scholarly journals Further evidence for lymphokine overproduction in severe aplastic anemia [see comments]

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 266-272
Author(s):  
W Hinterberger ◽  
G Adolf ◽  
G Aichinger ◽  
R Dudczak ◽  
K Geissler ◽  
...  
Keyword(s):  
T Cells ◽  
Aplastic Anemia ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Serum Levels ◽  
Severe Aplastic Anemia ◽  
Hematopoietic Progenitor Cell ◽  
Ifn Gamma ◽  
Hla Dr

Interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF) are lymphokines with a potent hematopoietic progenitor cell suppressive capacity. In untreated and immunosuppressed patients with severe aplastic anemia (SAA) and in control individuals we measured (a) serum levels of IFN-gamma and TNF and its production by peripheral blood mononuclear cells (PBMNC); (b) serum levels of neopterin, a product that reflects endogenous IFN production; (c) resting and activated lymphocyte subpopulations; and (d) serum levels of soluble interleukin- 2 receptor (IL-2R). Serum levels of IFN and TNF did not differ significantly in untreated and treated SAA patients and control individuals. Spontaneous and phytohemagglutinin-induced production of IFN and TNF by PBMNC, however, were highly increased in both untreated and treated SAA patients. Increased and decreased neopterin serum levels in untreated and treated SAA patients, respectively, suggest modulation of endogenous lymphokine release subsequent to immunosuppression. HLA-DR+ antigen was mainly expressed by CD8 T cells. Circulating numbers of activated (CD4 and CD8) T cells and serum levels of IL-2R were not increased in both untreated and treated SAA patients. The proportion of HLA-DR+ T cells in the PBMNC of untreated SAA patients correlated with the extent of lectin-induced IFN production. Although we were unable to confirm previous reports in SAA on (a) detectable IFN in blood and bone marrow serum, (b) improvement of stem cell growth upon neutralization of endogenous IFN, (c) absolutely increased numbers of circulating activated T cells, and (d) normalization of these abnormalities subsequent to successful immunosuppression, our data clearly support previous reports on abnormal lymphokine production in severe aplastic anemia. Our failure to relate this phenomenon to the severity of disease states, however, further raises doubts on the pathogenetic significance of lymphokine overproduction in SAA.

scholarly journals Further evidence for lymphokine overproduction in severe aplastic anemia [see comments]

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 266-272 ◽  
Author(s):  
W Hinterberger ◽  
G Adolf ◽  
G Aichinger ◽  
R Dudczak ◽  
K Geissler ◽  
...  
Keyword(s):  
T Cells ◽  
Aplastic Anemia ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Serum Levels ◽  
Severe Aplastic Anemia ◽  
Hematopoietic Progenitor Cell ◽  
Ifn Gamma ◽  
Hla Dr

Abstract Interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF) are lymphokines with a potent hematopoietic progenitor cell suppressive capacity. In untreated and immunosuppressed patients with severe aplastic anemia (SAA) and in control individuals we measured (a) serum levels of IFN-gamma and TNF and its production by peripheral blood mononuclear cells (PBMNC); (b) serum levels of neopterin, a product that reflects endogenous IFN production; (c) resting and activated lymphocyte subpopulations; and (d) serum levels of soluble interleukin- 2 receptor (IL-2R). Serum levels of IFN and TNF did not differ significantly in untreated and treated SAA patients and control individuals. Spontaneous and phytohemagglutinin-induced production of IFN and TNF by PBMNC, however, were highly increased in both untreated and treated SAA patients. Increased and decreased neopterin serum levels in untreated and treated SAA patients, respectively, suggest modulation of endogenous lymphokine release subsequent to immunosuppression. HLA-DR+ antigen was mainly expressed by CD8 T cells. Circulating numbers of activated (CD4 and CD8) T cells and serum levels of IL-2R were not increased in both untreated and treated SAA patients. The proportion of HLA-DR+ T cells in the PBMNC of untreated SAA patients correlated with the extent of lectin-induced IFN production. Although we were unable to confirm previous reports in SAA on (a) detectable IFN in blood and bone marrow serum, (b) improvement of stem cell growth upon neutralization of endogenous IFN, (c) absolutely increased numbers of circulating activated T cells, and (d) normalization of these abnormalities subsequent to successful immunosuppression, our data clearly support previous reports on abnormal lymphokine production in severe aplastic anemia. Our failure to relate this phenomenon to the severity of disease states, however, further raises doubts on the pathogenetic significance of lymphokine overproduction in SAA.

Study on the Pathways to Damage Hematopoiesis by CD8+ Effector T Cells of the Patients with Severe Aplastic Anemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4371-4371
Author(s):  
Zonghong Shao ◽  
Le Feng ◽  
Rong Fu ◽  
Jun Wang ◽  
Chunyan Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Aplastic Anemia ◽  
Cd8 T Cells ◽  
Bone Marrow Failure ◽  
Granzyme B ◽  
Effector T Cells ◽  
Severe Aplastic Anemia ◽  
Control Group ◽  
Hla Dr ◽  
Normal Controls

Abstract Abstract 4371 Objective To investigate the quantity and their pathways to damage hematopoietic cells of CD8+CD25+ and CD8+HLA-DR+ effector T cells in peripheral blood (PB) of the patients with severe aplastic anemia(SAA) and explore the heterogeneous immunopathogenesis of SAA further. Methods The quantity of CD8+CD25+and CD8+HLA-DR+ cells in PB and the expressions of perforin, granzyme B, tumor necrosis factor-β(TNF -β) and FasL of 29 SAA (14 untreated and 15 recovered) patients and 12 normal controls were analyzed by flow cytometry. Results The ratio of CD8+CD25+T cells in CD8+ T cells was (3.67±2.58)% in untreated SAA patients, (5.19±4.29)% in recovered patients and (4.84±2.31)% in normal controls, and the ratios of CD8+CD25+T cells in CD3+ cells in three groups were (2.25±1.35)%, (2.98±1.35)% and (2.11±1.88)% respectively. There was no statistic difference among 3 groups(P>0.05). The ratio of CD8+HLA-DR+T cells in CD8+T cells was (39.30±8.13)% in untreated patients, which was significantly higher than that of recovered patients[(20.65±5.38%)] and controls [(18.34±6.68%)](P<0.001). There was no statistic difference between recovered patients and controls(P>0.05). CD8+HLA-DR+T cells in CD3+ cells was (27.81±7.10)% in untreated group, higher than that of recovered patients (12.02±3.03)% and controls(8.50±2.33)%(P<0.01). And the ratio in recovered group was higher than in control group(P<0.05). The expressions of perforin, granzyme B, TNF-β and FasL of CD8+HLA-DR+ T cells of untreated SAA patients were 8.51% A96.08% A72.11% and 94.25% respectively, higher than those of recovered patients(1.78% A85.20% A34.38% A51.20%)and controls(1.86% A82.09% A17.92% A32.91%). There was no statistic difference between recovered patients and controls(P>0.05). Conclusion There were elevated quantity of CD8+HLA-DR+ T cells and high expressions of perforin, granzyme B, TNF-β and FasL in SAA, which might contribute to the bone marrow failure of SAA. Disclosures: No relevant conflicts of interest to declare.

TRAIL in CD8+ T cells from patients with severe aplastic anemia

2017 ◽  
Vol 106 (4) ◽  
pp. 490-499
Author(s):  
Chunyan Liu ◽  
Mengying Zheng ◽  
Tian Zhang ◽  
Rong Fu ◽  
Huaquan Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Aplastic Anemia ◽  
Cd8 T Cells ◽  
Severe Aplastic Anemia

scholarly journals Detection of hyperreactive T cells in multiple myeloma by multivalent cross-linking of the CD3/TCR complex [see comments]

Blood ◽  
1991 ◽  
Vol 78 (7) ◽  
pp. 1770-1780 ◽  
Author(s):  
M Massaia ◽  
A Bianchi ◽  
C Attisano ◽  
S Peola ◽  
V Redoglia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Normal Subjects ◽  
Cross Linking ◽  
Peripheral Blood Mononuclear ◽  
Hla Dr ◽  
Lower Ratio

Abstract Cellular immunity was investigated in 43 patients with multiple myeloma (MM) by assessing 3HTdR uptake induced by monocyte-dependent [CD3 monoclonal antibodies (MoAbs), phytohemagglutinin (PHA)] and monocyte- independent (CD2 MoAbs, ionomycin + phorbolester) stimulations. The former were evaluated in peripheral blood mononuclear cells (PBMNC) and purified T cells; the latter were evaluated in purified T-cell preparations only. MM showed significantly lower PBMNC responses to PHA (P less than .001), soluble OKT3 (CD3) (P = .01), and immobilized OKT3 MoAbs (P = .01). On purification of T cells, MM responses were still defective to soluble T11(2) + T11(3) (CD2) MoAbs (P = .004), phorbol myristate acetate (PMA) plus ionomycin (P less than .001), but significantly higher to plastic-immobilized OKT3 (P = .004). In some MM, 3HTdR uptake, interleukin-2 (IL-2) receptor (CD25) expression, and IL-2 production were as high on stimulation with plastic-immobilized OKT3 as that observed in normal subjects under optimal conditions (ie, plastic-immobilized OKT3 plus accessory signals). CD3 hyperreactivity correlated with the number of CD8+ HLA-DR+ cells in MM T-cell preparations. MM patients with more than 10% CD8+ HLA-DR+ cells had significantly higher responses to immobilized OKT3 (P less than .001), but lower responses to T11(2) plus T11(3) (P = .01), and PMA plus ionomycin (P = .03) than patients with less than 10% CD8+ HLA-DR+ cells. Phenotyping of CD45RA (naive) and CD45R0 (memory) expressions in resting MM T cells showed a lower ratio of CD45RA to CD45R0 in both CD4 (P less than .05) and CD8 (P less than .001) subpopulations. These data indicate that (a) some MM T cells require significantly fewer accessory signals (if any) to express the IL-2 receptor fully, secrete IL-2, and proliferate on multivalent cross-linking of the CD3/TCR complex; and (b) this peculiar state of activation is associated with high HLA-DR expression in CD8+ lymphocytes.

scholarly journals Inhibition of CD4 cross-linking-induced lymphocytes apoptosis by vesnarinone as a novel immunomodulating agent: vesnarinone inhibits Fas expression and apoptosis by blocking cytokine secretion

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2361-2368 ◽  
Author(s):  
N Oyaizu ◽  
TW McCloskey ◽  
S Than ◽  
S Pahwa
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Cytokine Secretion ◽  
Tnf Alpha ◽  
Cross Linking ◽  
Apoptosis Induction ◽  
Peripheral Blood Mononuclear ◽  
Cell Surface Molecule ◽  
Ifn Gamma

Evidence is accumulating that T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals show accelerated cell death through apoptosis. We have recently demonstrated that the cross-linking of CD4 molecules (CD4XL) results in death of normal peripheral T cells through apoptosis and imbalanced cytokine secretion (ie, induction of tumor necrosis factor-alpha [TNF-alpha] and interferon-gamma [IFN-gamma] in the absence of interleukin-2 [IL-2] or IL-4 secretion). These upregulated cytokines (TNF-alpha/IFN-gamma) largely contributed to upregulation of the apoptosis-inducing cell surface molecule, Fas (APO- 1/CD95) and apoptosis induction. The present study investigated the effect of vesnarinone as a novel immunomodulating agent on CD4XL- induced T-cell apoptosis. The addition of vesnarinone to peripheral blood mononuclear cells (PBMC) significantly inhibited CD4XL-induced lymphocyte apoptosis. This apoptosis-inhibitory effect of vesnarinone was associated with the blocking of CD4XL-induced TNF-alpha IFN-gamma secretion and of Fas antigen upregulation. However, vesnarinone did not block effects of exogenously supplemented TNF-alpha/IFN-gamma on Fas induction. These data suggest that vesnarinone inhibits CD4XL-induced TNF-alpha/IFN-gamma secretion, thereby blocking subsequent Fas upregulation and apoptosis induction. Given the potent pathogenic role of imbalanced cytokine secretion observed in HIV-infection, an agent such as vesnarinone may be of therapeutic value in slowing disease progression.

scholarly journals Lymphokine overproduction in severe aplastic anemia is not related to blood transfusions

Blood ◽  
1989 ◽  
Vol 74 (8) ◽  
pp. 2713-2717 ◽  
Author(s):  
W Hinterberger ◽  
G Adolf ◽  
P Bettelheim ◽  
K Geissler ◽  
C Huber ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Aplastic Anemia ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Severe Aplastic Anemia ◽  
Tnf Alpha ◽  
Blood Transfusions ◽  
Peripheral Blood Mononuclear ◽  
Ifn Gamma

Abstract The production of interferons (IFNs), IFN-gamma, tumor necrosis factors (TNFs) and TNF-alpha (TNF-alpha) by peripheral blood mononuclear cells (PBMNCs) of untransfused and transfused, but otherwise untreated patients with severe aplastic anemia (SAA) was determined using bioassays and immunoassays. In untransfused and pretransfused SAA patients, spontaneous and lectin-induced production of these cytokines by PBMNCs was strongly enhanced. Cytokine production in untransfused SAA patients did not differ from that in pretransfused patients. Similar relative frequencies of activated (HLA-DR+) lymphocyte subpopulations present in the PBMNCs demonstrated cytokine overproduction per cells. Cytokine production was studied in three SAA patients before and after blood cell transfusions. Spontaneous and lectin-induced production of these cytokines was abnormally high and unaffected by blood transfusions. In another patient exhibiting abnormal cytokine production, the hematopoietic response to cyclosporin- A in vivo was accompanied by normalization of cytokine production in vitro. We conclude that overproduction of IFN-gamma and TNF-alpha by lectin-stimulated PBMNCs is an intrinsic abnormality of SAA unrelated to blood transfusions. Normalization of production of IFN-gamma and TNF- alpha accompanying a clinical response to cyclosporin-A may cautiously be taken as further evidence suggesting a pathogenetic role of cytokine overproduction in SAA.

Sirt1 in the Regulation of Interferon Gamma in Severe Aplastic Anemia

2019 ◽  
Vol 142 (3) ◽  
pp. 142-148
Author(s):  
Xiaoyun Lin ◽  
Chunyan Liu ◽  
Ting Wang ◽  
Huaquan Wang ◽  
Zonghong Shao
Keyword(s):  
T Cells ◽  
Aplastic Anemia ◽  
Interferon Gamma ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Significant Negative Correlation ◽  
Severe Aplastic Anemia ◽  
Cytotoxic Lymphocytes ◽  
Inflammatory Status

Recent studies have indicated that Sirt1 plays critical roles in the suppression of inflammation, T cell activation, and differentiation of hematopoietic progenitor cells. Severe aplastic anemia (SAA) is an immune-mediated disease that is characterized by elevated cytotoxic lymphocytes and type 1 cytokines. As a negative effector cytokine, interferon gamma (IFNγ) takes part in aplastic anemia through its inhibitory effect on hematopoiesis. In this study, we investigated the role of Sirt1 in the regulation of IFNγ in patients with SAA. A significant decrease in relative SIRT1 (p< 0.05) and increase in IFNG (p< 0.05) expression levels was observed in the sorted CD8+T cells of SAA patients compared to the controls. There was a significant negative correlation (r = –0.53, p < 0.05) between SIRT1 and IFNG expression in SAA patients. SRT3025, a Sirt1 activator, was shown to significantly reduce IFNγ (p < 0.01) and elevate Sirt1 (p < 0.05) expression in the CD8+T cells of SAA patients, and also showed a therapeutic role in an aplastic anemia mouse model. In conclusion, the defective Sirt1 may be correlated to the abnormal IFNγ expression in SAA patients, and activation of Sirt1 signaling may help improve the inflammatory status of SAA.

Study on the Dendritic Cell Subsets and Their Relationship with the Expressions of T-Bet and GATA-3 in Peripheral Lymphocytes of Severe Aplastic Anemia Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4901-4901
Author(s):  
Zonghong Shao ◽  
Wang Jun ◽  
Rong Fu ◽  
Lijuan Li ◽  
Hui Liu ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Aplastic Anemia ◽  
Statistical Difference ◽  
Mononuclear Cells ◽  
Severe Aplastic Anemia ◽  
Healthy Controls ◽  
Peripheral Blood Mononuclear ◽  
Hla Dr ◽  
Immune Imbalance ◽  
Acquired Severe Aplastic Anemia

Abstract Objective To investigate the effects of the dendritic cell (DC) subsets and the transcriptive factors, T-bet and GATA-3, on immune imbalance in the pathogenesis of acquired severe aplastic anemia (SAA). Methods The mDCs(HLA-DR+Lin−CD11c+) and pDCs(HLA-DR+Lin−CD123+) in peripheral blood mononuclear cells (PBMNC) were measured with flow cytometry (FCM), the expressions of T-bet mRNA and GATA-3 mRNA in PBMNC with semiquantitive RT-PCR and the plasma levels of IFNγ and IL-4 with ELISA in 29 SAA patients (21 untreated and 8 recovered) and 16 healthy controls. Results The percentages of mDCs in PBMNC were (0.44±0.24) % and (0.73±0.30) % in untreated and recovered SAA patients respectively, either of which was higher than that of controls (0.29±0.10%) (P&lt;0.05). The percentage of pDCs in the untreated cases was lower than that of the recovered or controls [(0.18±0.14) % vs. (0.28±0.20) % and (0.29±0.13) %] (P&lt;0.05). mDCs/pDCs ratios were 3.45±2.71 and 2.90±0.95 in untreated and recovered groups respectively, either of which was higher than that of controls (1.15±0.56) (P&lt;0.05). No statistical difference of mDCs/pDCs was found between untreated and recovered patients (P&lt;0.05). The relative mRNA expressions of transcriptive factor T-bet were 0.37±0.07, 0.20±0.07 and 0.17±0.05 in 3 groups, respectively. The expression of T-bet of untreated patients was higher than that of recovered patients or healthy controls (P&lt;0.05). There was no statistical difference of GATA-3 expression among 3 groups(P&gt;0.05). T-bet/GATA-3 ratio was 0.72±0.13 in untreated patients, which was higher than that of recovered patients (0.33±0.08) or controls (0.35±0.11). The plasma level of IFNγ in the untreated cases was (50.9±1.1)ng/L, which was higher than that of recovered [(49.7±0.9) ng/L] or controls[(49.7±0.7) ng/L]. There were significant positive correlation between T-bet and mDCs/pDCs (r=0.445, P&lt;0.01), as well as T-bet and IFNγ (r=0.402, P&lt;0.01). Conclusion Both mDCs/pDCs and T-bet/GATA-3 ratios in SAA were higher and positively correlated which might contribute to the cascade activation of T lymphocytes. Immunosuppressive therapy for SAA should be kept on until both ratios become normal.

scholarly journals CD8+HLA-DR+ T cells are increased in patients with severe aplastic anemia

2014 ◽  
Vol 10 (3) ◽  
pp. 1252-1258 ◽  
Author(s):  
LIMIN XING ◽  
CHUNYAN LIU ◽  
RONG FU ◽  
HUAQUAN WANG ◽  
JUN WANG ◽  
...  
Keyword(s):  
T Cells ◽  
Aplastic Anemia ◽  
Severe Aplastic Anemia ◽  
Hla Dr

scholarly journals Replication-Defective Canarypox (ALVAC) Vectors Effectively Activate Anti–Human Immunodeficiency Virus-1 Cytotoxic T Lymphocytes Present in Infected Patients: Implications for Antigen-Specific Immunotherapy

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2406-2416 ◽  
Author(s):  
G. Ferrari ◽  
C. Berend ◽  
J. Ottinger ◽  
R. Dodge ◽  
J. Bartlett ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cd8 T Cells ◽  
Mammalian Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Cell Repertoire ◽  
Immunodeficiency Virus ◽  
Hiv 1

In the attempt to develop immunotherapeutic strategies for acquired immunodeficiency syndrome capable of activating effector cells in an antigen-specific manner while maintaining the broadest possible T-cell repertoire, we evaluated two canarypox (ALVAC)-based vectors for their capacity to induce ex vivo activation/expansion of human immunodeficiency virus (HIV)-specific CD8+ cytotoxic lymphocyte precursors (CTLp) obtained from HIV-1–infected donors. These two vectors, vCP205 encoding HIV-1 gp120 + TM (28 amino acid transmembrane anchor sequence) in addition to Gag/protease and vCP300 encoding gp120 + Gag/protease as well as Nef and Pol CTL determinants, are pancytotropic but replication incompetent in mammalian cells. Bulk peripheral blood mononuclear cells (PBMCs) or enriched CD8+ T cells were stimulated for 10 days with autologous ALVAC-infected PBMCs in the presence of different cytokine combinations (interleukin-2 [IL-2], IL-4, IL-7, and IL-12). Activation by ALVAC constructs was highly antigen-specific, because vCP205 elicited only Env and Gag CTL, whereas vCP300 elicited broader reactivities against Env, Gag, Pol, and Nef determinants. The ALVAC activation of CTLp was IL-2 dependent and enhanced by the addition of IL-7, whereas IL-4 and IL-12 failed to augment cytotoxic reactivities elicited by these constructs. The expansion of enriched CD8+ T cells after activation with vCP300 was higher in patients with CD4 counts greater than 400 cells/μL. Two rounds of in vitro stimulation (IVS) with vCP300 resulted in nearly an eightfold expansion of CD8+ lymphocytes over a 25-day period. After the second IVS, an average 3.2-fold increase among the different antigen-specific CTL frequencies was achieved. These studies clearly show that HIV-recombinant ALVAC vectors represent powerful polyvalent antigenic stimuli for activation and expansion of the CD8 lymphocyte response that occurs as a result of HIV infection.

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