scholarly journals Dietary strawberries increase the proliferative response of CD3/CD28-activated CD8+ T cells and the production of TNF-α in lipopolysaccharide-stimulated monocytes from obese human subjects

2013 ◽  
Vol 110 (11) ◽  
pp. 2011-2019 ◽  
Author(s):  
Susan J. Zunino ◽  
David H. Storms ◽  
Tammy L. Freytag ◽  
Bruce E. Mackey ◽  
Ling Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Mononuclear Cells ◽  
Global Changes ◽  
Obese People ◽  
Activated T Cells ◽  
Double Blind ◽  
Freeze Dried ◽  
Tnf Α

Obesity increases the risk of developing bacterial and viral infections compared with normal weight. In a 7-week double-blind, randomised, cross-over trial, twenty obese volunteers (BMI between 30 and 40 kg/m2) were fed freeze-dried strawberry powder or strawberry-flavoured placebo preparations to determine the effects of dietary strawberries on immune function. Blood was collected at six time points during the study and peripheral blood mononuclear cells (PBMC) were isolated at each time point and activated with CD3 plus CD28 antibodies (T-lymphocyte activation) or lipopolysaccharide (LPS, monocyte activation). Interferon-γ, TNF-α, IL-4 and IL-10 were measured in supernatants from the activated T cells. Supernatants from the activated monocytes were analysed for the production of TNF-α, IL-1β, IL-6 and IL-8. PBMC were pre-stained with PKH (Paul Karl Horan) dye and activated with CD3 plus CD28 antibodies to determine the proliferative responses of CD4+ and CD8+ T-lymphocytes by flow cytometry. To detect global changes in gene expression, microarray analysis was performed on LPS- and vehicle-treated PBMC from two subjects before and after the strawberry intervention. No difference was observed for the production of T-cell cytokines between the intervention groups. The production of TNF-α was increased in the supernatants from LPS-activated PBMC in the group consuming strawberries compared with the placebo. A modest increase in the proliferation of the CD8+ T-lymphocyte population was observed at 24 h post-activation. These data suggest that dietary strawberries may increase the immunological response of T-lymphocytes and monocytes in obese people who are at greater risk for developing infections.

Depleting Autologous Activated CD4+ t Lymphocytes Increased Generation of Colony-Forming-Cells(CFC) in Patients with Myelodysplastic Syndromes

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5092-5092
Author(s):  
Zheng Zhang ◽  
Xiao Li ◽  
Qianqiao Zhang ◽  
Ying Tao ◽  
Qi He
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Mononuclear Cells ◽  
Fish Analysis ◽  
Low Grade ◽  
Healthy Donors ◽  
Magnetic Sorting ◽  
Colony Forming Cell

Abstract Objective To investigate how autoimmune mechanism playing a role in generation of colony-forming-cells(CFC), bone mononuclear cells(BMNC) from MDS were removed of autologous activated CD4+ T cells in vitro and cultured to find out effect of T cells on MDS hemopietic progenitor. Methods BMNC from 25 patients with low-grade MDS and 5 normal donors were depleted of CD4+CCR5+ T lymphocytes using magnetic sorting. Depleted and plused CD4+CCR5+ T BMNC were seeded onto methycellulose and the correlation of colony-forming-cell (CFC) number and the polarization of T cells were analyzed, the generation of CFC, the immunophenotype and the clonal cells(which had cytogenetic markers detected by FISH), was compared respectively. Results ¢Å The capacity of BMNC from 5 healthy donors to generate CFC remained unchanged in the CD4+CCR5+ T lymphocyte-depleted and lymphocyte-plused BMNC. In contrast, cultures initiated with CD4+CCR5+ T lymphocyte-depleted BMNC from patients with low-grade MDS exhibited significantly increased generation of CFC compared with the corresponding lymphocyte-plused cultures, but the lymphocyte-plused cultures had no generation of CFC. ¢Æ The number of CFU-E from the CD4+CCR5+ T lymphocyte-depleted BMNC from patients with low-grade MDS showed significantly correlation with the percentage of Th1 (r=0.52, p≤¼ 0.05), but had no correlation with the percentage of Tc1 and the rate of Th1/Th2 and Tc1/Tc2 (p >0.05); The number of CFC, CFU-G and CFU-GE had no correlation with the polarization of T lymphocyte (P >0.05). ¢Ç The percentage of CD34 in bone nucleated cells of low-grade MDS was higher than that in healthy donors(1.8% vs. 1.0%, P >0.05), that of CD33 in nucleated cells of low-grade MDS was significantly higher than that in healthy donors[(20.3±5.8)% vs.(13.8±1.8)%(P≤¼0.05)], and that of CD13 in nucleated cells of low-grade MDS was significantly higher than that in healthy donors[(21.1±6.4)% vs. (11.6±1.8)%(p<0.05)]. After cultivation, the percentage of CD34 in low-grade MDS nucleated cells decreased to 1.4%(P >0.05), that of CD33 decreased to (12.1±3.7)%(p<0.05), and that of CD13 decreased to (17.1±5.4)%(p<0.05), but the percentage of CD34, CD33 and CD13 had no significantly changed in healthy donors between pre-culture and post-culture. ¢È FISH analysis in 6 patients revealed that +8 clone was increased(from 51% to 61%), but 20q- and -7 clone cell had no significantly changed. Conclusion In certain subtypes of MDS, selectedly removement of autologous activated CD4T cells can increase the generation of colony-forming-cells(CFC) in vitro, and improve the differentiation of MDS medullary system, but the increased CFC consisting of residual normal hemopoiesis or conal hemopoiesis were still unconcluded.

Targeted Depletion and Inhibition of Activated T Lymphocytes with SGN-70, a Humanized Antibody Specific for the Activation Antigen CD70.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1728-1728
Author(s):  
Julie A. McEarchern ◽  
Kerry Klussman ◽  
Tamar E. Boursalian ◽  
Iqbal S. Grewal ◽  
Che-Leung Law
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Influenza A ◽  
Matrix Protein ◽  
Mononuclear Cells ◽  
Therapeutic Potential ◽  
Cell Subset ◽  
Activated T Cells ◽  
Stimulation Of

Abstract CD70 (CD27L) is a member of the tumor necrosis factor superfamily that is predominantly expressed on activated lymphocytes and is important for generation of B and T memory and effector responses. High levels of CD70 are also found on chronically activated T cells and lymphocytes in patients with autoimmune disorders. Blockade of CD70 interaction with its receptor has been shown to inhibit the onset of experimental autoimmune encephalomyelitis and cardiac allograft rejection in mice. We have engineered a humanized anti-CD70, SGN-70, that mediates Fc-dependent antibody effector functions and blocks binding of CD70 to its receptor. In this report we show that SGN-70 inhibits co-stimulation of T lymphocytes, and selectively depletes CD70+ activated T cells. Depletion of antigen-specific T cells by SGN-70 was demonstrated using CD8+ T cells specific for a peptide (M58-66) derived from the influenza A matrix protein M1. Stimulation of peripheral blood mononuclear cells with the M1 peptide markedly induced CD70 expression within a discrete expanding of M1 peptide-specific CD8+Vβ17+ T cell subset. Treatment of peptide-stimulated cultures with SGN-70 (0.01–1 μg/mL) decreased the number of CD70+CD8+Vβ17+ cells by >80%. This depletion was dependent on the activity of CD16+ cells within the culture since blocking CD16 completely eliminated the depleting effect of SGN-70. Non-activated Vβ17 negative cells were not affected by SGN-70 and were functionally equivalent to untreated control cultures in subsequent response to mitogenic re-stimulation. Together, these data demonstrate the capacity of SGN-70 to selectively target activated cells and its potential to limit expansion of antigen-specific T lymphocytes. Thus, SGN-70 may have therapeutic potential to target T cell-mediated autoimmune and inflammatory diseases.

scholarly journals This Is a Title: Cytarabine Combined with PD-1 Inhibitor in the Treatment of R/R-AML: A Report of 3 Cases and Literature Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-26
Author(s):  
Yu Wang ◽  
Chuanyan Jiang ◽  
Xi Yang ◽  
Jingying Dai ◽  
Mengying Zou ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Treg Cells ◽  
Hematological Toxicity ◽  
High Dose ◽  
Dynamic Changes ◽  
Cd8 T Lymphocytes ◽  
Tnf Α ◽  
High Dose Cytarabine

Objectives: To explore the efficacy and safety of high-dose cytarabine combined with PD-1 inhibitors and demethylation drugs in relapsed and refractory acute myeloid leukemia (R/R-AML) in Chinaand to investigatethe dynamic changes of Treg cells, CD4+ T cells, CD8+ T cells, TNF-α, INF-γ, and IL-6 in the prognosis of the disease. Methods:A total of three patients with R/R-AML treated in our department were included in the study. None of the three patients had received at least two courses of standard chemotherapy before and did not obtain remission.The cellular immunity and cytokines were evaluated on the 1st, 8th, 15th, and 22nd day of the treatment.In the study,eligible R/ R-AML patients (n=3) were treated with azacytidine 75mg/m2 d1-d7, cytarabine 2g/m2 d1-d5, PD-1 inhibitor 200mg d1、d14.The efficacy were evaluated by CR, PR, ORR, PFS, OS, and ED. The safety were evaluated by hematological and non-hematological toxicity. Results: Among the three patients, one patient achieved CR, and one patient achieved PR. The patient who achieved CR successfully underwent allo-HSCT. One patient did not achieve remission and died of disease progression. Three patients were well tolerated to chemotherapy, and non-hematological toxicity was mainly respiratory tract infection, gastrointestinal reaction, and liver function damage.At present, no immune-related tissue injury was observed. Grade III-IV hematologic toxicity was the major adverse reaction, and the longest duration of agranulocytosis was 22 days.The proportion of Treg cells decreased, and the proportion of CD4+ T cells and CD8+ T lymphocytes increased in 2 patients after treatment. One patient received CR and underwent allo-HSCT. One patient showed an increase in the proportion of Treg cells, but there was no significant dynamic change in CD4+ T lymphocytes and CD8+ T lymphocytes. INF-γ increased in 1 patient. Dynamic changes in IL-10, IL-6, and TNF-α were not observed. Conclusions: PD-1 inhibitor combined with high dose cytarabine based chemotherapy may be a salvage treatment for R/R-AML. The dynamic changes of CD4+ T lymphocyte, CD8+ T lymphocyte, Treg cell, and INF-α may reflect the therapeutic effect in advance. Disclosures No relevant conflicts of interest to declare.

scholarly journals Enhanced Migratory Capacity of T Lymphocytes in Severe Chagasic Patients Is Correlated With VLA-4 and TNF-α Expression

2021 ◽  
Vol 11 ◽  
Author(s):  
Luiz Ricardo Berbert ◽  
Florencia Belén González ◽  
Silvina Raquel Villar ◽  
Carlos Vigliano ◽  
Susana Lioi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Fibronectin Receptor ◽  
Migratory Capacity ◽  
Hla Dr ◽  
Tnf Α

Trypanosoma cruzi infection in humans leads to progression to chronic chagasic myocarditis (CCM) in 30% of infected individuals, paralleling T cell inflammatory infiltrates in the heart tissue. T-cell trafficking into the hearts of CCM patients may be modulated by in situ expression of chemotactic or haptotactic molecules, as the chemokine CXCL12, the cytokine tumor necrosis factor-alpha (TNF-α), and extracellular matrix proteins (ECM), such as fibronectin. Herein we evaluated the expression of fibronectin, CXCL12, and TNF-α in the myocardial tissue of T. cruzi seropositive (asymptomatic or with CCM), as well as seronegative individuals as healthy controls. Hearts from CCM patients exhibited enhanced expression of these three molecules. CXCL12 and TNF-α serum levels were also increased in CCM individuals. We then evaluated T lymphocytes from chronic chagasic patients by cytofluorometry, in terms of membrane expression levels of molecules involved in cell activation and cell migration, respectively, HLA-DR and the VLA-4 (very late antigen-4, being one integrin-type fibronectin receptor). Indeed, the expression of HLA-DR and VLA-4 was enhanced on T lymphocytes from chagasic patients, especially in the CCM group. To further approach the dynamics of T cell migratory events, we performed fibronectin-, TNF-α-, and CXCL12-driven migration. Peripheral blood mononuclear cells (PBMCs) and T cells from CCM patients presented an ex vivo enhanced migratory capacity driven by fibronectin alone when this ECM protein was placed in the membrane of transwell migration chambers. When TNF-α was previously placed upon fibronectin, we observed a further and significant increase in the migratory response of both PBMCs and T lymphocytes. Overall, these data suggest the existence in patients with chronic Chagas disease of a cardiac inflammatory infiltrate vector that promotes the recruitment and accumulation of activated T cells, driven in part by enhanced tissue expression of fibronectin and TNF-α, as well as the respective corresponding VLA-4 and TNF receptors.

scholarly journals Single-Cell RNAseq Profiling of Human γδ T Lymphocytes in Virus-Related Cancers and COVID-19 Disease

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2212
Author(s):  
Juan Pablo Cerapio ◽  
Marion Perrier ◽  
Fréderic Pont ◽  
Marie Tosolini ◽  
Camille Laurent ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Single Cell ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Γδ T Cells ◽  
Lymphocyte Differentiation

The detailed characterization of human γδ T lymphocyte differentiation at the single-cell transcriptomic (scRNAseq) level in tumors and patients with coronavirus disease 2019 (COVID-19) requires both a reference differentiation trajectory of γδ T cells and a robust mapping method for additional γδ T lymphocytes. Here, we incepted such a method to characterize thousands of γδ T lymphocytes from (n = 95) patients with cancer or adult and pediatric COVID-19 disease. We found that cancer patients with human papillomavirus-positive head and neck squamous cell carcinoma and Epstein–Barr virus-positive Hodgkin’s lymphoma have γδ tumor-infiltrating T lymphocytes that are more prone to recirculate from the tumor and avoid exhaustion. In COVID-19, both TCRVγ9 and TCRVγnon9 subsets of γδ T lymphocytes relocalize from peripheral blood mononuclear cells (PBMC) to the infected lung tissue, where their advanced differentiation, tissue residency, and exhaustion reflect T cell activation. Although severe COVID-19 disease increases both recruitment and exhaustion of γδ T lymphocytes in infected lung lesions but not blood, the anti-IL6R therapy with Tocilizumab promotes γδ T lymphocyte differentiation in patients with COVID-19. PBMC from pediatric patients with acute COVID-19 disease display similar γδ T cell lymphopenia to that seen in adult patients. However, blood γδ T cells from children with the COVID-19-related multisystem inflammatory syndrome are not lymphodepleted, but they are differentiated as in healthy PBMC. These findings suggest that some virus-induced memory γδ T lymphocytes durably persist in the blood of adults and could subsequently infiltrate and recirculate in tumors.

scholarly journals Increased Frequency of Regulatory T Cells and T Lymphocyte Activation in Persons with Previously Treated Extrapulmonary Tuberculosis

2011 ◽  
Vol 19 (1) ◽  
pp. 45-52 ◽  
Author(s):  
Alexandre S. de Almeida ◽  
Christina T. Fiske ◽  
Timothy R. Sterling ◽  
Spyros A. Kalams
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Pulmonary Tuberculosis ◽  
Treg Cell ◽  
T Lymphocyte ◽  
Extrapulmonary Tuberculosis ◽  
Lymphocyte Activation ◽  
Content Type ◽  
T Lymphocyte Activation ◽  
Previously Treated

ABSTRACTExtrapulmonary tuberculosis may be due to underlying immune compromise. Immunosuppressive regulatory T cells (Treg cells), and CD4+T lymphocytes in general, are important in the host immune response toMycobacterium tuberculosis. We evaluated T lymphocytes from patients after recovery from extrapulmonary tuberculosis, which may reflect conditions beforeM. tuberculosisinfection. A case-control study was conducted among HIV-uninfected adults with previously treated extrapulmonary tuberculosis and 3 sets of controls: (i) subjects with previously treated pulmonary tuberculosis, (ii) close tuberculosis contacts withM. tuberculosisinfection, and (iii) close tuberculosis contacts with no infection. Monocyte-depleted peripheral blood mononuclear cells (PBMC-M) were stained for CD4+CD25hiCD127lowFoxP3+cell (Treg cell) and T lymphocyte activation. Both characteristics were compared as continuous variables between groups with the Kruskal-Wallis test. There were 7 extrapulmonary tuberculosis cases, 18 pulmonary tuberculosis controls, 17 controls withM. tuberculosisinfection, and 18 controls withoutM. tuberculosisinfection. The median Treg cell proportion was highest among persons with previous extrapulmonary tuberculosis (1.23%) compared to subjects with pulmonary tuberculosis (0.56%), latentM. tuberculosisinfection (0.14%), or noM. tuberculosisinfection (0.20%) (P= 0.001). The median proportion of CD4+T lymphocytes that expressed the activation markers HLA-DR and CD38 was highest for CD4+T lymphocytes from persons with previous extrapulmonary tuberculosis (0.79%) compared to subjects with pulmonary tuberculosis (0.44%), latentM. tuberculosisinfection (0.14%), or noM. tuberculosisinfection (0.32%) (P= 0.005). Compared with controls, persons with previously treated extrapulmonary tuberculosis had the highest Treg cell frequency, but also the highest levels of CD4+T lymphocyte activation. Immune dysregulation may be a feature of individuals at risk for extrapulmonary tuberculosis.

Abstract 14723: Autoreactive T Lymphocytes Activate Cardiac Endothelium Independently of Tnf-α and Cause Endothelial Dysfunction Through Exosomes in Experimental Autoimmune Myocarditis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Filip Rolski ◽  
Marcin Czepiel ◽  
Kazimierz Weglarczyk ◽  
Maciej Siedlar ◽  
Gabriela Kania ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Dysfunction ◽  
T Lymphocytes ◽  
Conditioned Medium ◽  
Autoimmune Myocarditis ◽  
Autoreactive T Cells ◽  
Tnf Α ◽  
Experimental Autoimmune Myocarditis ◽  
Experimental Autoimmune ◽  
Stimulation Of

Background: Inflammatory heart diseases represent an important clinical problem, nonetheless data regarding activation of cardiac microvascular endothelial cells (MVECs) are limited. Aim: To examine influence of TNF-α and exosomes produced by heart-reactive CD4+ T lymphocytes on activation of cardiac MVECs. Methods: Experimental autoimmune myocarditis (EAM) was induced in wild-type (WT) and TNF-α-deficient (TNF-KO) mice. CD4+ T lymphocytes were isolated from EAM mice at day 21 and activated in vitro to produce conditioned medium and exosomes. Activation of MVECs was assessed by specific assays and leukocyte-to-endothelial adhesion was analysed under shear flow condition using the BioFlux microfluidic system. Results: TNF-KO mice showed lower prevalence of myocarditis when compared to WT mice (50% vs. 90%). Stimulation of MVECs with secretome of antigen-activated autoreactive T cells resulted in upregulation of adhesion molecules (ICAM-1, VCAM-1 and P-selectin), increased ROS and decreased NO production. Addition of anti-TNF-α neutralizing antibodies effectively blocked adhesion of leukocytes to MVECs activated with the conditioned medium. Endothelial activation and dysfunction induced by the conditioned medium were independent of TNF-α produced by T cells. Stimulation of MVECs with T cell-derived exosomes increased ROS and decreased levels of NO and eNOS activation, but exosomes neither increased expression of adhesion molecules in MVECs nor induced their ability to bind leukocytes. Conclusions: TNF-α promotes MVEC activation and EAM development. In this model, autoreactive T cells activate MVECs, and TNF-a produced by MVECs rather than T cells is essential in this process. On the other hand, endothelial dysfunction caused by T cells seems to be mediated mainly by exosomes.

scholarly journals Human Mast Cells Release Metalloproteinase-9 on Contact with Activated T Cells: Juxtacrine Regulation by TNF-α

2001 ◽  
Vol 167 (7) ◽  
pp. 4008-4016 ◽  
Author(s):  
Dana Baram ◽  
Gayle G. Vaday ◽  
Pazit Salamon ◽  
Ilana Drucker ◽  
Rami Hershkoviz ◽  
...  
Keyword(s):  
T Cells ◽  
Mast Cells ◽  
Activated T Cells ◽  
Human Mast Cells ◽  
Tnf Α ◽  
Metalloproteinase 9

scholarly journals Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth.

1986 ◽  
Vol 163 (5) ◽  
pp. 1037-1050 ◽  
Author(s):  
J H Kehrl ◽  
L M Wakefield ◽  
A B Roberts ◽  
S Jakowlew ◽  
M Alvarez-Mon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Transforming Growth Factor Beta ◽  
Potential Role ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Tgf Beta ◽  
Activated T Cells ◽  
Growth Factor Beta

This study examines the potential role of transforming growth factor beta (TGF-beta) in the regulation of human T lymphocyte proliferation, and proposes that TGF-beta is an important autoregulatory lymphokine that limits T lymphocyte clonal expansion, and that TGF-beta production by T lymphocytes is important in T cell interactions with other cell types. TGF-beta was shown to inhibit IL-2-dependent T cell proliferation. The addition of picograms amounts of TGF-beta to cultures of IL-2-stimulated human T lymphocytes suppressed DNA synthesis by 60-80%. A potential mechanism of this inhibition was found. TGF-beta inhibited IL-2-induced upregulation of the IL-2 and transferrin receptors. Specific high-affinity receptors for TGF-beta were found both on resting and activated T cells. Cellular activation was shown to result in a five- to sixfold increase in the number of TGF-beta receptors on a per cell basis, without a change in the affinity of the receptor. Finally, the observations that activated T cells produce TGF-beta mRNA and that TGF-beta biologic activity is present in supernatants conditioned by activated T cells is strong evidence that T cells themselves are a source of TGF-beta. Resting T cells were found to have low to undetectable levels of TGF-beta mRNA, while PHA activation resulted in a rapid increase in TGF-beta mRNA levels (within 2 h). Both T4 and T8 lymphocytes were found to make mRNA for TGF-beta upon activation. Using both a soft agar assay and a competitive binding assay, TGF-beta biologic activity was found in supernatants conditioned by T cells; T cell activation resulted in a 10-50-fold increase in TGF-beta production. Thus, TGF-beta may be an important antigen-nonspecific regulator of human T cell proliferation, and important in T cell interaction with other cell types whose cellular functions are modulated by TGF-beta.

scholarly journals Induction of Fas (Apo-1, CD95)-Mediated Apoptosis of Activated Lymphocytes by Polyclonal Antithymocyte Globulins

Blood ◽  
1998 ◽  
Vol 91 (7) ◽  
pp. 2360-2368 ◽  
Author(s):  
Laurent Genestier ◽  
Sylvie Fournel ◽  
Monique Flacher ◽  
Olga Assossou ◽  
Jean-Pierre Revillard ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Fas Ligand ◽  
Mononuclear Cells ◽  
Resting Cells ◽  
Activated T Cells ◽  
Peripheral Blood Mononuclear ◽  
Gene And Protein Expression ◽  
Fas L ◽  
Induced Apoptosis

Polyclonal horse antilymphocyte and rabbit antithymocyte globulins (ATGs) are currently used in severe aplastic anemia and for the treatment of organ allograft acute rejection and graft-versus-host disease. ATG treatment induces a major depletion of peripheral blood lymphocytes, which contributes to its overall immunosuppressive effects. Several mechanisms that may account for lymphocyte lysis were investigated in vitro. At high concentrations (.1 to 1 mg/mL) ATGs activate the human classic complement pathway and induce lysis of both resting and phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells. At low, submitogenic, concentration ATGs induce antibody-dependent cell cytotoxicity of PHA-activated cells, but not resting cells. They also trigger surface Fas (Apo-1, CD95) expression in naive T cells and Fas-ligand gene and protein expression in both naive and primed T cells, resulting in Fas/Fas-L interaction-mediated cell death. ATG-induced apoptosis and Fas-L expression were not observed with an ATG preparation lacking CD2 and CD3 antibodies. Susceptibility to ATG-induced apoptosis was restricted to activated cells, dependent on IL-2, and prevented by Cyclosporin A, FK506, and rapamycin. The data suggest that low doses of ATGs could be clinically evaluated in treatments aiming at the selective deletion of in vivo activated T cells in order to avoid massive lymphocyte depletion and subsequent immunodeficiency.

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