNA level using quantitative polymerase chain reaction (qPCR) to analyze gene expression of cytotoxic molecules including granzymes A/B, perforins, Fas-FasL, and TNF-α. Th9 cells were expected to be among the most effective of the indicated subtypes due to their longevity and coordination of the immune response. Results: T cells in all conditions were effectively transduced for CAR expression, although Th9 cells demonstrated a greater proportion of cultured cells that were transduced with the CAR. QPCR results suggest that there is specification of cytotoxic programs among the culture conditions. In Th9 cells, qPCR results suggest their use of perforin and TNF-α. Ongoing studies will compare cytotoxic activity. Potential Impact: Further steps after determining the most effective culture conditions include injecting transduced Th cells of the optimized subtype into mice afflicted with BALL to assess cancer killing in vivo as well as the potential harm of the therapy to the patient.

Abstract P285: Hydralazine Attenuates the Development of Hypertension in the Female Dahl Salt-sensitive Rat in a T Cell-independent Manner

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Amrita V Pai ◽  
Crystal A West ◽  
Aline Souza ◽  
Parnika S Kadam ◽  
Emma J Pollner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rat Kidney ◽  
T Helper ◽  
Independent Manner ◽  
Th Cells ◽  
Time Treatment ◽  
Salt Sensitive Hypertension ◽  
Cell Profile

Introduction: Several studies in Dahl salt-sensitive ( DS ) rats suggest that T cells play a role in salt-sensitive hypertension. To further investigate the role of T cells, we compared T cell profiles in hypertensive DS and normotensive Dahl salt-resistant ( DR ) rats as well as in DS rats treated with hydralazine ( HYD ) to attenuate the development of hypertension. Methods: Mean arterial pressure ( MAP ) was measured by telemetry in DS rats (n=13) from 1 to 4.5 months ( mo ) of age. At 1.5 mo, all of the DR (n=8) and half of the DS rats were treated with vehicle (VEH, n=7). The other half of the DS rats (n=6) received HYD (25 mg/kg/day) in the drinking water. At 4.5 mo, renal T helper ( Th ) and cytotoxic ( Tc ) cells were assessed by multicolor flow cytometry. Results: In the DS kidney, the frequency of CD4 + Th cells [(%): DS-VEH, 76±1.2* vs. DR-VEH, 55±0.7; *p<0.0001; n=7-8/group] was higher while the frequency of CD8 + Tc cells [(%): DS-VEH, 14±1.2* vs. DR-VEH, 35±1; *p<0.0001; n=7-8/group] was lower compared to DR rats. 10 weeks of HYD treatment attenuated the age-associated increase in MAP observed in DS rats [p<0.0001, Two-Way ANOVA (time, treatment); MAP (mmHg): DS-VEH, 157±4 vs. DS-HYD, 133±3; *p<0.0004; n=6-7/group]. HYD had no effect on the frequency of CD4 + [(%):77±1.5] or CD8 + [(%):15.5±0.9] T cells in the kidney of DS rats [(CD4 + ): DS-VEH vs. DS-HYD, p=0.83; (CD8 + ): DS-VEH vs. DS-HYD, p=0.5; n=7-8/group]. In summary, the ratio of Th (CD4 + ) to Tc (CD8 + ) cells is higher in the kidney of DS compared to DR rats and HYD had no effect on the T cell profile in the DS rat kidney under conditions in which the MAP was attenuated by 20 mm Hg. Conclusions: These findings indicate the DS rat has more active Th cells in the kidney compared to the DR rat. Our study also suggests that vasodilators can attenuate the development of hypertension in the DS rat in a Th- and Tc-independent manner.

scholarly journals TNF-α in T lymphocytes attenuates renal injury and fibrosis during nephrotoxic nephritis

2020 ◽  
Vol 318 (1) ◽  
pp. F107-F116 ◽  
Author(s):  
Yi Wen ◽  
Nathan P. Rudemiller ◽  
Jiandong Zhang ◽  
Taylor Robinette ◽  
Xiaohan Lu ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Renal Injury ◽  
Kidney Injury ◽  
Mrna Levels ◽  
T Helper ◽  
T Helper 17 ◽  
Immune Mediated ◽  
Tnf Α ◽  
Lymphocyte Responses

Nephrotoxic serum nephritis (NTN) models immune-mediated human glomerulonephritis and culminates in kidney inflammation and fibrosis, a process regulated by T lymphocytes. TNF-α is a key proinflammatory cytokine that contributes to diverse forms of renal injury. Therefore, we posited that TNF-α from T lymphocytes may contribute to NTN pathogenesis. Here, mice with T cell-specific deletion of TNF-α (TNF TKO) and wild-type (WT) control mice were subjected to the NTN model. At 14 days after NTN, kidney injury and fibrosis were increased in kidneys from TNF TKO mice compared with WT mice. PD1+CD4+ T cell numbers and mRNA levels of IL-17A were elevated in NTN kidneys of TNF TKO mice, suggesting that augmented local T helper 17 lymphocyte responses in the TNF TKO kidney may exaggerate renal injury and fibrosis. In turn, we found increased accumulation of neutrophils in TNF TKO kidneys during NTN. We conclude that TNF-α production in T lymphocytes mitigates NTN-induced kidney injury and fibrosis by inhibiting renal T helper 17 lymphocyte responses and infiltration of neutrophils.

scholarly journals INCREASED BETA2-ADRENERGIC RECEPTOR SIGNALING ENHANCES PROGRESSION OF HEPATOCELLULAR CARCINOMA

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S106-S106
Author(s):  
Jason Pizzini ◽  
Hanzhou Wang ◽  
Chih-Ko Yeh ◽  
Amrita Kamat
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cardiovascular Diseases ◽  
Beta Blocker ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Beta Blockers ◽  
Therapeutic Option ◽  
Propranolol Treatment ◽  
Receptor Action ◽  
And Control

Abstract We investigated whether increased signaling by beta2-adrenergic receptors (β2-ARs), which mediate the action of catecholamines, enhances the progression of hepatocellular carcinoma (HCC). Mean age of patients with HCC, the most prolific form of liver cancer, has progressively increased over the last decade. Beta2-AR-mediated signaling in liver increases with age. We also observed increased β2-AR levels in liver tissues of patients with HCC compared to control subjects. We, therefore, hypothesized that increased β2-AR signaling enhances HCC progression while inhibition of β2-AR signaling by treatment with beta blockers suppresses its progression. To test this hypothesis, we used N-nitrosodiethylamine (DEN) to induce HCC in liver-specific β2-AR knockout (LKO) and control mice in the absence or presence of beta blocker propranolol. At the end of 25 weeks, we observed increased numbers of visible tumors, disarray of liver architecture, and mortality in DEN-induced control mice which was reduced by propranolol treatment. We also observed that DEN-treated LKO mice demonstrated reduced mortality, disarray of architecture, and phosphorylation of oncogene Src compared to DEN-treated control mice. Taken together, these results indicate that decreased β2-AR signaling because of a lack of receptors in the liver or inhibition of receptor action with propranolol reduces HCC progression. Studies are in progress to determine the β2-AR-mediated mechanisms involved in HCC progression. Our studies suggest that beta blocker propranolol, used to treat cardiovascular diseases, may be repurposed as a potential therapeutic option for treatment of HCC.

scholarly journals H-2-controlled suppression of T cell response to lactate dehydrogenase B. Characterization of the lactate dehydrogenase B suppressor pathway.

1982 ◽  
Vol 156 (3) ◽  
pp. 822-833 ◽  
Author(s):  
C N Baxevanis ◽  
N Ishii ◽  
Z A Nagy ◽  
J Klein
Keyword(s):  
Lactate Dehydrogenase ◽  
T Cell ◽  
Cell Response ◽  
Cell Types ◽  
T Cell Response ◽  
T Helper ◽  
Th Cells ◽  
Th Cell ◽  
Antigen Presenting

We characterized the cell types involved in the H-2-controlled suppression of T cell response to lactate dehydrogenase B (LDHB). The suppressor effector (Tse) was found to be an Lyt-1+2+, J+ cell that recognizes antigen together with Ek molecules of antigen-presenting cells (APC). To become functional, the Tse cell requires a second signal from a nonspecific, Lyt-1+2-, J+ suppressor-inducer (Tsi) cell. The Tsi-Tse interaction is not subject to any genetic restriction. The target cell of suppression is an Lyt-1+2-, J- (most likely T helper [Th]) cell that recognizes LDHB in the context of A molecules on APC. The suppression is manifested in inhibition of the antigen-specific, A-restricted proliferation of Th cells. The interaction between Tse and Th is restricted by the A region of the H-2 complex. Because this restriction is determined by the receptor of Th cells, the mechanism of Th-Tse interaction most likely involves a concomitant recognition of LDHB and A region-controlled molecules by Th cells on the surface of Tse cells.

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