scholarly journals Loss of bone marrow adrenergic beta 1 and 2 receptors modifies transcriptional networks, reduces circulating inflammatory factors, and regulates blood pressure

2016 ◽  
Vol 48 (7) ◽  
pp. 526-536 ◽  
Author(s):  
Niousha Ahmari ◽  
Jordan T. Schmidt ◽  
Gregory A. Krane ◽  
Wendi Malphurs ◽  
Bruce E. Cunningham ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Bone Marrow ◽  
Nervous System ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nervous System Development ◽  
Differentially Expressed ◽  
Inflammatory Factors ◽  
Transcriptional Networks

Hypertension (HTN) is a prevalent condition with complex etiology and pathophysiology. Evidence exists of significant communication between the nervous system and the immune system (IS), and there appears to be a direct role for inflammatory bone marrow (BM) cells in the pathophysiology of hypertension. However, the molecular and neural mechanisms underlying this interaction have not been characterized. Here, we transplanted whole BM cells from the beta 1 and 2 adrenergic receptor (AdrB1tm1BkkAdrB2tm1Bkk/J) knockout (KO) mice into near lethally irradiated C57BL/6J mice to generate a BM AdrB1.B2 KO chimera. This allowed us to evaluate the role of the BM beta 1 and beta 2 adrenergic receptors in mediating BM IS homeostasis and regulating blood pressure (BP) in an otherwise intact physiological setting. Fluorescence-activated cell sorting demonstrated that a decrease in systolic and mean BP in the AdrB1.B2 KO chimera is associated with a decrease in circulating inflammatory T cells, macrophage/monocytes, and neutrophils. Transcriptomics in the BM identified 7,419 differentially expressed transcripts between the C57 and AdrB1.B2 KO chimera. Pathway analysis revealed differentially expressed transcripts related to several cell processes in the BM of C57 compared with AdrB1.B2 KO chimera, including processes related to immunity (e.g., T-cell activation, T-cell recruitment, cytokine production, leukocyte migration and function), the cardiovascular system (e.g., blood vessel development, peripheral nerve blood flow), and the brain (e.g., central nervous system development, neurite development) among others. This study generates new insight into the molecular events that underlie the interaction between the sympathetic drive and IS in modulation of BP.

CD4+ T-cell activation of bone marrow causes bone fragility and insulin resistance in type 2 diabetes

Bone ◽  
2021 ◽  
pp. 116292
Author(s):  
S.E. Cifuentes-Mendiola ◽  
D.L. Solis-Suarez ◽  
A. Martínez-Dávalos ◽  
M. Godínez-Victoria ◽  
A.L. García-Hernández
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Bone Marrow ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bone Fragility ◽  
Cd4 T Cell

Characterization of a subset of bone marrow-derived natural killer cells that regulates T cell activation in rats

2008 ◽  
Vol 83 (5) ◽  
pp. 1128-1135 ◽  
Author(s):  
Taba Kheradmand ◽  
Prachi P. Trivedi ◽  
Norbert A. Wolf ◽  
Paul C. Roberts ◽  
Robert H. Swanborg
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Natural Killer Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Killer Cells

scholarly journals IL-9 is important for T-cell activation and differentiation in autoimmune inflammation of the central nervous system

2011 ◽  
Vol 41 (8) ◽  
pp. 2197-2206 ◽  
Author(s):  
Hongmei Li ◽  
Bardia Nourbakhsh ◽  
Melissa Cullimore ◽  
Guang-Xian Zhang ◽  
Abdolmohamad Rostami
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Autoimmune Inflammation ◽  
The Central Nervous System

CD4 + T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T‐cell receptor repertoires

2019 ◽  
Vol 49 (6) ◽  
pp. 653-662
Author(s):  
Ryo Nakagawa ◽  
Ryosuke Muroyama ◽  
Chisato Saeki ◽  
Tsunekazu Oikawa ◽  
Yoshimi Kaise ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cell Receptor ◽  
Differentially Expressed ◽  
Primary Biliary Cholangitis

SAP (SH2D1A), the Immunomodulator Deficient in X-Linked Lymphoproliferative Syndrome (XLP), Is Profoundly Decreased in Aplastic Anemia: An Immunologic Link between Constitutional and Acquired Bone Marrow Failure.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1141-1141
Author(s):  
Elena E. Solomou ◽  
Valeria Visconte ◽  
Federica Gibellini ◽  
Neal S. Young
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Aplastic Anemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bone Marrow Failure ◽  
Protein Levels ◽  
Ifn Γ ◽  
Th1 Polarization

Abstract Ligation of the signaling lymphocyte activation molecule (SLAM), a member of the immunoglobulin superfamily expressed in T and B cells, results in T cell activation and Th1 cytokine production. SAP is a small cytoplasmic protein expressed in T- and NK cells that controls the activation signals mediated by SLAM. On T cell activation, SAP binds to Fyn kinase; Fyn is activated and phosphorylates tyrosine residues on SLAM; phosphorylation results in the formation of a complex that selectively down-regulates co-stimulatory signals in activated T cells, resulting in inhibition of IFN-γ production. Thus SAP acts as a natural suppressor of SLAM-mediated T cell activation, and, in the absence of SAP, T cells are constitutively activated and overproduce IFN-γ. Mutations in the SAP gene lead to abnormal T cell activation and enhanced Th1 cytokine production in mouse models and in humans: about half of patients with X-linked lympoproliferative disease (XLP) have functionally disabling SAP mutations. Acquired aplastic anemia (AA) is a bone marrow failure syndrome in which hematopoietic cell destruction is effected by cytotoxic T cells and type 1 cytokines. We have recently shown that T cells from patients with AA have increased protein levels of T-bet, resulting in IFN-γ overproduction (Solomou EE et al, Blood2006; 107:3983). IFN-γ inhibits hematopoietic stem cell proliferation and induces Fas-mediated apoptosis; stem cell depletion results in marrow hypoplasia and peripheral blood pancytopenia. We examined SAP expression as an explanation for aberrant T cell activation and extreme Th1 polarization. SAP protein expression on immunoblot was very low to absent in unstimulated T cells from 16 of 20 AA patients examined, as compared to normal levels of expression in equivalent numbers of healthy donors (p<0.001). No significant differences were detected in Fyn and SLAM protein levels between AA and controls. SAP mRNA levels were also significantly decreased in T cells from those AA patients with low SAP protein levels, as determined by RT-PCR. Peripheral blood DNA samples from 18 patients with AA were analyzed for SAP mutations: three novel intronic mutations, not present in controls, were identified among 7 unrelated patients: one mutation was in the promoter region of SAP (position 106, C to T; 3 patients), and two mutations in the intron-exon junction between exons 1 and 2 (position 38975, C toT; 3 patients) and 3 and 4 (position 62771, C to A; 1 patient). IFN-γ, as measured by ELISA, in three patients with undetectable SAP protein levels was significantly increased compared to healthy controls (n=5, p<0.001). Increased IFN-γ levels and Th1 polarization in AA can in part be explained by functional SAP deficiency. SAP-deficient T cells in AA would be unable to block co-stimulatory signals, leading to an activated T cell phenotype and ultimately hematopoietic cell destruction and bone marrow failure. The SAP-deficient phenotype in T cells from patients with aplastic anemia may be secondary to subtle genetic alteration in the gene’s regulation (abnormal promoter binding sites or epigenetic modulation due to mutations in introns) or as yet unidentified aberrant upstream pathways (Ets-1 and Ets-2, the transcription factors that regulate SAP expression).

Presence of Vasoactive Intestinal Polypeptide Signaling in Plasmacytoid Dendritic Cells Improves Survival in a Murine Allo-BMT Model

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2154-2154
Author(s):  
Jing-Xia Li ◽  
Jian-Ming Li ◽  
Edmund K Waller
Keyword(s):  
Bone Marrow ◽  
Weight Loss ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Expansion ◽  
Cell Activation ◽  
Post Transplant ◽  
Cytokine Analysis

Abstract Introduction: Pre-clinical murine experiments and clinical data from allogeneic bone marrow transplantation (allo-BMT) have shown that increased numbers of plasmacytoid dendritic cells (pDC) in the bone marrow graft results in better clinical outcomes with less severe graft-versus-host disease (GvHD) and improved survival. The mechanism by which donor pDC modulate GvHD is unknown. Knowing that vasoactive intestinal polypeptide (VIP) is an immunosuppressive peptide , we reasoned that VIP signaling might play a role in regulating T-cell activation and expansion, and the VIP pathway may be a potential therapeutic target for regulating GvHD in allo-BMT. We have tested the hypothesis that VIP synthesis by donor pDCs can modulate T cell alloreactivity. Methods: To explore the mechanisms by which pDC and VIP signaling regulate T cell activation in murine allo-BMT, we prepared B6-background donor cell grafts and transplanted them into lethally irradiated B10.BR recipients. In experiment 1, recipients were transplanted with grafts containing the combination of 5 x 103 VIP-GFP hematopoietic stem cells (HSC) and 3 x 106 VIP-wild type (VIP-WT) or VIP-knock out (VIP-KO) splenocytes. At day 7, splenocytes were isolated for flow cytometric analysis looking for GFP signal, which represents VIP-promotor activity. Experiment 2 used combinations of 5 x 103 VIP-WT HSC, 1 x 106 luciferase+ T cells, and 50 x 103 VIP-WT or VIP-KO pDC from B6 as donor grafts. Recipients were monitored for survival and GvHD based on fur texture, posture, activity, skin integrity and weight loss. T cell expansion was measured by bioluminescent imaging (BLI). Serum cytokines from bleeds at day 3 and day 8 post-transplant were analyzed using a Luminex 38 plex panel. Some recipients were euthanized on day 3 for intracellular cytokine analysis of splenic T cells. Results: In experiment 1, 7 days post-transplant, analysis of splenocytes from all mice showed increased activity of the VIP gene promoter in donor pDC that were derived from HSC, compared to other cell types. The VIP promoter signal was also stronger in donor HSC-derived pDCs, if originally transplanted with VIP-KO splenocytes. In experiment 2 over 70% of mice receiving HSC+T+VIP-WT pDC in the BM graft survived to day 100 post-transplant, while those getting VIP-KO pDC instead only had 30% survival (Fig 1A). All surviving recipients were fully engrafted by day 30. BLI revealed greater total T-cell proliferation (measured as radiance) in recipients of VIP-KO pDC (Fig 1B). Furthermore, recipients of VIP-KO pDC had more severe acute GvHD, with increased weight loss and GvHD clinical scores (Fig 1C, 1D). Some recipients were euthanized and their serum were collected for cytokine analysis on day 8 post-transplant, which showed up-regulation of pro-inflammatory or chemotactic cytokines MCP1, IL-1, IL-12, IL-17 in T cells co-transplanted with VIP-KO pDC compared to WT pDC. Conclusion: The present findings show that: 1) VIP is produced by donor pDC early after allo-BMT; 2) absence of VIP production by donor pDC leads to increased T-cell expansion in a murine allo-BMT model. Thus the pDC-T cell VIP signaling pathway is a critical element in controlling donor T cell alloreactivity after allo-BMT. Future studies will include VIP qPCR to confirm VIP production in donor pDC post-transplant, and determine the mechanism by which VIP production by pDC regulates T cell activity and modulates GvHD. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

A phase I/II study of blinatumomab in combination with pembrolizumab for adults with relapsed refractory B-lineage acute lymphoblastic leukemia: University of California Hematologic Malignancies Consortium Study 1504.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7064-TPS7064 ◽  
Author(s):  
Marc Saul Schwartz ◽  
Deepa Jeyakumar ◽  
Lloyd Earl Damon ◽  
Gary J. Schiller ◽  
Matthew Joseph Wieduwilt
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Phase I ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphoblastic Leukemia ◽  
Multicenter Trial ◽  
Response To Therapy ◽  
Phase Iii

TPS7064 Background: Outcomes for adults with relapsed/refractory B-cell ALL (R/R B-ALL) remain poor despite new targeted therapies. Blinatumomab is an anti-CD19/CD3 bifunctional T-cell engaging antibody that was superior to conventional salvage therapy for remission and overall survival in a Phase III study of patients with R/R B-ALL. The CR/CRh rate for blinatumomab was 65.5% with < 50% marrow lymphoblasts but dropped to 34.4% with ≥ 50% marrow lymphoblasts. Clinical and pre-clinical findings suggest that PD-L1 overexpression on lymphoblasts and in the bone marrow may mediate resistance to blinatumomab by inhibiting T-cell activation. We hypothesize that addition of pembrolizumab will improve CR/CRh rates to blinatumomab in R/R B-cell ALL. Methods: We are conducting a phase I/II multicenter trial to evaluate the safety and efficacy of blinatumomab with pembrolizumab in adults with R/R B-ALL and a high bone marrow lymphoblast percentage (NCT 03160079). The primary endpoint is ORR (CR+CRh) after 1-2 cycles with secondary endpoints of AEs, MRD-negative CR/CRh rate, 2-year DFS, 2-year OS, and allogeneic HCT rate. Exploratory studies are evaluating cytokine expression, PD-1 expression on T-cells, PD-L1 and PD-L2 protein expression on lymphoblasts, and T-cell populations at diagnosis and in response to therapy. Eligibility includes: adults with R/R CD19+ B-ALL after ≥ 1 prior line of therapy, R/R Ph+ B-ALL must fail a 2nd- or 3rd-generation TKI or be TKI intolerant, > 50% lymphoblasts on screening bone marrow sample. Blinatumomab is given by continuous IV at 9 mcg/day days 1-7 of cycle 1, 28 mcg/day days 8-28 of cycle 1, then at 28 mcg/day days 1-28 in subsequent cycles. Pembrolizumab 200 mg IV is given on days 15 and 36 of each 42-day cycle. Patients in CR/CRh after 1-2 cycles will complete 5 cycles. Patients not in CR/CRh after 2 cycles of therapy or progressing after Day 15 of cycle 1 go off study. CNS prophylaxis with IT methotrexate is given at screening and once per cycle. A phase I run-in of 3-6 patients precedes accrual of 18-21 patients for a target of 24. The study opened in July 2017 and 4 patients have been treated. No DLTs have occurred to date. Clinical trial information: NCT03160079.

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