scholarly journals Refractory T-Cell Anergy and Rapidly Fatal Progressive Multifocal Leukoencephalopathy After Prolonged CTLA4 Therapy

2017 ◽  
Vol 4 (2) ◽  
Author(s):  
Manon Dekeyser ◽  
Marie-Ghislaine de Goër de Herve ◽  
Houria Hendel-Chavez ◽  
Céline Labeyrie ◽  
David Adams ◽  
...  
Keyword(s):  
T Cell ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Human Polyomavirus ◽  
Therapeutic Approaches ◽  
Cell Responses ◽  
T Cell Anergy ◽  
Immunosuppressed Patients ◽  
Cell Anergy

Abstract Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to central nervous system replication of the human polyomavirus JC virus (JCV) in immunosuppressed patients. The only effective therapeutic approach is to restore anti-JCV T-cell responses. In this study, we describe a case of rapidly fatal PML with JCV T-cell anergy in a renal transplant patient treated with CTLA4-Ig (belatacept, a CD28-B7 costimulation blocker and T-cell anergy inducer). T-cell anergy could not be reversed despite several therapeutic approaches. Progressive multifocal leukoencephalopathy secondary to biotherapy-induced T-cell anergy may thus represent a subset of PML with major resistance to anti-JCV immune recovery.

scholarly journals Changes in JC Virus-Specific T Cell Responses during Natalizumab Treatment and in Natalizumab-Associated Progressive Multifocal Leukoencephalopathy

2012 ◽  
Vol 8 (11) ◽  
pp. e1003014 ◽  
Author(s):  
Molly R. Perkins ◽  
Caroline Ryschkewitsch ◽  
Julia C. Liebner ◽  
Maria Chiara G. Monaco ◽  
Danielle Himelfarb ◽  
...  
Keyword(s):  
T Cell ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Jc Virus ◽  
T Cell Responses ◽  
Cell Responses ◽  
Natalizumab Treatment

scholarly journals The Role of ICOS in Directing T Cell Responses: ICOS-Dependent Induction of T Cell Anergy by Tolerogenic Dendritic Cells

2009 ◽  
Vol 182 (6) ◽  
pp. 3349-3356 ◽  
Author(s):  
Andrea Tuettenberg ◽  
Eva Huter ◽  
Mario Hubo ◽  
Julia Horn ◽  
Jürgen Knop ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Cell Responses ◽  
T Cell Anergy ◽  
Tolerogenic Dendritic Cells ◽  
Cell Anergy

scholarly journals JC Virus-Specific Immune Responses in Human Immunodeficiency Virus Type 1 Patients with Progressive Multifocal Leukoencephalopathy

2009 ◽  
Vol 83 (9) ◽  
pp. 4404-4411 ◽  
Author(s):  
Nina Khanna ◽  
Marcel Wolbers ◽  
Nicolas J. Mueller ◽  
Christian Garzoni ◽  
Renaud A. Du Pasquier ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Mononuclear Cells ◽  
Jc Virus ◽  
T Cell Responses ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses ◽  
Cell Counts ◽  
Immunodeficiency Virus

ABSTRACT Progressive multifocal leukoencephalopathy (PML) is a frequently fatal disease caused by uncontrolled polyomavirus JC (JCV) in severely immunodeficient patients. We investigated the JCV-specific cellular and humoral immunity in the Swiss HIV Cohort Study. We identified PML cases (n = 29), as well as three matched controls per case (n = 87), with prospectively cryopreserved peripheral blood mononuclear cells and plasma at diagnosis. Nested controls were matched according to age, gender, CD4+ T-cell count, and decline. Survivors (n = 18) were defined as being alive for >1 year after diagnosis. Using gamma interferon enzyme-linked immunospot assays, we found that JCV-specific T-cell responses were lower in nonsurvivors than in their matched controls (P = 0.08), which was highly significant for laboratory- and histologically confirmed PML cases (P = 0.004). No difference was found between PML survivors and controls or for cytomegalovirus-specific T-cell responses. PML survivors showed significant increases in JCV-specific T cells (P = 0.04) and immunoglobulin G (IgG) responses (P = 0.005). IgG responses in survivors were positively correlated with CD4+ T-cell counts (P = 0.049) and negatively with human immunodeficiency virus RNA loads (P = 0.03). We conclude that PML nonsurvivors had selectively impaired JCV-specific T-cell responses compared to CD4+ T-cell-matched controls and failed to mount JCV-specific antibody responses. JCV-specific T-cell and IgG responses may serve as prognostic markers for patients at risk.

Induction of CD4+ T-cell anergy and apoptosis by activated human B cells

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4555-4564 ◽  
Author(s):  
Theresa Tretter ◽  
Ram K. C. Venigalla ◽  
Volker Eckstein ◽  
Rainer Saffrich ◽  
Serkan Sertel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cell Contact ◽  
Activated T Cells ◽  
Cell Responses ◽  
T Cell Anergy ◽  
Human B Cells ◽  
Cell Anergy

Abstract B cells are well-known mediators of humoral immunity and serve as costimulators in the generation of T cell–mediated responses. In several mouse models, however, it was observed that B cells can also down-regulate immune reactions, suggesting a dual role for B cells. Due to this discrepancy and so far limited data, we directly tested the effects of primary human B cells on activated CD4+ T helper cells in vitro. We found that under optimal costimulation large, activated CD25+ B cells but not small CD25− B cells induced temporary T-cell anergy, determined by cell division arrest and down-regulation of cytokine production. In addition, large CD25+ B cells directly induced CD95-independent apoptosis in a subpopulation of activated T cells. Suppression required direct B-T-cell contact and was not transferable from T to T cell, excluding potential involvement of regulatory T cells. Moreover, inhibitory effects involved an IL-2–dependent mechanism, since decreasing concentrations of IL-2 led to a shift from inhibitory toward costimulatory effects triggered by B cells. We conclude that activated CD25+ B cells are able to costimulate or down-regulate T-cell responses, depending on activation status and environmental conditions that might also influence their pathophysiological impact.

scholarly journals Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 180-185 ◽  
Author(s):  
Fumihiko Tsushima ◽  
Sheng Yao ◽  
Tahiro Shin ◽  
Andrew Flies ◽  
Sarah Flies ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphoid Organs ◽  
Activated T Cells ◽  
Central Tolerance ◽  
Cell Responses ◽  
T Cell Anergy ◽  
Cell Anergy ◽  
Anergic T Cells ◽  
Self Antigen

Although self-reactive T-cell precursors can be eliminated upon recognition of self-antigen presented in the thymus, this central tolerance process is often incomplete, and additional mechanisms are required to prevent autoimmunity. Recent studies indicates that the interaction between B7-H1 and its receptor PD-1 on activated T cells plays an important role in the inhibition of T-cell responses in peripheral organs. Here, we show that, before their exit to the periphery, T cells in lymphoid organs rapidly up-regulate PD-1 upon tolerogen recognition. Ablation of the B7-H1 and PD-1 interaction when T cells are still in lymphoid organs prevents anergy. Furthermore, blockade of B7-H1 and PD-1 interaction could render anergic T cells responsive to antigen. Our results thus reveal previously unappreciated roles of B7-H1 and PD-1 interaction in the control of initiation and reversion of T-cell anergy.

Critical role of JC virus-specific CD4 T-cell responses in preventing progressive multifocal leukoencephalopathy

AIDS ◽  
2003 ◽  
Vol 17 (10) ◽  
pp. 1443-1449 ◽  
Author(s):  
Jacques Gasnault ◽  
Mufide Kahraman ◽  
Marie Ghislaine de Goër de Herve ◽  
Deniz Durali ◽  
Jean-François Delfraissy ◽  
...  
Keyword(s):  
T Cell ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Jc Virus ◽  
Critical Role ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Cell Responses

scholarly journals NFAT4 Is Required for JC Virus Infection of Glial Cells

2006 ◽  
Vol 80 (24) ◽  
pp. 12079-12085 ◽  
Author(s):  
Kate Manley ◽  
Bethany A. O'Hara ◽  
Gretchen V. Gee ◽  
Carl P. Simkevich ◽  
John M. Sedivy ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Glial Cells ◽  
Demyelinating Disease ◽  
Jc Virus ◽  
Human Polyomavirus ◽  
Luciferase Reporter ◽  
Viral Gene ◽  
Activated T Cells ◽  
Immunosuppressed Patients ◽  
Reporter Assays

ABSTRACT The human polyomavirus JC virus (JCV) infects 70% of the population worldwide. In immunosuppressed patients, JCV infection can lead to progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system (CNS). The majority of PML cases occur in the setting of human immunodeficiency virus (HIV) infection, and it has been suggested that the link between HIV and the development of PML is in part related to the production of numerous cytokines in the CNS during HIV infection. To examine the link between the expression of inflammatory cytokines and JCV infection, we tested an anti-inflammatory compound, cyclosporine A (CsA), for its ability to block JCV infection of glial cells. We found that CsA inhibited JCV infection by preventing the activation of the transcription factor nuclear factor of activated T cells 4 (NFAT4). Luciferase reporter assays and chromatin immunoprecipitation assays revealed that NFAT4 directly bound the JCV promoter during infection and was important for the activation of both early and late transcription. In addition, the expression of the JCV early viral gene products increased NFAT activity to further aid viral transcription. The necessity of NFAT for JCV infection suggests that calcium signaling and the activation of NFAT in glial cells are required for JCV infection of the CNS.

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