A Positive Correlation between the Precursor Frequency of Cytotoxic Lymphocytes to Autologous Epstein‐Barr Virus‐Transformed B Cells and Antibody Titer Level against Epstein‐Barr Virus‐Associated Nuclear Antigen in Healthy Seropositive Individuals

Kusunoki, Yoichiro; Huang, Hua; Fukuda, Yasuko; Ozaki, Kyoko; Saito, Mayumi; Hirai, Yuko; Akiyama, Mitoshi

doi:10.1111/j.1348-0421.1993.tb03237.x

Cited by 29 publications

(16 citation statements)

References 28 publications

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“…Although an increase in EBV antibody titers is observed in other EBV-related conditions, a specific increase in anti-EBNA-1 and the anti-EBNA complex without a concomitant increase in anti-VCA is unique to MS and is consistent with the hypothesis of T-cell hyperreactivity because anti-EBNA-1 titers are positively correlated with T-cell function. 14 Overall, the results of these studies are consistent with the hypothesis that elevations in the anti-EBNA complex and anti-EBNA-1 titers in individuals who develop MS occur in the late teenage years or early 20s and may precede the time of onset of MS symptoms by 10 years or more. This hypothesis needs to be tested in further studies including teenagers and young adults.…”

Section: Commentsupporting

confidence: 81%

Epstein-Barr Virus and Multiple Sclerosis

DeLorenze¹,

Munger²,

Lennette³

et al. 2006

Arch Neurol

222

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To determine whether serum titers of anti-Epstein-Barr virus (EBV) antibodies are elevated in blood specimens collected up to 30 years prior to onset of multiple sclerosis (MS).Methods: Individuals with MS were identified among members of the Kaiser Permanente Northern California health plan who participated in the multiphasic examinations administered between 1965 and 1974. Stored serum samples were used to compare anti-EBV antibody titers in 42 individuals who developed MS with agematched and sex-matched controls. Results:The geometric mean titers of antibodies to the Epstein-Barr nuclear antigen (EBNA) complex and its component EBNA-1 were significantly higher in the MS cases when compared with matched controls. The relative risk of MS associated with a 4-fold increase in antibody titers was 2.1 (95% confidence interval, 1.1-3.8) for the EBNA complex and 1.8 (95% confidence interval, 1.1-2.9) for EBNA-1. Elevations of antibody titers to the EBNA complex and EBNA-1 among MS cases first occurred between 15 to 20 years before the onset of symptoms and persisted thereafter. Conclusion:The elevation of anti-EBV titers is probably an early event in the pathogenesis of MS and is unlikely to be the result of an aspecific immune dysregulation.

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Section: Commentsupporting

confidence: 81%

Epstein-Barr Virus and Multiple Sclerosis

DeLorenze¹,

Munger²,

Lennette³

et al. 2006

Arch Neurol

222

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“…Notably, the MS-associated EBNA-1 394-451 region identified encompasses several immunodominant HLA DR-, including potential HLA DRB1*1501-restricted CD4 + Tcell epitopes. 31,32 Moreover, MS patients have elevated frequencies and broader epitope reactivity of EBNA-1-specific CD4 + T-cells 32 , including specific T-cells that cross-reacted with MS-associated myelin proteins. [26][27][28][29][30][31][32][33] We hypothesize that in genetically predisposed individuals 1,34 , EBNA-1 expression evokes a neuroantigen cross-reactive anti-EBNA-1 T-cell response, that upon entry into the CNS recognizes and target cells expressing the cognate neuroantigen.…”

Section: Discussionmentioning

confidence: 99%

No evidence for intrathecal IgG synthesis to Epstein Barr virus nuclear antigen-1 in multiple sclerosis

Jafari

Nierop

Verjans

et al. 2010

Journal of Clinical Virology

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“…37,38 It has also been reported that self-antigen-specific T cells, for any particular protein, are usually present at frequencies of 10 Ϫ5 cells-approximately 100-fold more rare than virusspecific T cells. 39,40 Therefore, when we use approximately 10 7 T cells for stimulation in our assays, it is mathematically possible to generate anywhere from 10 5 to 10 9 antigen-specific T cells in a 1-week expansion. In any case, our data strongly support that AAV-loading-derived CTLs are antigen/HM1.24 specific.…”

Section: Discussionmentioning

confidence: 99%

Testing recombinant adeno-associated virus-gene loading of dendritic cells for generating potent cytotoxic T lymphocytes against a prototype self-antigen, multiple myeloma HM1.24

Chiriva‐Internati

Liu

Weidanz

et al. 2003

Blood

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Recent studies demonstrate that recombinant adeno-associated virus (rAAV)-based antigen loading of dendritic cells (DCs) generates significant and rapid (one stimulation per week) cytotoxic T-lymphocyte (CTL) responses in vitro against viral antigens. As a more extensive analysis of the rAAV system, we have used a selfantigen, HM1.24, expressed in multiple myeloma (MM). Again, with one stimulation, significant major histocompatibility complex (MHC) class 1-restricted, anti-HM1.24-specific CTL killing was demonstrated against MM cells. Furthermore, higher expression of interferon-␥ (IFN-␥) in T cells and higher expression levels of, in order of significance, CD80 (2.6-to 3.8-fold increase), CD86, and CD40 on DCs were also observed. The use of synthetic HM1.24-positive target cells further demonstrated the antigen specificity of these CTLs. There was also no evidence of natural killer cell involvement. These data extend our earlier studies and suggest that the rAAV-loading of DCs may be a particularly good protocol for generating CTLs against self-antigens, which may not otherwise be considered good targets because of their low immunogenicity. We also show that HM1.24 may be an effective antigen for targeting MM. IntroductionMultiple myeloma (MM) is a malignancy characterized by clonal proliferation and accumulation of immunoglobulin-producing plasma cells, which are terminally differentiated B cells. 1 It is important to note that patients who have not responded to high-dose chemotherapy treatment plus autologous stem cell transplantation respond well to allogeneic transplantation and that a graft-versus-myeloma effect can be extremely powerful. 2 These studies suggest that immunologic manipulations might be an appropriate treatment avenue for myeloma, especially if a state of minimal residual disease can be achieved after autotransplantation. In the search for an appropriate anti-MM antigenic target for immunotherapy, the self-antigen HM1.24 protein appears plausible. The HM1.24 antigen is defined by a monoclonal antibody (mAb HM1.24) that appears to be a novel terminal B-cellrestricted antigen 3,4 expressed on tumor cells and on mature immunoglobulin-secreting B cells (plasma cells and lymphoplasmacytoid cells) but not on other cells in the peripheral blood, bone marrow, liver, spleen, kidney, or heart of healthy persons or patients with non-plasma-cell-related malignancies. HM1.24 effectiveness against MM has been demonstrated through tumor cell lysis by mAb and complement. 5,6 The HM1.24 coding sequence is 1 kb long, an ideal size for ligation into any viral vector including adeno-associated virus (AAV). 4 Manipulating antigen-presenting cells, such as dendritic cells (DCs), is a recognized approach toward developing effective immunotherapeutic protocols. DCs are potent, professional antigenpresenting cells that can initiate a primary immune response to antigens by naive T cells. 7 Various protocols for generating DCs in vitro from peripheral blood have recently been developed. These new technologies permit ...

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A Positive Correlation between the Precursor Frequency of Cytotoxic Lymphocytes to Autologous Epstein‐Barr Virus‐Transformed B Cells and Antibody Titer Level against Epstein‐Barr Virus‐Associated Nuclear Antigen in Healthy Seropositive Individuals

Cited by 29 publications

References 28 publications

Epstein-Barr Virus and Multiple Sclerosis

Epstein-Barr Virus and Multiple Sclerosis

No evidence for intrathecal IgG synthesis to Epstein Barr virus nuclear antigen-1 in multiple sclerosis

Testing recombinant adeno-associated virus-gene loading of dendritic cells for generating potent cytotoxic T lymphocytes against a prototype self-antigen, multiple myeloma HM1.24

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