Electrical Properties and Anion Permeability of Doubly Rectifying Junctions in the Leech Central Nervous System

1988 ◽  
Vol 137 (1) ◽  
pp. 1-11
Author(s):  
Susan E. Acklin
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Action Potentials ◽  
Sodium Pump ◽  
Current Flow ◽  
Cell Movement ◽  
Voltage Dependent ◽  
Electrical Connections

A study has been made of the electrical connections between touch sensory (T) neurones in the leech central nervous system (CNS) which display remarkable double rectification: depolarization spreads in both directions although hyperpolarization spreads poorly. Tests were made to determine whether this double rectification was a property of the junctions themselves or whether it resulted from changes in the length constants of processes intervening between the cell body and the junctions. Following trains of action potentials, T cells and their fine processes within the neuropile became hyperpolarized through the activity of an electrogenie sodium pump. When any T cell was hyperpolarized by 25 mV by repetitive stimulation, hyperpolarization failed to spread to the T cells to which it was electrically coupled. Further evidence for double rectification of junctions linking T cells was provided by experiments in which Cl− was injected electrophoretically. Cl− injection into one T cell caused inhibitory potentials recorded in it to become reversed. After a delay, Cl− spread to reverse IPSPs in the coupled T cell. Movement of Cl−, like current flow, was dependent on membrane potential. When the T cell into which Cl− was injected was kept hyperpolarized, Cl− failed to move into the adjacent T cell. Upon release of the hyperpolarization in the injected T cell, Cl− moved and reversed IPSPs in the coupled T cell. Together these results indicate that the gating properties of channels linking T cells are voltage-dependent, such that depolarization of either cell allows channels to open whereas hyperpolarization causes them to close.

scholarly journals The Majority of Infiltrating CD8+ T Cells in the Central Nervous System of Susceptible SJL/J Mice Infected with Theiler's Virus Are Virus Specific and Fully Functional

2002 ◽  
Vol 76 (13) ◽  
pp. 6577-6585 ◽  
Author(s):  
Bong-Su Kang ◽  
Michael A. Lyman ◽  
Byung S. Kim
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Demyelinating Disease ◽  
Class I ◽  
Theiler's Virus ◽  
Ctl Response ◽  
The Central Nervous System ◽  
Ifn Γ

ABSTRACT Theiler's virus infection of the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains, such as SJL/J, and serves as a relevant infectious model for human multiple sclerosis. It has been previously suggested that susceptible SJL/J mice do not mount an efficient cytotoxic T-lymphocyte (CTL) response to the virus. In addition, genetic studies have shown that resistance to Theiler's virus-induced demyelinating disease is linked to the H-2D major histocompatibility complex class I locus, suggesting that a compromised CTL response may contribute to the susceptibility of SJL/J mice. Here we show that SJL/J mice do, in fact, generate a CD8+ T-cell response in the CNS that is directed against one dominant (VP3159-166) and two subdominant (VP111-20 and VP3173-181) capsid protein epitopes. These virus-specific CD8+ T cells produce gamma interferon (IFN-γ) and lyse target cells in the presence of the epitope peptides, indicating that these CNS-infiltrating CD8+ T cells are fully functional effector cells. Intracellular IFN-γ staining analysis indicates that greater than 50% of CNS-infiltrating CD8+ T cells are specific for these viral epitopes at 7 days postinfection. Therefore, the susceptibility of SJL/J mice is not due to the lack of an early functional Theiler's murine encephalomyelitis virus-specific CTL response. Interestingly, T-cell responses to all three epitopes are restricted by the H-2Ks molecule, and this skewed class I restriction may be associated with susceptibility to demyelinating disease.

scholarly journals New Therapeutic Approach for Central Nervous System Lymphoma By Intracerebroventricular Delivery of CD19CAR T Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2161-2161
Author(s):  
Xiuli Wang ◽  
Ryan Urak ◽  
Walter Miriam ◽  
Laura Lim ◽  
Brenda Aguilar ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
B Cell ◽  
Central Nervous System Lymphoma ◽  
Car T Cell ◽  
Car T ◽  
Systemic Lymphoma ◽  
Cns Lymphomas

Abstract Central nervous system lymphoma (CNSL) is a lymphoid malignancy in which tumors from lymph tissue start in the brain, spinal cord, eye, and/or meninges (primary CNSL) or present as a result of metastasis from initial systemic sites to the CNS (secondary CNSL). The most common CNS lymphomas (about 90%) are B-cell lymphomas. The incidence of primary CNS lymphoma has been increasing over the past 20 years. Multifocal lesions are common. CNS lymphomas carry a worse prognosis than systemic lymphoma. Only a few chemotherapeutic drugs can cross and achieve a therapeutic concentration in the CNS. Therefore, effective treatment is limited and the outcome of disease in relapsed or refractory setting is poor. Recent studies show that intraventricular delivery of rituximab in CNS lymphomas is well tolerated. T cell products that are genetically engineered with chimeric antigen receptors (CARs) targeting CD19 have broad application for adoptive therapy of B cell lineage malignancies and have shown tremendous potential in treatment of systemic lymphoma. In all CD19CAR T cell trials, T cell products are administrated intravenously. CD19CAR T cell trafficking in cerebrospinal fluid (CSF) is frequently reported but most if not all protocols exclude patients with active CNS involvement. In this study, we set out to investigate the feasibility and efficacy of the use of CD19CAR T cells to treat CNSL. Methods and Results: Isolated naïve and central memory T cells (Tn/Tmem) were genetically modified with CD19CAR lentivirus and expanded in vitro for 14 days. 0.1x10^6 human B cell lymphoma Daudi cells were injected intracranially into NSG mice. Tumor was allowed to engraft for 5 days. We administered CD19CAR T cells via three different delivery routes: intracranial local infusion with 1x10^6 CD19CAR T cells (i.c), intracerebroventricular (i.c.v) administration with 1x10^6 cells to bypass the blood-brain barrier and target tumor throughout the entire CNS, and intravenous injection (i.v) with 3x10^6 cells. We repeatedly observed in 2 separate experiments (N=5 mice in each experiment) that both a single i.c infusion and a single i.c.v delivery of CD19CAR T cells were able to completely eradicated CNS lymphoma in all mice by day 14 post CAR T cell infusion; and that a single dose of i.v infusion induced significant anti-CNSL activity with a slightly delayed response as compared to i.c and i.c.v treatment and all mice achieved complete remission 21 days post T cell infusion. CAR T cells were detected in peripheral blood obtained from retro-orbital bleeding, not only in the i.v treated mice, but also in i.c.v treated mice 28 days after CAR T cell infusion, suggesting that i.c.v not only controls CNSL but may also play a role in immune surveillance for systemic tumors. To confirm this, we established an NSG CNS B cell lymphoma model by also inoculating subcutaneous tumors on the animal's flank, 3 weeks prior to i.c tumor injection into the same mouse. CD19CAR T cells were delivered via i.c.v 5 days after i.c. tumor injection. CAR T cell injection resulted in complete remission of both the brain tumor and the flank tumor 14 days after CAR T cell administration. In conclusion,intracerebroventricular delivery of CD19CAR T cells is a promising and feasible therapeutic approach for both primary central nervous system lymphoma and systemic lymphoma with concurrent CNS involvement. Disclosures No relevant conflicts of interest to declare.

scholarly journals Priming of CD8+ T Cells during Central Nervous System Infection with a Murine Coronavirus Is Strain Dependent

2008 ◽  
Vol 82 (13) ◽  
pp. 6150-6160 ◽  
Author(s):  
Katherine C. MacNamara ◽  
Susan J. Bender ◽  
Ming Ming Chua ◽  
Richard Watson ◽  
Susan R. Weiss
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cns Infection ◽  
Cervical Lymph Nodes ◽  
T Cell Priming ◽  
The Brain

ABSTRACT Virus-specific CD8+ T cells are critical for protection against neurotropic coronaviruses; however, central nervous system (CNS) infection with the recombinant JHM (RJHM) strain of mouse hepatitis virus (MHV) elicits a weak CD8+ T-cell response in the brain and causes lethal encephalomyelitis. An adoptive transfer model was used to elucidate the kinetics of CD8+ T-cell priming during CNS infection with RJHM as well as with two MHV strains that induce a robust CD8+ T-cell response (RA59 and SJHM/RA59, a recombinant A59 virus expressing the JHM spike). While RA59 and SJHM/RA59 infections resulted in CD8+ T-cell priming within the first 2 days postinfection, RJHM infection did not lead to proliferation of naïve CD8+ T cells. While all three viruses replicated efficiently in the brain, only RA59 and SJHM/RA59 replicated to appreciable levels in the cervical lymph nodes (CLN), the site of T-cell priming during acute CNS infection. RJHM was unable to suppress the CD8+ T-cell response elicited by RA59 in mice simultaneously infected with both strains, suggesting that RJHM does not cause generalized immunosuppression. RJHM was also unable to elicit a secondary CD8+ T-cell response in the brain following peripheral immunization against a viral epitope. Notably, the weak CD8+ T-cell response elicited by RJHM was unique to CNS infection, since peripheral inoculation induced a robust CD8+ T-cell response in the spleen. These findings suggest that the failure of RJHM to prime a robust CD8+ T-cell response during CNS infection is likely due to its failure to replicate in the CLN.

scholarly journals CC Chemokines Mediate Leukocyte Trafficking into the Central Nervous System during Murine Neurocysticercosis: Role of γδ T Cells in Amplification of the Host Immune Response

2003 ◽  
Vol 71 (5) ◽  
pp. 2634-2642 ◽  
Author(s):  
Astrid E. Cardona ◽  
Paula A. Gonzalez ◽  
Judy M. Teale
Keyword(s):  
Central Nervous System ◽  
Immune Response ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Γδ T Cells ◽  
Host Immune Response ◽  
Leukocyte Trafficking ◽  
Cellular Infiltration ◽  
The Brain

ABSTRACT According to a previous report, the degree of the host immune response highly correlates with severity of the disease in the murine model for neurocysticercosis. In wild-type mice, Mesocestoides corti infection induced a rapid and extensive accumulation of γδ T cells and macrophages in the brain. NK cells, dendritic cells, αβ T cells, and B cells were also recruited to the brain but at lower levels. In contrast, γδ T-cell-deficient mice exhibited decreased cellular infiltration and reduced central nervous system (CNS) pathology. To understand the mechanisms of leukocyte recruitment into the CNS, chemokine expression was analyzed in infected brains in the present study. MCP-1 (CCL2), MIP-1α (CCL3), and MIP-1β (CCL4) were up-regulated within 2 days after M. corti infection. Protein expression of RANTES (CCL5), eotaxin (CCL11), and MIP-2 was detected later, at 1 week postinfection. Correlating with the decreased cellular infiltration, delta chain T-cell receptor-deficient (TCRδ−/−) mice exhibited substantially reduced levels of most of the chemokines analyzed (with the exception of eotaxin). The results suggest that γδ T cells play an important role in the CNS immune response by producing chemokines such as MCP-1 and MIP-1α, enhancing leukocyte trafficking into the brain during murine neurocysticercosis.

scholarly journals CD4 T Cells Contribute to Virus Control and Pathology following Central Nervous System Infection with Neurotropic Mouse Hepatitis Virus

2007 ◽  
Vol 82 (5) ◽  
pp. 2130-2139 ◽  
Author(s):  
Stephen A. Stohlman ◽  
David R. Hinton ◽  
Beatriz Parra ◽  
Roscoe Atkinson ◽  
Cornelia C. Bergmann
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Virus Replication ◽  
Hepatitis Virus ◽  
Mouse Hepatitis Virus ◽  
Wild Type ◽  
Virus Control ◽  
Ifn Γ

ABSTRACT Replication of the neurotropic mouse hepatitis virus strain JHM (JHMV) is controlled primarily by CD8+ T-cell effectors utilizing gamma interferon (IFN-γ) and perforin-mediated cytotoxicity. CD4+ T cells provide an auxiliary function(s) for CD8+ T-cell survival; however, their direct contribution to control of virus replication and pathology is unclear. To examine a direct role of CD4+ T cells in viral clearance and pathology, pathogenesis was compared in mice deficient in both perforin and IFN-γ that were selectively reconstituted for these functions via transfer of virus-specific memory CD4+ T cells. CD4+ T cells from immunized wild-type, perforin-deficient, and IFN-γ-deficient donors all initially reduced virus replication. However, prolonged viral control by IFN-γ-competent donors suggested that IFN-γ is important for sustained virus control. Local release of IFN-γ was evident by up-regulation of class II molecules on microglia in recipients of IFN-γ producing CD4+ T cells. CD4+ T-cell-mediated antiviral activity correlated with diminished clinical symptoms, pathology, and demyelination. Both wild-type donor CD90.1 and recipient CD90.2 CD4+ T cells trafficked into the central nervous system (CNS) parenchyma and localized to infected white matter, correlating with decreased numbers of virus-infected oligodendrocytes in the CNS. These data support a direct, if limited, antiviral role for CD4+ T cells early during acute JHMV encephalomyelitis. Although the antiviral effector mechanism is initially independent of IFN-γ secretion, sustained control of CNS virus replication by CD4+ T cells requires IFN-γ.

scholarly journals PD-1 Blockade Aggravates Epstein–Barr Virus+ Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4+ T Cell Dysregulations

2021 ◽  
Vol 10 ◽  
Author(s):  
Valery Volk ◽  
Sebastian J. Theobald ◽  
Simon Danisch ◽  
Sahamoddin Khailaie ◽  
Maja Kalbarczyk ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Stem Cell ◽  
T Cell ◽  
Lymphoproliferative Disorder ◽  
Epstein Barr Virus ◽  
Humanized Mice ◽  
Barr Virus ◽  
Epstein Barr

Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies after solid organ or allogeneic stem cell transplantation. Most PTLD cases are B cell neoplasias carrying Epstein-Barr virus (EBV). A therapeutic approach is reduction of immunosuppression to allow T cells to develop and combat EBV. If this is not effective, approaches include immunotherapies such as monoclonal antibodies targeting CD20 and adoptive T cells. Immune checkpoint inhibition (ICI) to treat EBV+ PTLD was not established clinically due to the risks of organ rejection and graft-versus-host disease. Previously, blockade of the programmed death receptor (PD)-1 by a monoclonal antibody (mAb) during ex vivo infection of mononuclear cells with the EBV/M81+ strain showed lower xenografted lymphoma development in mice. Subsequently, fully humanized mice infected with the EBV/B95-8 strain and treated in vivo with a PD-1 blocking mAb showed aggravation of PTLD and lymphoma development. Here, we evaluated vis-a-vis in fully humanized mice after EBV/B95-8 or EBV/M81 infections the effects of a clinically used PD-1 blocker. Fifteen to 17 weeks after human CD34+ stem cell transplantation, Nod.Rag.Gamma mice were infected with two types of EBV laboratory strains expressing firefly luciferase. Dynamic optical imaging analyses showed systemic EBV infections and this triggered vigorous human CD8+ T cell expansion. Pembrolizumab administered from 2 to 5 weeks post-infections significantly aggravated EBV systemic spread and, for the M81 model, significantly increased the mortality of mice. ICI promoted Ki67+CD30+CD20+EBER+PD-L1+ PTLD with central nervous system (CNS) involvement, mirroring EBV+ CNS PTLD in humans. PD-1 blockade was associated with lower frequencies of circulating T cells in blood and with a profound collapse of CD4+ T cells in lymphatic tissues. Mice treated with pembrolizumab showed an escalation of exhausted T cells expressing TIM-3, and LAG-3 in tissues, higher levels of several human cytokines in plasma and high densities of FoxP3+ regulatory CD4+ and CD8+ T cells in the tumor microenvironment. We conclude that PD-1 blockade during acute EBV infections driving strong CD8+ T cell priming decompensates T cell development towards immunosuppression. Given the variety of preclinical models available, our models conferred a cautionary note indicating that PD-1 blockade aggravated the progression of EBV+ PTLD.

scholarly journals Characterization of and Functional Antigen Presentation by Central Nervous System Mononuclear Cells from Mice Infected with Theiler’s Murine Encephalomyelitis Virus

1998 ◽  
Vol 72 (10) ◽  
pp. 7762-7771 ◽  
Author(s):  
Jonathan G. Pope ◽  
Carol L. Vanderlugt ◽  
Sandra M. Rahbe ◽  
Howard L. Lipton ◽  
Stephen D. Miller
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Persistently Infected ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus

ABSTRACT We examined the phenotype and function of cells infiltrating the central nervous system (CNS) of mice persistently infected with Theiler’s murine encephalomyelitis virus (TMEV) for evidence that viral antigens are presented to T cells within the CNS. Expression of major histocompatibility complex (MHC) class II in the spinal cords of mice infected with TMEV was found predominantly on macrophages in demyelinating lesions. The distribution of I-As staining overlapped that of the macrophage marker sialoadhesin in frozen sections and coincided with that of another macrophage/microglial cell marker, F4/80, by flow cytometry. In contrast, astrocytes, identified by staining with glial fibrillary acidic protein, rarely expressed detectable MHC class II, although fibrillary gliosis associated with the CNS damage was clearly seen. The costimulatory molecules B7-1 and B7-2 were expressed on the surface of most MHC class II-positive cells in the CNS, at levels exceeding those found in the spleens of the infected mice. Immunohistochemistry revealed that B7-1 and B7-2 colocalized on large F4/80+macrophages/microglia in the spinal cord lesions. In contrast, CD4+ T cells in the lesions expressed mainly B7-2, which was found primarily on blastoid CD4+ T cells located toward the periphery of the lesions. Most interestingly, plastic-adherent cells freshly isolated from the spinal cords of TMEV-infected mice were able to process and present TMEV and horse myoglobin to antigen-specific T-cell lines. Furthermore, these cells were able to activate a TMEV epitope-specific T-cell line in the absence of added antigen, providing conclusive evidence for the endogenous processing and presentation of virus epitopes within the CNS of persistently infected SJL/J mice.

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