scholarly journals Regulation of the immune tolerance system determines the susceptibility to HLA-mediated abacavir-induced skin toxicity

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Takeshi Susukida ◽  
Saki Kuwahara ◽  
Binbin Song ◽  
Akira Kazaoka ◽  
Shigeki Aoki ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Tolerance ◽  
Human Leukocyte ◽  
Skin Toxicity ◽  
Effector Memory ◽  
T Cell Infiltration ◽  
Cytolytic Granule ◽  
Life Threatening ◽  
Programmed Death 1

AbstractIdiosyncratic drug toxicity (IDT) associated with specific human leukocyte antigen (HLA) allotype is a rare and unpredictable life-threatening adverse drug reaction for which prospective mechanistic studies in humans are difficult. Here, we show the importance of immune tolerance for IDT onset and determine whether it is susceptible to a common IDT, HLA-B*57:01-mediated abacavir (ABC)-induced hypersensitivity (AHS), using CD4+ T cell-depleted programmed death-1 receptor (PD-1)-deficient HLA-B*57:01 transgenic mice (B*57:01-Tg/PD-1−/−). Although AHS is not observed in B*57:01-Tg mice, ABC treatment increases the proportion of cytokine- and cytolytic granule-secreting effector memory CD8+ T cells in CD4+ T cell-depleted B*57:01-Tg/PD-1−/− mice, thereby inducing skin toxicity with CD8+ T cell infiltration, mimicking AHS. Our results demonstrate that individual differences in the immune tolerance system, including PD-1highCD8+ T cells and regulatory CD4+ T cells, may affect the susceptibility of humans to HLA-mediated IDT in humans.

scholarly journals CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

2016 ◽  
Vol 113 (39) ◽  
pp. 10956-10961 ◽  
Author(s):  
Raphaël Bernard-Valnet ◽  
Lidia Yshii ◽  
Clémence Quériault ◽  
Xuan-Hung Nguyen ◽  
Sébastien Arthaud ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Manifestations ◽  
Neuronal Loss ◽  
Human Leukocyte ◽  
T Cell Infiltration ◽  
Cytolytic Granule ◽  
Tight Association ◽  
Genetic And Environmental Factors ◽  
Self Antigen

Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin+ neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a “neo-self-antigen” specifically in hypothalamic orexin+ neurons (called Orex-HA), which were transferred with effector neo-self-antigen–specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin+ neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin+ neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin+ neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.

scholarly journals Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model

2016 ◽  
Vol 113 (30) ◽  
pp. 8490-8495 ◽  
Author(s):  
Baihao Zhang ◽  
Shunsuke Chikuma ◽  
Shohei Hori ◽  
Sidonia Fagarasan ◽  
Tasuku Honjo
Keyword(s):  
T Cells ◽  
Immune Tolerance ◽  
Autoimmune Pancreatitis ◽  
Treg Cells ◽  
Regulatory Function ◽  
Effector Memory ◽  
Activated T Cells ◽  
Self Tolerance ◽  
Life Threatening ◽  
Programmed Death 1

PD-1 (programmed-death 1), an immune-inhibitory receptor required for immune self-tolerance whose deficiency causes autoimmunity with variable severity and tissue specificity depending on other genetic factors, is expressed on activated T cells, including the transcription factor FoxP3+ Treg cells known to play critical roles in maintaining immune tolerance. However, whether PD-1 expression by the Treg cells is required for their immune regulatory function, especially in autoimmune settings, is still unclear. We found that mice with partial FoxP3 insufficiency developed early-onset lympho-proliferation and lethal autoimmune pancreatitis only when PD-1 is absent. The autoimmune phenotype was rescued by the transfer of FoxP3-sufficient T cells, regardless of whether they were derived from WT or PD-1–deficient mice, indicating that Treg cells dominantly protect against development of spontaneous autoimmunity without intrinsic expression of PD-1. The absence of PD-1 combined with partial FoxP3 insufficiency, however, led to generation of ex-FoxP3 T cells with proinflammatory properties and expansion of effector/memory T cells that contributed to the autoimmune destruction of target tissues. Altogether, the results suggest that PD-1 and FoxP3 work collaboratively in maintaining immune tolerance mostly through nonoverlapping pathways. Thus, PD-1 is modulating the activation threshold and maintaining the balance between regulatory and effector T cells, whereas FoxP3 is sufficient for dominant regulation through maintaining the integrity of the Treg function. We suggest that genetic or environmental factors that even moderately affect the expression of both PD-1 and FoxP3 can cause life-threatening autoimmune diseases by disrupting the T-cell homeostasis.

scholarly journals Extracorporeal photopheresis as a non-specific immune therapy of autoimmune diseases and skin T-cell lymphoma (a review of the literature and own studies)

2019 ◽  
Vol 47 (5) ◽  
pp. 419-434
Author(s):  
A. V. Kil'dyushevskiy ◽  
V. A. Molochkov ◽  
T. A. Mitina ◽  
Ya. G. Moysyuk ◽  
A. V. Molochkov
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Immune Tolerance ◽  
Immune Therapy ◽  
Effector Memory ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Extracorporeal Photopheresis ◽  
Antigen Presenting

Aim: To present well-known and disputable mechanisms of the effects of extracorporeal photopheresis (ECP) in heterogeneous clinical conditions, as well as to demonstrate its advantages over conventional hormonal, immunosuppressive and cytostatic treatments, with a recommendation to widely implement it into practical management of autoimmune disease and cutaneous T-cell lymphomas (CTCLs).Key points: Despite convincing evidence of the ECP efficacy in the treatment of T-cell mediated disorders, a unifying concept of its mechanism has not been established so far. In this review, we attempted to determine the value of multiple, sometimes contradictory and equivocal points of view to immunobiochemical processes underlying the restoration of mechanism of immune tolerance in some autoimmune diseases and CTCLs. We focused our attention on our own clinical and immunological data obtained during a 20-years' experience with the use of ECP in clinical departments of MONIKI (Russia). Based on this, we have shown that ECP is more effective in autoimmune diseases than conventional treatment approaches with hormones, immunosuppressants and cytostatics. Unlike them, ECP is selectively targeted to auto-aggressive T-cells without induction of systemic immunosuppression. The leading role is played by the transformation of activated (immunogenic) myeloid dendrite cells (DC) into tolerogenic cell associated with their synthesis of inhibitor cytokines. The interplay of the cytokines with an antigen results in polarization of CD4+ Т lymphocytes via the Th2 pathway with restoration of the Th1/Th2 balance and their cytokine production. ECP triggers regulatory anti-clonotypic effector memory cells at the end stage of CD3+/CD8+/CD27-/CD28-/CD62L+ differentiation, that provide and maintain the peripheral immune tolerance, by deletion of the clone of auto-reactive cytotoxic lymphocytes and inducing their apoptosis. In autoimmune disorders, ECP results in reduction of the expression of integrin adhesion molecules on auto-reactive cell membranes with subsequent loss of their ability to migrate through the endothelium to their target cells. In its turn, it leads to decreasing immunoinflammatory response in the lesion. Both clinical and experimental data indicate that the mechanism of ECP action against CTCLs is characterized by activation of tumor cell apoptosis, unblocking of co-activation receptors on the antigen-presenting DC providing the functioning of the second signaling pathway for T lymphocyte activation. This results in proliferation of anti-tumor effector cells pool, production of DC activating cytokines that participate in the CD4+ polarization via Th1 pathway. In addition, this review considers the mechanism of the immunomodulating effect of ECP in the context of its influence at the levels of transcription and translation of proteins contributing to the pathophysiology of the disorders, based on molecular immunogenetic studies. Thus, ECP is able to induce antigen-specific immunological tolerance through the transformation of antigen-presenting cells, modulation of cytokine profile, adhesion and activation molecules, as well as through formatting of the regulatory T cells (Tregs).Conclusion: Undoubtedly, the immunobiological ECP technique has significant advantages over well-known conventional hormonal, immunosuppressive, and cytostatic therapies of autoimmune diseases and CTCLs.

Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412

Blood ◽  
2011 ◽  
Vol 118 (26) ◽  
pp. 6772-6782 ◽  
Author(s):  
Paula S. Römer ◽  
Susanne Berr ◽  
Elita Avota ◽  
Shin-Young Na ◽  
Manuela Battaglia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Density ◽  
Effector Memory ◽  
Cell Contact ◽  
Cytokine Release ◽  
Recent Trial ◽  
Life Threatening ◽  
Circulating T Cells ◽  
Tcr Signals

Abstract Human volunteers receiving TGN1412, a humanized CD28-specific monoclonal antibody, experienced a life-threatening cytokine release syndrome during a recent trial. Preclinical tests using human PBMCs had failed to announce the rapid release of TNF, IFN-γ, and other toxic cytokines in response to this CD28 “superagonist” (CD28SA). CD28SA activate T-lymphocytes by ligating CD28 without overt engagement of the TCR. They do, however, depend on “tonic” TCR signals, which they amplify. Here we show that short-term preculture of PBMCs at high, but not at low, cell density results in massive cytokine release during subsequent stimulation with soluble TGN1412. Restoration of reactivity was cell-contact dependent, involved functional maturation of both monocytes and T cells, was sensitive to blockade by HLA-specific mAb, and was associated with TCR polarization and tyrosine phosphorylation. CD4 effector memory T cells were identified as the main source of proinflammatory cytokines. Importantly, responses to other T-cell activating agents, including microbial antigens, were also enhanced if PBMCs were first allowed to interact under tissue-like conditions. We provide a protocol, which strongly improves reactivity of circulating T cells to soluble stimulants, thereby allowing for more reliable preclinical testing of both activating and inhibitory immunomodulatory drugs.

Abstract 350: Immune Profiling and Causal Antigen Discovery in Mouse and Human Models of Immune Checkpoint Inhibitor-induced Myocarditis

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Han Zhu ◽  
Daniel Lee ◽  
Waliany Sarah ◽  
Francisco X Galdos ◽  
Jessica D’Addabbo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Myocardial Damage ◽  
T Cell Subsets ◽  
Immune Checkpoints ◽  
Fulminant Myocarditis ◽  
T Cell Infiltration ◽  
Life Threatening

Introduction: Immune checkpoint inhibitors (ICIs) are novel drugs that activate T cell-mediated anti-tumor response by blocking immune checkpoints such as PD-1 or CTLA-4, leading to improved cancer patient survival. Despite these benefits, ICIs can result in autoimmune side effects including fulminant myocarditis and heart failure. While ICI-induced myocarditis is characterized by myocardial T cell infiltration, the causal mechanisms remain unknown. We hypothesize that ICI-induced myocarditis is caused by cardiac-specific auto-antigens triggering clonal expansion of myocardial CD8+ T-cells, leading to T-cell mediated myocardial damage. Methods/Results: We have explored the ICI-induced inflammatory response in a mouse model of myocarditis induced by PD-1 knockout and in patients with ICI-induced myocarditis. PD-1 deficient-mice on a lupus-like autoimmune background (i.e. MRL/Pcd1-/- mice) develop spontaneous fatal myocarditis in 70% of animals by 5 weeks of age, with massive cardiac infiltration of CD8>CD4+ T-cells. Likewise, patients with ICI-induced myocarditis have CD8>CD4+ T-cell infiltrate in the heart. We have performed time-of-flight mass cytometry (CyTOF) to immunophenotype the T-cell subsets in the blood/myocardium of MRL/Pcd1-/- mice and in ICI-myocarditis patients. We have also conducted single cell sequencing of T-cell receptors (TCRs) from the blood +/- myocardial-derived T-cell samples of the mice and patients. Our preliminary results in ICI-myocarditis patients confirmed the previously reported CD8+ T-cell expansion in the blood and myocardium of myocarditis patients compared with healthy control. We are currently identifying candidate cardiac auto-antigen(s) responsible for this disease by performing Grouping Lymphocyte Interactions by Paratope Hotspots (GLIPH). Conclusion: Myocarditis is a serious and life-threatening complication of ICI treatment. By understanding the unique immune response present during ICI-induced myocarditis and the responsible cardiac auto-antigen(s) involved, we will pave the way for the development of adjuvant therapies that target these antigens and mitigate their deleterious effects.

Activation of central/effector memory T cells in advanced gastric cancer patients treated with antiprogrammed death-1 antibody.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 54-54 ◽  
Author(s):  
Hirofumi Ohmura ◽  
Kyoko Yamaguchi ◽  
Fumiyasu Hanamura ◽  
Mamoru Ito ◽  
Akitaka Makiyama ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
T Cell ◽  
Advanced Gastric Cancer ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Effector Memory ◽  
Cytotoxic T Cell ◽  
Programmed Death ◽  
Programmed Death 1

54 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances antitumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 (PD-L1) and has shown efficacy for advanced gastric cancer (AGC) in the salvage line. However, specific subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood mononuclear cells of 20 AGC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). The proportion of immune cell subsets were systematically analyzed by flow cytometry, including the expression of costimulatory and coinhibitory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T cell antigen-4 (CTLA-4), CD28, OX40, and inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were analyzed. Results: Median progression free survival (PFS) of the whole patients was 51 days (95% CI 35–83). After a single course of nivolumab, patients showed a significant increase in activated effector memory and activated effector subsets of CD4+/CD8+ T cells (p = 0.018, 0.018, 0.032, 0.024). At the time of PD, proportions of myeloid dendritic cell, IgM memory B cell and Tfh-Th1/17 cell subsets decreased (p = 0.024, 0.013, 0.0039). On the other hand, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells increased at the time of PD (p = 0.013, 0.032, 0.042, 0.042). Significant positive correlations were found between PFS and the proportion of LAG3 positive CD4+/CD8+ T cells (p = 0.0056, 0.0054), OX 40 positive CD4+/CD8+ T cells (p = 0.0034, 0.0006) prior to the initial nivolumab therapy. Conclusions: Nivolumab therapy enhances activation of effector memory and effector subsets of CD4+/CD8+ T cells. The expression level of LAG3 and OX40 on T cells might be correlated with efficacy of nivolumab therapy.

scholarly journals Acute Gvhd Induce the Critical Depletion of Naïve Pool in Regulatory T Cells: Implication for Linked Pathogenesis into Chronic Gvhd

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 923-923
Author(s):  
Takanori Yoshioka ◽  
Yusuke Meguri ◽  
Takeru Asano ◽  
Yuriko Kishi ◽  
Miki Iwamoto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Tolerance ◽  
Cd4 T Cells ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Ki 67

Abstract CD4+Foxp3+ regulatory T cells (Treg) play a central role in establishing immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). We previously reported that the long-term severe lymphopenia could result in the collapse of Treg homeostasis leading to the onset of chronic GVHD (Matsuoka et al. JCI 2010). We recently found that, not only in the chronic phase but also in the acute phase, the homeostasis of Treg is more susceptible to the post-transplant environment as compared to other lymphocyte subsets (Yoshioka et al. ASH 2014). However, the impact of acute GVHD on Treg homeostasis and the pathogenesis of following chronic GVHD has not been well studied. In this study, we examined Treg reconstitution in the early phase after transplant in patients with or without acute GVHD. For the purpose, we obtained peripheral blood samples at 2, 4, 8 and 12 weeks after transplant from 52 patients who received allogeneic HSCT, and then analyzed CD4+CD25med-highCD127lowFoxp3+ Treg comparing with CD4+CD25neg-lowCD127highFoxp3- conventional T cell (Tcon) and CD8+ T cells. CD4 T cell subsets are further divided into subpopulations by the expression of CD45RA and CD31. The expressions of Helios, Ki-67 and Bcl-2 on these subsets were also examined. After transplant, total lymphocyte counts in examined patients were significantly lower than the counts before the start of conditioning (median lymphocytes 95/ul at 2 weeks and 302/ul at 4 weeks vs 600/ul before conditioning, P<0.01 and P<0.01, respectively). As we reported before, Treg showed the active proliferation without diminishing Bcl-2 levels in the severe lymphopenia, resulted in the increased %Treg of CD4 T cells at 4 weeks after transplant (%Treg of CD4 T cells; 12.2% at 4 weeks, 4.6% in healthy controls, P<0.005). 18 patients who developed acute GVHD were studied Treg homeostasis before and after the onset of GVHD more in detail. Before the onset of acute GVHD, % Ki-67+ cells in Treg and Tcon were in the equivalent levels in these patients. After the onset of acute GVHD, % Ki-67+ cells in Treg was dramatically increased from 19.1% to 61.2% (median) and this was significantly higher than % Ki-67+ cells in Tcon after acute GVHD (P<0.05). %Treg of total CD4 T cells were significantly increased after GVHD (% Treg; Median 7.2% vs 12.2%, P<0.004). Expanded Treg after acute GVHD showed a predominant Helios+CD45RA-CD31- effector/memory phenotype with the lower level of Bcl-2 expression as compared to CD45RA+ naïve Treg. As a consequence, naïve Treg pool including CD45RA+CD31+ recent thymic emigrant Treg (RTE-Treg) were critically decreased during acute GVHD (%CD45RA+ cells; 12.7% into 6.5%, P<0.004: CD45RA+CD31+ cells; 3.6% into 2.1%, P<0.003). In contrast, Tcon still retained a relatively higher level of naïve pool (%CD45RA+ cells; 20.5%, % CD45RA+CD31+ cells; 10.9%) after acute GVHD. These data indicated that Treg proliferation was rapidly promoted in face with the inflammatory condition during acute GVHD and this appears to contribute the amelioration of developing GVHD. However, the prompt reaction resulted in the depletion of naïve Treg pool which is important to maintain stable Treg homeostasis in the long period. In conclusion, our findings suggest that acute GVHD drives aggressive Treg proliferation resulting in the increased percentage of this subset but this also induce the severe alteration of Treg homeostasis by depleting naïve Treg, which may provide the linked pathogenesis of the subsequent onset of chronic GVHD. The careful monitoring of Treg from the point of view might provide important information to promote immune tolerance. Disclosures No relevant conflicts of interest to declare.

scholarly journals Longitudinal Changes in Cd4+, Cd8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis

2019 ◽  
Vol 5 (3) ◽  
pp. 63
Author(s):  
Alice Bayiyana ◽  
Samuel Okurut ◽  
Rose Nabatanzi ◽  
Godfrey Zziwa ◽  
David R. Boulware ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Surface ◽  
Cd8 T Cells ◽  
Cryptococcal Meningitis ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Effector Memory ◽  
Memory Subset

Despite improvement in the prognosis of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) patients on antiretroviral therapy (ART), cryptococcal meningitis (CM) still causes 10–15% mortality among HIV-infected patients. The immunological impact of ART on the CD4+ and CD8+ T cell repertoire during cryptococcal co-infection is unclear. We determined longitudinal phenotypic changes in T cell subsets among patients with CM after they initiated ART. We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+ and CD8+ T cells during CM co-infection. For this substudy, peripheral blood mononuclear cells (PBMC) were isolated at four time points from CM patients following ART initiation during the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+ and CD8+ T cells was done using T cell surface marker monoclonal antibodies by flow cytometry. There was variation in the expression of immunophenotypic markers defining central memory (CD27+CD45R0+), effector memory (CD45R0+CD27–), immune activation (CD38+ and Human Leucocyte Antigen DR (HLA-DR+), and exhaustion (Programmed cell death protein one (PD-1) in the CD4+ T cell subset. In comparison to the CD4+ T cell population, the CD8+ central memory subset declined gradually with minimal increase in the effector memory subset. Both CD4+ and CD8+ T cell immune exhaustion and activation markers remained elevated over 12 weeks. The relative surge and decline in the expression of T cell surface markers outlines a variation in the differentiation of CD4+ T cells during ART treatment during CM co-infection.

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