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Fluctuations of Spleen Cytokine and Blood Lactate, Importance of Cellular Immunity in Host Defense Against Blood Stage Malaria .
Imai T, Suzue K, Ngo-Thanh H, Ono S, Orita W, Suzuki H, Shimokawa C, Olia A, Obi S, Taniguchi T, Ishida H, Van Kaer L, Murata S, Tanaka K, Hisaeda H
(2019) Front Immunol 10: 2207
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cytokines, Erythrocytes, Female, Immunity, Cellular, Lactates, Macrophages, Malaria, Male, Mice, Inbred C57BL, Mice, Knockout, Parasitemia, Plasmodium yoelii, Spleen
Show Abstract · Added March 3, 2020
Our previous studies of protective immunity and pathology against blood stage malaria parasites have shown that not only CD4 T cells, but also CD8 T cells and macrophages, are important for host defense against blood stage malaria infection. Furthermore, we found that 17XNL (PyNL) parasitizes erythroblasts, the red blood cell (RBC) precursor cells, which then express MHC class I molecules. In the present study, we analyzed spleen cytokine production. In CD8 T cell-depleted mice, IL-10 production in early stage infection was increased over two-fold relative to infected control animals and IL-10 CD3 cells were increased, whereas IFN-γ production in the late stage of infection was decreased. At day 16 after PyNL infection, CD8 T cells produced more IFN-γ than CD4 T cells. We evaluated the involvement of the immunoproteasome in induction of immune CD8 T cells, and the role of Fas in protection against PyNL both of which are downstream of IFN-γ. In cell transfer experiments, at least the single molecules LMP7, LMP2, and PA28 are not essential for CD8 T cell induction. The Fas mutant LPR mouse was weaker in resistance to PyNL infection than WT mice, and 20% of the animals died. LPR-derived parasitized erythroid cells exhibited less externalization of phosphatidylserine (PS), and phagocytosis by macrophages was impaired. Furthermore, we tried to identify the cause of death in malaria infection. Blood lactate concentration was increased in the CD8 T cell-depleted PyNL-infected group at day 19 (around peak parasitemia) to similar levels as day 7 after infection with a lethal strain of Py. When we injected mice with lactate at day 4 and 6 of PyNL infection, all mice died at day 8 despite demonstrating low parasitemia, suggesting that hyperlactatemia is one of the causes of death in CD8 T cell-depleted PyNL-infected mice. We conclude that CD8 T cells might control cytokine production to some extent and regulate hyperparasitemia and hyperlactatemia in protection against blood stage malaria parasites.
Copyright © 2019 Imai, Suzue, Ngo-Thanh, Ono, Orita, Suzuki, Shimokawa, Olia, Obi, Taniguchi, Ishida, Van Kaer, Murata, Tanaka and Hisaeda.
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1 Members
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16 MeSH Terms
NKG2A Blockade Potentiates CD8 T Cell Immunity Induced by Cancer Vaccines.
van Montfoort N, Borst L, Korrer MJ, Sluijter M, Marijt KA, Santegoets SJ, van Ham VJ, Ehsan I, Charoentong P, André P, Wagtmann N, Welters MJP, Kim YJ, Piersma SJ, van der Burg SH, van Hall T
(2018) Cell 175: 1744-1755.e15
MeSH Terms: Animals, Antibodies, Neoplasm, Antigens, CD, CD8-Positive T-Lymphocytes, Cancer Vaccines, Cell Line, Tumor, Histocompatibility Antigens Class I, Humans, Immunity, Cellular, Integrin alpha Chains, Mice, NK Cell Lectin-Like Receptor Subfamily C, Neoplasm Proteins, Neoplasms, Experimental, Vaccination
Show Abstract · Added December 11, 2020
Tumor-infiltrating CD8 T cells were found to frequently express the inhibitory receptor NKG2A, particularly in immune-reactive environments and after therapeutic cancer vaccination. High-dimensional cluster analysis demonstrated that NKG2A marks a unique immune effector subset preferentially co-expressing the tissue-resident CD103 molecule, but not immune checkpoint inhibitors. To examine whether NKG2A represented an adaptive resistance mechanism to cancer vaccination, we blocked the receptor with an antibody and knocked out its ligand Qa-1, the conserved ortholog of HLA-E, in four mouse tumor models. The impact of therapeutic vaccines was greatly potentiated by disruption of the NKG2A/Qa-1 axis even in a PD-1 refractory mouse model. NKG2A blockade therapy operated through CD8 T cells, but not NK cells. These findings indicate that NKG2A-blocking antibodies might improve clinical responses to therapeutic cancer vaccines.
Copyright © 2018 Elsevier Inc. All rights reserved.
2 Communities
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MeSH Terms
HLAs: Key regulators of T-cell-mediated drug hypersensitivity.
Redwood AJ, Pavlos RK, White KD, Phillips EJ
(2018) HLA 91: 3-16
MeSH Terms: B-Lymphocytes, Dideoxynucleosides, Drug Hypersensitivity, HLA-B Antigens, Humans, Immunity, Cellular, Risk Factors, T-Lymphocytes
Show Abstract · Added March 30, 2020
Adverse drug reactions (ADR) can be broadly categorised as either on-target or off-target. On-target ADRs arise as a direct consequence of the pharmacological properties of the drug and are therefore predictable and dose-dependent. On-target ADRs comprise the majority (>80%) of ADRs, relate to the drug's interaction with its known pharmacological target and are a result of a complex interplay of genetic and ecologic factors. In contrast, off-target ADRs, including immune-mediated ADRs (IM-ADRs), are due to unintended pharmacological interactions such as inadvertent ligation of host cell receptors or non-pharmacological interactions mediated through an adaptive immune response. IM-ADRs can be classified according to the primary immune cell involved and include B-cell-mediated (Gell-Coombs type I-III reactions) and T-cell-mediated (Gell-Coombs type IV or delayed hypersensitivity) reactions. IM-ADRs mediated by T cells are associated with phenotypically distinct clinical diagnoses and can vary from a mild delayed rash to a life-threatening cutaneous, systemic or organ disease, such as Stephen Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms and drug-induced liver disease. T-cell-mediated ADRs are strongly linked to the carriage of particular HLA risk alleles which are in the case of abacavir hypersensitivity and HLA-B*57:01 has led to translation into the clinic as a routine screening test. In this review, we will discuss the immunogenetics and pathogenesis of IM-ADRs and how HLA associations inform both pre-drug screening strategies and mechanistic understanding.
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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MeSH Terms
Smoldering myocarditis following immune checkpoint blockade.
Norwood TG, Westbrook BC, Johnson DB, Litovsky SH, Terry NL, McKee SB, Gertler AS, Moslehi JJ, Conry RM
(2017) J Immunother Cancer 5: 91
MeSH Terms: Female, Humans, Immunity, Cellular, Immunotherapy, Male, Myocarditis
Show Abstract · Added December 2, 2017
BACKGROUND - Severe myocarditis associated with electrical conduction abnormalities and occasionally heart failure has been well documented following treatment with immune checkpoint blockade with an estimated incidence of less than 1%. However, the incidence, early detection, and management of less severe immune-related myocarditis are unknown since most immunotherapy trials have not included routine cardiac monitoring. Herein, we provide the first description of subclinical or smoldering myocarditis with minimal signs and symptoms following immune checkpoint blockade with a single dose of ipilimumab and nivolumab.
CASE PRESENTATION - Our patient was diagnosed with immune checkpoint blockade-induced myocarditis based upon an acute rise in serum cardiac troponin I beginning 2 weeks after the initial dose of ipilimumab/nivolumab consistent with the reported median onset of clinical myocarditis at 17 days, as well as a lack of other causes despite extensive cardiac evaluation. The patient initially presented with intractable nausea with no known gastrointestinal etiology. High dose glucocorticoid therapy led to rapid resolution of nausea and a four-fold decrease in troponin I over 4 days. Serum troponin I spiked again following a steroid taper to 13 times the upper limit of normal with endomyocardial biopsy revealing collagen fibrosis and lymphocytic inflammation predominantly comprised of CD8+ T cells consistent with chronic smoldering myocarditis. Serum anti-striated muscle antibodies were also detected with no evidence of rhabdomyolysis. Serum cardiac troponin I levels as an indicator of ongoing myocyte damage gradually improved with chronic prednisone at 10 mg daily. Late addition of intravenous immunoglobulin was associated with rapid normalization of creatine kinase-myocardial band.
CONCLUSIONS - This case demonstrates that subclinical, smoldering myocarditis may occur following immune checkpoint blockade, with evidence of both humoral and cell-mediated immunity responsive to corticosteroid therapy. This experience supports early monitoring for myocarditis with serial electrocardiograms and serum troponin I determinations in large, prospective cohorts of patients receiving combination immune checkpoint blockade as early detection and initiation of immunosuppression may forestall fulminant presentation of this disease and limit myocardial damage.
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6 MeSH Terms
PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses.
Sai J, Owens P, Novitskiy SV, Hawkins OE, Vilgelm AE, Yang J, Sobolik T, Lavender N, Johnson AC, McClain C, Ayers GD, Kelley MC, Sanders M, Mayer IA, Moses HL, Boothby M, Richmond A
(2017) Clin Cancer Res 23: 3371-3384
MeSH Terms: Aminopyridines, Animals, Cell Line, Tumor, Cell Proliferation, Class Ib Phosphatidylinositol 3-Kinase, Female, Humans, Immunity, Cellular, Mammary Neoplasms, Animal, Mice, Morpholines, Neoplasm Metastasis, Phosphoinositide-3 Kinase Inhibitors, Programmed Cell Death 1 Receptor, Protein Kinase Inhibitors, Signal Transduction, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added January 4, 2017
Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3Kα,β in tumor growth and PI3Kγ,δ in immune cell function, we sought to determine whether PI3K inhibition altered antitumor immunity. The effect of PI3K inhibition on tumor growth, metastasis, and antitumor immune response was characterized in mouse models utilizing orthotopic implants of 4T1 or PyMT mammary tumors into syngeneic or -null mice, and patient-derived breast cancer xenografts in humanized mice. Tumor-infiltrating leukocytes were characterized by IHC and FACS analysis in BKM120 (30 mg/kg, every day) or vehicle-treated mice and versus mice. On the basis of the finding that PI3K inhibition resulted in a more inflammatory tumor leukocyte infiltrate, the therapeutic efficacy of BKM120 (30 mg/kg, every day) and anti-PD1 (100 μg, twice weekly) was evaluated in PyMT tumor-bearing mice. Our findings show that PI3K activity facilitates tumor growth and surprisingly restrains tumor immune surveillance. These activities could be partially suppressed by BKM120 or by genetic deletion of in the host. The antitumor effect of loss in host, but not tumor, was partially reversed by CD8 T-cell depletion. Treatment with therapeutic doses of both BKM120 and antibody to PD-1 resulted in consistent inhibition of tumor growth compared with either agent alone. PI3K inhibition slows tumor growth, enhances antitumor immunity, and heightens susceptibility to immune checkpoint inhibitors. We propose that combining PI3K inhibition with anti-PD1 may be a viable therapeutic approach for triple-negative breast cancer. .
©2016 American Association for Cancer Research.
2 Communities
4 Members
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18 MeSH Terms
Early Th1 immunity promotes immune tolerance and may impair graft-versus-leukemia effect after allogeneic hematopoietic cell transplantation.
Engelhardt BG, Paczesny S, Jung DK, Daguindau E, Jagasia M, Savani BN, Chinratanalab W, Cornell RF, Goodman S, Greer JP, Kassim AA, Sengsayadeth S, Yoder SM, Rock MT, Crowe JE
(2016) Haematologica 101: e204-8
MeSH Terms: Adult, Aged, Allografts, Female, Graft vs Leukemia Effect, Hematopoietic Stem Cell Transplantation, Humans, Immune Tolerance, Immunity, Cellular, Leukemia, Male, Middle Aged, Th1 Cells
Added February 4, 2016
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2 Members
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13 MeSH Terms
Renal Denervation Prevents Immune Cell Activation and Renal Inflammation in Angiotensin II-Induced Hypertension.
Xiao L, Kirabo A, Wu J, Saleh MA, Zhu L, Wang F, Takahashi T, Loperena R, Foss JD, Mernaugh RL, Chen W, Roberts J, Osborn JW, Itani HA, Harrison DG
(2015) Circ Res 117: 547-57
MeSH Terms: Angiotensin II, Animals, Hypertension, Immunity, Cellular, Kidney, Mice, Mice, Inbred C57BL, Mice, Knockout, Random Allocation, Sympathectomy
Show Abstract · Added August 7, 2015
RATIONALE - Inflammation and adaptive immunity play a crucial role in the development of hypertension. Angiotensin II and probably other hypertensive stimuli activate the central nervous system and promote T-cell activation and end-organ damage in peripheral tissues.
OBJECTIVE - To determine if renal sympathetic nerves mediate renal inflammation and T-cell activation in hypertension.
METHODS AND RESULTS - Bilateral renal denervation using phenol application to the renal arteries reduced renal norepinephrine levels and blunted angiotensin II-induced hypertension. Bilateral renal denervation also reduced inflammation, as reflected by decreased accumulation of total leukocytes, T cells, and both CD4+ and CD8+ T cells in the kidney. This was associated with a marked reduction in renal fibrosis, albuminuria, and nephrinuria. Unilateral renal denervation, which partly attenuated blood pressure, only reduced inflammation in the denervated kidney, suggesting that this effect is pressure independent. Angiotensin II also increased immunogenic isoketal-protein adducts in renal dendritic cells (DCs) and increased surface expression of costimulation markers and production of interleukin (IL)-1α, IL-1β, and IL-6 from splenic DCs. Norepinephrine also dose dependently stimulated isoketal formation in cultured DCs. Adoptive transfer of splenic DCs from angiotensin II-treated mice primed T-cell activation and hypertension in recipient mice. Renal denervation prevented these effects of hypertension on DCs. In contrast to these beneficial effects of ablating all renal nerves, renal afferent disruption with capsaicin had no effect on blood pressure or renal inflammation.
CONCLUSIONS - Renal sympathetic nerves contribute to DC activation, subsequent T-cell infiltration and end-organ damage in the kidney in the development of hypertension.
© 2015 American Heart Association, Inc.
0 Communities
4 Members
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10 MeSH Terms
Tumor Necrosis Factor Receptor 2 Restricts the Pathogenicity of CD8(+) T Cells in Mice With Colitis.
Punit S, Dubé PE, Liu CY, Girish N, Washington MK, Polk DB
(2015) Gastroenterology 149: 993-1005.e2
MeSH Terms: Adoptive Transfer, Animals, CD8-Positive T-Lymphocytes, Cell Proliferation, Colitis, Colon, DNA-Binding Proteins, Disease Models, Animal, Gene Expression Regulation, Immunity, Cellular, Interleukin-10, Lymphocyte Activation, Male, Mice, Inbred C57BL, Mice, Knockout, Receptors, Tumor Necrosis Factor, Type II, Signal Transduction, Time Factors
Show Abstract · Added April 12, 2016
BACKGROUND & AIMS - Tumor necrosis factor receptor 2 (TNFR2, Tnfrsf1b) regulates multiple aspects of immune function, but little is known about its role in the immunopathogenesis of inflammatory bowel disease (IBD). We investigated whether TNFR2 restricts the activity of specific immune cell subtypes to protect against the development of colitis in mice.
METHODS - Tnfr2(-/-) mice were crossed with interleukin (Il) 10(-/-) mice, which spontaneously develop colitis, to generate Il10(-/-)Tnfr2(-/-) mice. Colonic tissues were collected from Il10(-/-)Tnfr2(-/-) mice along with Il10(-/-) mice (controls) and analyzed by flow cytometry and histology. Bone marrow was transplanted into Il10(-/-) and Il10(-/-)Tnfr2(-/-) mice from Il10(-/-) or Il10(-/-)Tnfr2(-/-) donors by intravenous injection. CD8(+) T cells were neutralized in Il10(-/-)Tnfr2(-/-) mice by intraperitoneal injection of anti-CD8 or isotype control antibodies. Colitis was induced in Rag2(-/-) mice by intravenous injections of naïve CD8(+) T cells isolated from C57BL/6 or Tnfr2(-/-) mice.
RESULTS - Il10(-/-)Tnfr2(-/-) mice spontaneously developed more severe colitis compared with Il10(-/-) controls, characterized by selective expansion of colonic CD8(+) T cells. Transplantation of TNFR2-deficient bone marrow resulted in significantly increased incidence and severity of colitis. Transcriptome analyses showed that the expression of genes regulated by TNFR2 were specific to CD8(+) T cells and included genes associated with risk for IBD. Depletion of CD8(+) T cells from Il10(-/-)Tnfr2(-/-) mice prevented colonic inflammation. Adoptive transfer of TNFR2-null naïve CD8(+) T cells compared with CD8(+) T cells from control mice increased the severity of colitis that developed in Rag2(-/-) mice.
CONCLUSIONS - TNFR2 protects mice from colitis by inhibiting the expansion of colonic CD8(+) T cells. TNFR2 regulates expression of genes that regulate CD8(+) T cells and have been associated with susceptibility to IBD. Disruption in TNFR2 signaling might therefore be associated with pathogenesis. Strategies to increase levels or activity of TNFR2 and thereby reduce the activity of CD8(+) T cells might be developed to treat IBD patients with CD8(+) T cell dysfunction.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
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1 Members
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18 MeSH Terms
Exacerbation of blast-induced ocular trauma by an immune response.
Bricker-Anthony C, Hines-Beard J, D'Surney L, Rex TS
(2014) J Neuroinflammation 11: 192
MeSH Terms: Animals, Blast Injuries, Electroretinography, Eye Injuries, Immunity, Cellular, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Visual Acuity
Show Abstract · Added January 20, 2015
BACKGROUND - Visual prognosis after an open globe injury is typically worse than after a closed globe injury due, in part, to the immune response that ensues following open globe trauma. There is a need for an animal model of open globe injury in order to investigate mechanisms of vision loss and test potential therapeutics.
METHODS - The left eyes of DBA/2 J mice were exposed to an overpressure airwave blast. This strain lacks a fully functional ocular immune privilege, so even though the blast wave does not rupture the globe, immune infiltrate and neuroinflammation occurs as it would in an open globe injury. For the first month after blast wave exposure, the gross pathology, intraocular pressure, visual function, and retinal integrity of the blast-exposed eyes were monitored. Eyes were collected at three, seven, and 28 days to study the histology of the cornea, retina, and optic nerve, and perform immunohistochemical labeling with markers of cell death, oxidative stress, and inflammation.
RESULTS - The overpressure airwave caused anterior injuries including corneal edema, neovascularization, and hyphema. Immune infiltrate was detected throughout the eyes after blast wave exposure. Posterior injuries included occasional retinal detachments and epiretinal membranes, large retinal pigment epithelium vacuoles, regional photoreceptor cell death, and glial reactivity. Optic nerve degeneration was evident at 28 days post-blast wave exposure. The electroretinogram (ERG) showed an early deficit in the a wave that recovered over time. Both visual acuity and the ERG b wave showed an early decrease, then a transient improvement that was followed by further decline at 28 days post-blast wave exposure.
CONCLUSIONS - Ocular blast injury in the DBA/2 J mouse recapitulates damage that is characteristic of open globe injuries with the advantage of a physically intact globe that prevents complications from infection. The injury was more severe in DBA/2 J mice than in C57Bl/6 J mice, which have an intact ocular immune privilege. Early injury to the outer retina mostly recovers over time. In contrast, inner retinal dysfunction seems to drive later vision loss.
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9 MeSH Terms
Adipose tissue and immune function: a review of evidence relevant to HIV infection.
Koethe JR, Hulgan T, Niswender K
(2013) J Infect Dis 208: 1194-201
MeSH Terms: Adipose Tissue, HIV Infections, Humans, Immunity, Cellular, Inflammation, Obesity
Show Abstract · Added May 27, 2014
Human immunodeficiency virus type 1 (HIV) infection and antiretroviral therapy (ART) have long been associated with abnormalities in adipose tissue distribution and metabolism. More-recent evidence demonstrates that adipocytes and adipose-resident immune cells have a role in the response to HIV. Clinical and laboratory studies indicate that viral proteins and antiretroviral medications alter adipocyte biology to enhance the persistent, systemic inflammatory state characteristic of untreated and treated HIV infection. Relationships between body composition and lymphocyte populations, cellular immune activation, and immune reconstitution in HIV-infected individuals receiving ART suggest that adipose tissue may also affect cellular immune function. This is further supported by in vitro studies demonstrating the effect of adipocytes and adipokines on lymphocyte proliferation, differentiation, and activation. Synthesis of the literature on adipose tissue biology and immune function in uninfected individuals may shed light on major outstanding research questions in the HIV field.
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6 MeSH Terms