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.

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.

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 PKM2 Is Required to Activate Myeloid Dendritic Cells from Patients with Severe Aplastic Anemia

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Chunyan Liu ◽  
Mengying Zheng ◽  
Ting Wang ◽  
Huijuan Jiang ◽  
Rong Fu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Aplastic Anemia ◽  
Immune Status ◽  
Bone Marrow Failure ◽  
Severe Aplastic Anemia ◽  
Myeloid Dendritic Cells ◽  
Protein Levels ◽  
Immune Mediated ◽  
Normal Controls

Severe aplastic anemia (SAA) is an autoimmune disease in which bone marrow failure is mediated by activated myeloid dendritic cells (mDCs) and T lymphocytes. Recent research has identified a strong immunomodulatory effect of pyruvate kinase M2 (PKM2) on dendritic cells in immune-mediated diseases. In this study, we aimed to explore the role of PKM2 in the activation of mDCs in SAA. We observed conspicuously higher levels of PKM2 in mDCs from SAA patients compared to normal controls at both the gene and protein levels. Concurrently, we unexpectedly discovered that after the mDC-specific downregulation of PKM2, mDCs from patients with SAA exhibited weakened phagocytic activity and significantly decreased and shortened dendrites relative to their counterparts from normal controls. The expression levels of the costimulatory molecules CD86 and CD80 were also reduced on mDCs. Our results also suggested that PKM2 knockdown in mDCs reduced the abilities of these cells to promote the activation of CD8+ T cells (CTLs), leading to the decreased secretion of cytotoxic factors by the latter cell type. These findings demonstrate that mDC activation requires an elevated intrinsic PKM2 level and that PKM2 improves the immune status of patients with SAA by enhancing the functions of mDCs and, consequently, CTLs.

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.

Cyclosporine A Effect the CD28 Expression on CD8+T Cells of Patients with Aplastic Anemia through down Regulate FLIP.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3767-3767
Author(s):  
Haiwen Huang ◽  
De Pei Wu ◽  
Guanghua Chen ◽  
Jinxiang Fu
Keyword(s):  
T Cells ◽  
Aplastic Anemia ◽  
Effective Treatment ◽  
Cd8 T Cells ◽  
Cyclosporine A ◽  
Peripheral Blood ◽  
Caspase 8 ◽  
Healthy Controls ◽  
Rt Pcr ◽  
Normal Controls

Abstract Objective The exact reason of aplastic anemia is still unknown. Recently more and more researchers realized that immune factors play an important role in aplastic anemia. In this study, we detected the expression of CD28 on different subgroups of T cells in patients with aplastic anemia and furthermore studied the effect of cyclosporine A to CD28 and FLIP on these cells. Method 21 patients and 15 healthy controls were investigated. The Expression of CD4CD28 and CD8CD28 on patients’ T cells was detected with FCM; patients’ CD8+T cells were purified with Mini MACR system, then the expression of FLIP, caspase-8 in CD8+T cells were analyzed by RT-PCR; we also detected the expression of CD28, FLIP and caspase-8 in patients’ CD8+T cells after incubation with cyclosporine A. Result: The percentage of CD8+CD28−T cells in the patients is significantly higher than that of normal controls (30.45±5.26% versus 19.32±4.72%, p<0.05) and it can be induced to return to normal after effective treatment with Cyclosporine A; the expression of FLIP in patients’ purified CD8+ T cells is higher than that in healthy controls’ CD8+ T cells, but there is no difference in the expression of caspase-8; after being cultured with Cyclosporine A, the expression of FLIP in patient’s CD8+T cells was down regulated and the quantity of CD28 on the surface of patient’s CD8+T cells increased significantly (28.3±5.1% versus 40.6±7.71%40.6±7.71%). Conclusion: The increased expression of FLIP in patients’ CD8+T cells is related to the increased percentage of CD8+CD28−T cells in patients’ peripheral blood. Cyclosporine A can down regulate the FLIP expression and correct the abnormal percentage of CD8+CD28−T cells in patients with aplastic anemia.

Failure of Rituximab in Immune Thrombocytopenia Is Associated with the Activation of Splenic CD8 T Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 623-623
Author(s):  
Sylvain Audia ◽  
Maxime Samson ◽  
Malika Trad ◽  
Nona Janikashvili ◽  
Denis Caillot ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Thrombocytopenia ◽  
Granzyme B ◽  
Humoral Response ◽  
Interferon Γ ◽  
Off Label Use ◽  
Platelet Destruction ◽  
Off Label ◽  
Hla Dr

Abstract Abstract 623 Background: Different mechanisms are involved in the pathogenesis of immune thrombocytopenia (ITP). Platelet production is impaired as result of an immune response directed against megakaryocytes and an inappropriate level of thrombopoietin. Furthermore, platelets targeted by autoantibodies against their membrane glycoproteins are cleared by the reticuloendothelial system, mainly in the spleen. Thus, treatments targeting the autoimmune humoral response, notably rituximab (off-label use), have been proposed. However, the one-year response rate after rituximab (RTX) is not greater than 40% and the mechanisms involved in its failure remain to be defined. CD8 T cells which have been demonstrated to be involved in platelet destruction both in a mouse ITP model and in humans may play a part in the inefficiency of RTX. Purpose: To compare the splenic CD8 T cell response of ITP patients who have been refractory to RTX with untreated ITP patients Methods: The spleens of 23 primary ITP patients were assessed: 12 patients previously treated with RTX without improvement were examined as RTX refractory patients and 11 patients who have not received RTX were referred as untreated patients. Splenectomy was performed at a median of 7.1 months after RTX administration. Nine post-traumatic spleens were used as controls. Flow cytometry analysis was performed on CD8+ splenocytes to determine the expression of activation marker (HLA-DR), memory T cell markers (CD27, CD28), chemokine receptor (CCR7), adhesion molecule (CD62L) and intracellular cytotoxic proteins (granzyme B, perforin). Lineage commitment of T cells was determined after stimulation for 4 hours with PMA and ionomycin in presence of brefeldin-A, by intracellular staining of interferon-γ (Tc1, Th1), IL-4 (Tc2, Th2) and IL-17 (Tc17, Th17). Results are expressed by median and [interquartile range]. Statistical analysis was performed using non parametric tests (Kruskal-Wallis and Mann-Whitney) to compare the different groups. Results: After RTX infusion, B cells represented only 1.4% [0.3–3.4] in total splenic lymphocytes compared to about 35% in controls and untreated patients. No alteration in the CD8/CD4 ratio was observed after RTX. Nevertheless, expression of HLA-DR and granzyme B by splenic CD8 T cells was increased in RTX refractory patients when compared to untreated patients: 60% [50.6–68.9] vs. 41.8% [33.7–54.2] (p=0.02) and 50.3% [32.2–72.3] vs. 23.9% [14.4–27.7] (p=0.006), respectively. Upon stimulation, interferon-γ expression was significantly higher in CD3+CD8+ (68% [59.1–81.6]) but also in CD3+CD8− (32.5% [24.8–44]) in RTX refractory patients compared to untreated patients. The percentage of CCR7−CD62L− and CD27−CD28− among CD8+ T cells was increased in RTX refractory patients compared to untreated patients, respectively 85.4%[77.1–93.2] vs. 66.5%[56.2–73.2] (p=0.001) and 33.2% [23.3–67.1] vs. 13.4%[11.6–24.9] (p=0.04). Conclusions: Our results show that splenic CD8 T cells from RTX refractory patients express more HLA-DR, granzyme B and interferon-γ, whereas CCR7, CD62L, CD27 and CD28 are lower in comparison to untreated patients. This phenotype is consistent with effector T cells localizing in the red pulp as they lack CCR7 expression, and presumably playing a main role in splenic platelet destruction. Our results strongly support that platelet destruction is preferentially mediated by CD8 T cells rather than by the humoral response in some ITP patients, which may explain their unresponsiveness to rituximab. Disclosures: Off Label Use: Rituximab used during Immune Thrombocytopenia.

Decreased TIM-3 Expression Level of Peripheral Blood Natural Killer Cells in Severe Aplastic Anemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5078-5078
Author(s):  
Rong Fu ◽  
Tian Zhang ◽  
Xin Yuan ◽  
Zonghong Shao
Keyword(s):  
T Cells ◽  
Aplastic Anemia ◽  
Nk Cells ◽  
Mrna Expression ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Statistical Significance ◽  
Severe Aplastic Anemia ◽  
Hematopoietic Stem ◽  
Normal Controls

Abstract Severe aplastic anemia (SAA) is a life threatening disease characterized by severe pancytopenia and bone marrow failure. Natural killer (NK) cells are large granular lymphocytes which are one important component of the innate immune system and play a core role in regulation of adaptive immunity. T cell immunoglobulin mucin-3 (TIM-3), a member of the TIM family, appears to play an important negative regulatory role in T cells initial. Now, TIM-3 is widely detected on NK cells, and may contribute as a marker for activation and maturation of NK cells. Our previous studies have confirmed that the decrease of total NK cells, and CD56bright, CD56dim NK cell subsets and the higher expressions of NKp46 and perforin on NK cells may cause the over-function of T lymphocytes and thus lead to hematopoiesis failure in SAA. But, the expression of TIM-3 on NK cells in patients with SAA was still unknown. In this study, we investigated the expression of TIM-3 and its mRNA on NK cells in peripheral blood of untreated and recovered SAA patients by flow cytometry and Real-time PCR. Results showed that the expression of TIM-3 on peripheral blood NK cells in SAA patients before IST was (63.57±12.14) %, which was significantly decreased than that in normal controls (85.62±9.03) % ( p<0.01). The expression of TIM-3 on CD56dim NK cells was (66.41±11.74) % and (83.83±1.59) % separately in SAA patients before IST and normal controls. TIM-3 expressed in SAA patients before IST was lower than that in normal controls ( p<0.01). We also measured TIM-3 expressed on the surface of CD56bright NK cells, but the result showed that there was no statistical difference between SAA patients before IST (61.11±24.99%) and normal controls (62.64±12.06%) (p>0.05). More interesting, the expression of TIM-3 on NK cells was (75.88±12.83) % in SAA patients after IST, which was significantly increased than that in SAA patients before IST, and was no difference with normal controls. As well, we found TIM-3 expression on both CD56dim NK cells and CD56bright NK cells in SAA patients after IST also has a rising trend compared with SAA patients before IST. However, these differences had no statistical significance. Further, we detected TIM-3 mRNA expression in NK cells isolated from peripheral blood. TIM-3 mRNA expression in peripheral blood NK cells from newly diagnosis SAA patients, recovering SAA patients and normal controls was evaluated, respectively. The relative TIM-3 mRNA expression was significantly increased in NK cells in SAA patients after IST compared with SAA patients before IST and normal controls, and this difference had statistical significance. Meanwhile, the relative TIM-3 mRNA expression was lower in NK cells in SAA patients before IST compared with normal controls. However, the difference had no statistical significance. In SAA patients, the expression of TIM-3 on NK cells was positively correlated with the level of WBC (r=0.685, p=0.000), proportion of neutrophil (r=0.825, p=0.000), and proportion of reticulocyte in peripheral blood (r=0.465, p=0.029). And it was negatively correlated with the proportion of lymphocyte in peripheral blood (r=-0.802, p=0.000). According to our series studies, we hypothesize that the lower numbers and dysfunction of NK cells induce the failure of suppressing the over function of DC cells and T cells, that lead damage to healthy hematopoietic stem cells and the onset of SAA. Disclosures No relevant conflicts of interest to declare.

Inhibition of diacylglycerol kinase alpha to augment antitumor effector T cells in tumor-bearing host.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 293-293
Author(s):  
Naoki Okada ◽  
Ko Sugiyama ◽  
Hidemitsu Kitamura ◽  
Akinobu Taketomi
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
Granzyme B ◽  
Diacylglycerol Kinase ◽  
Effector T Cells ◽  
Control Group ◽  
Antigen Stimulation ◽  
Tumor Bearing

293 Background: Diacylglycerol kinases (DGKs), lipid kinases transforming diacylglycerol to phosphatidic acid, play important roles in intracellular signal transduction. Diacylglycerol kinase alpha (DGKa), an isozyme of DGKs, is well-known to promote proliferation of cancer cells by suppression of the apoptosis. Additionally, a previous report demonstrated that activation of DGKa induced anergy state of T lymphocytes in vivo. In this study, we investigated whether inhibition of DGKa not only suppress the tumorigenesis of cancer cells but also activate anti-tumor immunity. Methods: We first investigated the effect of DGKa inhibitor on in vitro proliferation of murine hepatoma cell lines (Hepa1-6) by cell proliferation assay. Cytokine and Granzyme B productions by CD8+ T cells from OT-1 mice after the OVA antigen stimulation were evaluated by ELISA and flowcytometry, respectively. Next, we established a tumor-bearing mice model by injection of mCherry-transfected Hepa1-6 cells into spleen. Tumorigenesis and tumor-infiltrating T cells in the liver were evaluated by in vivo imaging system, HE staining, and immunohistochemistry. CD8+ T cells were collected from the liver and stimulated with PMA and Ca2+ ionophore and the IFN-g production levels were evaluated by flowcytometry. Results: Proliferation of Hepa1-6 cells were suppressed in the presence of DGKa inhibitor in vitro. IL-2 production levels of OT-1 CD8 T cells in control group was augmented by the addition of DGKa inhibitor (246 vs 579 pg/ml, p < 0.05). Granzyme B-positive cells in OT-1 CD8+ T cells were increased by the treatment with DGKa inhibitor compared to the control group (4.4 vs 8.9 %, P < 0.05) after the antigen stimulation. In vivo administration of DGKa inhibitor significantly suppressed the tumor size (fluorescence (AU) 2.0x1010 vs 6.3x109, area (μm2) 1.5x107 vs 0.9x107, p < 0.05) in the liver of tumor bearing mice. Then, the number of tumor-infiltrating T cells (582 vs 1506, 5 HPF, p < 0.05) and the IFN-g-producing cells (9.2 vs 16.0 %) in CD8+ T cells were elevated by the DGKa treatment. Conclusions: Inhibition of DGKa not only suppressed the proliferation of hepatoma but also activated anti-tumor effector T cells in vivo.

Hepatitis durch Checkpunkt-Therapie – periphere Immunaktivierung als möglicher Biomarker

2021 ◽  
Vol 3 (2) ◽  
pp. 75-76
Author(s):  
Bertram Bengsch
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Transcriptional Profiling ◽  
Granzyme B ◽  
Enhanced Production ◽  
Hla Dr ◽  
Cytotoxic Effector ◽  
Pro Inflammatory Cytokines

<b>Background &amp; aims:</b> Checkpoint inhibitor-related hepatitis (CPI-Hep) is an emerging clinical challenge. We aim to gain insights into the immunopathology of CPI-Hep by comprehensive characterisation of myeloid and lymphoid subsets. <b>Methods:</b> CPI-treated patients with or without related hepatitis (CPI-Hep; n = 22 and CPI-noHep; n = 7) were recruited. Phenotypic and transcriptional-profiling of peripheral immune subsets was performed and compared with 19 healthy controls (HC). In vitro monocyte-derived macrophages (MoMF) were assessed for activation and cytokine production. CD163, CCR2, CD68, CD3, CD8 and granzyme B expression was assessed using immunohistochemistry/immunofluorescence (n = 4). <b>Results:</b> A significant total monocyte depletion was observed in CPI-Hep compared with HC (p = 0.04), along with a proportionate increase in the classical monocyte population (p = 0.0002) and significant upregulation of CCR2, CD163 and downregulation of CCR7. Soluble CD163 levels were significantly elevated in CPI-Hep compared with HC (p &#x3c; 0.0001). In vitro MoMF from CPI-Hep showed enhanced production of pro-inflammatory cytokines. CD8+ T cells demonstrated increased perforin, granzyme B, ICOS and HLA-DR expression in CPI-Hep. Transcriptional profiling supported activated monocyte and enhanced effector CD8+ T cell populations in CPI-Hep. Immunohistochemistry demonstrated co-localisation of CD8+/granzyme B+ T cells with CD68+CCR2+/ CD68+CD163+ macrophages in CPI-Hep liver tissue. <b>Conclusions:</b> CPI-Hep is associated with an activation of peripheral monocytes and enhanced cytotoxic, effector phenotype of CD8+ T cells. These changes were reflected by liver inflammation composed of CD163+/CCR2+ macrophage and CD8+ T cells.

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