scholarly journals Epstein-Barr Virus (EBV)-Specific Cytotoxic T Lymphocytes for the Treatment of Patients With EBV-Positive Relapsed Hodgkin's Disease

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2925-2934 ◽  
Author(s):  
Marie A. Roskrow ◽  
Nobuhiro Suzuki ◽  
Yan-jun Gan ◽  
John W. Sixbey ◽  
Catherine Y.C. Ng ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cytotoxic T Lymphocytes ◽  
Hodgkin's Disease ◽  
Epstein Barr Virus ◽  
Hodgkin’S Disease ◽  
Barr Virus ◽  
Specific Ctls ◽  
Epstein Barr ◽  
Relapsed Disease

Adoptive transfer of Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) is effective prophylaxis and treatment of EBV-positive immunoblastic lymphoma in immunocompromised patients. In 50% of patients with Hodgkin's disease, the tumor cells are EBV antigen-positive and may therefore also be suitable targets for treatment with virus-specific CTLs. However, Hodgkin's disease may produce several inhibitory effects on immune induction and effector function in vivo, which may preclude the generation or effector function of CTLs reactive against EBV viral proteins, including those expressed by the tumor cells. We have investigated whether EBV-specific CTLs could be generated ex vivo from 13 patients with Hodgkin's disease: nine with active relapsed disease and four who were in clinical remission after a first or subsequent relapse. CTL lines were successfully generated from nine of 13 patients (five active disease, four remission). Although these lines had an abnormal pattern of expansion comparable to EBV-specific CTLs generated from normal donors, their phenotype was normal except for reduced expression of the zeta chain of the T-cell receptor (TCR). Their cytotoxicity was also compared to EBV-specific lines generated from normal donors and included activity against LMP2a, one of the three weakly immunogenic viral antigens expressed by Hodgkin's tumor cells. To assess the activity of the CTLs in vivo, they were gene-marked and infused into three patients with multiply relapsed disease. The CTLs persisted for more than 13 weeks postinfusion and retained their potent antiviral effects in vivo, thereby enhancing the patient immune response to EBV. This approach may therefore have value in the treatment of EBV-positive Hodgkin's disease.

Effect of Epstein-Barr Virus Infection on Response to Chemotherapy and Survival in Hodgkin’s Disease

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 442-447 ◽  
Author(s):  
Paul G. Murray ◽  
Lucinda J. Billingham ◽  
Hassan T. Hassan ◽  
Joanne R. Flavell ◽  
Paul N. Nelson ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Hodgkin's Disease ◽  
Epstein Barr Virus ◽  
Remission Rate ◽  
Hodgkin’S Disease ◽  
Clinical Stage ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Response To Chemotherapy ◽  
Epstein Barr

Abstract We have analyzed paraffin sections from 190 patients with histologically confirmed Hodgkin’s disease (HD) for the presence of Epstein-Barr virus (EBV) using in situ hybridization to detect the EBV-encoded Epstein-Barr virus early RNAs (EBERs) and immunohistochemistry to identify latent membrane protein-1 (LMP1) expression. EBV was present in the tumor cells in 51 HD cases (27%) and was mainly confined to the mixed cellularity and nodular sclerosis subtypes. There was no difference between EBV-positive and EBV-negative HD patients with regard to age, clinical stage, presentation, and the number of alternating chemotherapy cycles of ChIVPP and PABIOE received. The complete remission rate after study chemotherapy was 80% in EBV-positive patients versus 69% in EBV-negative patients (P = .05). The 2-year failure-free survival rate was significantly better for EBV-positive patients when compared with the EBV-negative HD group (P = .02). Although 2-year and 5-year overall survival rates were better for EBV-positive HD patients, the differences were not statistically significant (P = .18 andP = .40, respectively). In conclusion, the results confirm the favorable prognostic value of EBV in the tumor cells of HD patients and suggest important differences in response to chemotherapy between EBV-positive and EBV-negative patients.

Effect of Epstein-Barr Virus Infection on Response to Chemotherapy and Survival in Hodgkin’s Disease

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 442-447
Author(s):  
Paul G. Murray ◽  
Lucinda J. Billingham ◽  
Hassan T. Hassan ◽  
Joanne R. Flavell ◽  
Paul N. Nelson ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Hodgkin's Disease ◽  
Epstein Barr Virus ◽  
Remission Rate ◽  
Hodgkin’S Disease ◽  
Clinical Stage ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Response To Chemotherapy ◽  
Epstein Barr

We have analyzed paraffin sections from 190 patients with histologically confirmed Hodgkin’s disease (HD) for the presence of Epstein-Barr virus (EBV) using in situ hybridization to detect the EBV-encoded Epstein-Barr virus early RNAs (EBERs) and immunohistochemistry to identify latent membrane protein-1 (LMP1) expression. EBV was present in the tumor cells in 51 HD cases (27%) and was mainly confined to the mixed cellularity and nodular sclerosis subtypes. There was no difference between EBV-positive and EBV-negative HD patients with regard to age, clinical stage, presentation, and the number of alternating chemotherapy cycles of ChIVPP and PABIOE received. The complete remission rate after study chemotherapy was 80% in EBV-positive patients versus 69% in EBV-negative patients (P = .05). The 2-year failure-free survival rate was significantly better for EBV-positive patients when compared with the EBV-negative HD group (P = .02). Although 2-year and 5-year overall survival rates were better for EBV-positive HD patients, the differences were not statistically significant (P = .18 andP = .40, respectively). In conclusion, the results confirm the favorable prognostic value of EBV in the tumor cells of HD patients and suggest important differences in response to chemotherapy between EBV-positive and EBV-negative patients.

scholarly journals In situ demonstration of Epstein-Barr virus small RNAs (EBER 1) in acquired immunodeficiency syndrome-related lymphomas: correlation with tumor morphology and primary site

Blood ◽  
1993 ◽  
Vol 82 (2) ◽  
pp. 619-624 ◽  
Author(s):  
SJ Hamilton-Dutoit ◽  
M Raphael ◽  
J Audouin ◽  
J Diebold ◽  
I Lisse ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Hodgkin's Disease ◽  
Epstein Barr Virus ◽  
Hodgkin’S Disease ◽  
Large Cell ◽  
Barr Virus ◽  
Acquired Immunodeficiency ◽  
Epstein Barr ◽  
Immunodeficiency Syndrome

Abstract Some acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARLs) are infected with Epstein-Barr virus (EBV), although the frequency and importance of this association is disputed. Using paraffin section RNA in situ hybridization (ISH) with digoxigenin-labeled riboprobes, we screened 16 central nervous system (CNS) non-Hodgkin's lymphomas (NHLs), 101 systemic NHLs, and 11 Hodgkin's disease cases arising in human immunodeficiency virus-seropositive individuals for EBV-encoded small RNA (EBER 1) expression, an EBV gene product transcribed in abundance during latent infection. Tumor cells contained EBV in 85 of 128 ARLs (66%), but infection rates differed with lymphoma type. EBER 1 was expressed in tumor cells in 11 of 11 Hodgkin's disease cases (100%), 15 of 16 CNS NHLs (94%), and 46 of 60 systemic immunoblast- rich/large-cell lymphomas (77%), but in only 12 of 35 Burkitt-type (small noncleaved cell) (34%) and 1 of 6 monomorphic centroblastic (diffuse large noncleaved cell) (17%) lymphomas. In most EBV-positive ARLs, all recognizable viable tumor cells expressed EBER 1. We conclude that (1) EBV infects tumor cells in all AIDS-related Hodgkin's disease cases, in virtually all primary CNS ARLs, and in most systemic immunoblast-rich/large-cell ARLs; (2) only a minority of Burkitt-type and monomorphic centroblastic lymphomas are associated with EBV; and (3) EBER-ISH is ideal for the histopathologic detection of latent EBV in routine tissue specimens.

scholarly journals In situ demonstration of Epstein-Barr virus small RNAs (EBER 1) in acquired immunodeficiency syndrome-related lymphomas: correlation with tumor morphology and primary site

Blood ◽  
1993 ◽  
Vol 82 (2) ◽  
pp. 619-624 ◽  
Author(s):  
SJ Hamilton-Dutoit ◽  
M Raphael ◽  
J Audouin ◽  
J Diebold ◽  
I Lisse ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Hodgkin's Disease ◽  
Epstein Barr Virus ◽  
Hodgkin’S Disease ◽  
Large Cell ◽  
Barr Virus ◽  
Acquired Immunodeficiency ◽  
Epstein Barr ◽  
Immunodeficiency Syndrome

Some acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARLs) are infected with Epstein-Barr virus (EBV), although the frequency and importance of this association is disputed. Using paraffin section RNA in situ hybridization (ISH) with digoxigenin-labeled riboprobes, we screened 16 central nervous system (CNS) non-Hodgkin's lymphomas (NHLs), 101 systemic NHLs, and 11 Hodgkin's disease cases arising in human immunodeficiency virus-seropositive individuals for EBV-encoded small RNA (EBER 1) expression, an EBV gene product transcribed in abundance during latent infection. Tumor cells contained EBV in 85 of 128 ARLs (66%), but infection rates differed with lymphoma type. EBER 1 was expressed in tumor cells in 11 of 11 Hodgkin's disease cases (100%), 15 of 16 CNS NHLs (94%), and 46 of 60 systemic immunoblast- rich/large-cell lymphomas (77%), but in only 12 of 35 Burkitt-type (small noncleaved cell) (34%) and 1 of 6 monomorphic centroblastic (diffuse large noncleaved cell) (17%) lymphomas. In most EBV-positive ARLs, all recognizable viable tumor cells expressed EBER 1. We conclude that (1) EBV infects tumor cells in all AIDS-related Hodgkin's disease cases, in virtually all primary CNS ARLs, and in most systemic immunoblast-rich/large-cell ARLs; (2) only a minority of Burkitt-type and monomorphic centroblastic lymphomas are associated with EBV; and (3) EBER-ISH is ideal for the histopathologic detection of latent EBV in routine tissue specimens.

scholarly journals Distribution and phenotype of Epstein-Barr virus-harboring cells in Hodgkin's disease

Blood ◽  
1992 ◽  
Vol 80 (2) ◽  
pp. 484-491 ◽  
Author(s):  
H Herbst ◽  
E Steinbrecher ◽  
G Niedobitek ◽  
LS Young ◽  
L Brooks ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Hodgkin's Disease ◽  
Epstein Barr Virus ◽  
Hodgkin’S Disease ◽  
Lymphoid Cells ◽  
Small Cells ◽  
Barr Virus ◽  
Epstein Barr

Distribution and phenotype of Epstein-Barr virus (EBV)-harboring cells were determined in Hodgkin's disease (HD) biopsies by in situ hybridization with [35S]-labeled RNA probes specific for the small EBV- encoded nuclear RNAs, EBER1 and EBER2, in some instances preceded by immunohistology for CD20, CD30, CD45RO, and CD68 antigens, the T-cell receptor beta-chain, and latent membrane antigen (LMP) of EBV. Twenty- three of 46 HD cases displayed EBER transcripts in all Hodgkin and Reed- Sternberg (H-RS) cells, and 18 of these cases showed LMP expression exclusively in neoplastic cells. EBER+ small reactive cells were present in 39 cases in low numbers, and in three cases in abundance. Thus, presence of H-RS cells with or without LMP expression was not accompanied by an unrestricted proliferation of reactive EBER+/LMP- lymphoid cells in the majority of HD patients. Simultaneous in situ hybridization with [35S]-labeled immunoglobulin light chain (IgLC) gene probes and nonisotopically labeled EBER probe showed a phenotype of mature B lymphocytes and a polyclonal composition for a large proportion of the EBER+ small cells. However, in contrast to noninfected cells, CD20 expression was not detectable in many of these cells, which may indicate downregulation of certain differentiation antigens in latently EBV-infected small lymphoid cells in vivo.

scholarly journals Distribution and phenotype of Epstein-Barr virus-harboring cells in Hodgkin's disease

Blood ◽  
1992 ◽  
Vol 80 (2) ◽  
pp. 484-491 ◽  
Author(s):  
H Herbst ◽  
E Steinbrecher ◽  
G Niedobitek ◽  
LS Young ◽  
L Brooks ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Hodgkin's Disease ◽  
Epstein Barr Virus ◽  
Hodgkin’S Disease ◽  
Lymphoid Cells ◽  
Small Cells ◽  
Barr Virus ◽  
Epstein Barr

Abstract Distribution and phenotype of Epstein-Barr virus (EBV)-harboring cells were determined in Hodgkin's disease (HD) biopsies by in situ hybridization with [35S]-labeled RNA probes specific for the small EBV- encoded nuclear RNAs, EBER1 and EBER2, in some instances preceded by immunohistology for CD20, CD30, CD45RO, and CD68 antigens, the T-cell receptor beta-chain, and latent membrane antigen (LMP) of EBV. Twenty- three of 46 HD cases displayed EBER transcripts in all Hodgkin and Reed- Sternberg (H-RS) cells, and 18 of these cases showed LMP expression exclusively in neoplastic cells. EBER+ small reactive cells were present in 39 cases in low numbers, and in three cases in abundance. Thus, presence of H-RS cells with or without LMP expression was not accompanied by an unrestricted proliferation of reactive EBER+/LMP- lymphoid cells in the majority of HD patients. Simultaneous in situ hybridization with [35S]-labeled immunoglobulin light chain (IgLC) gene probes and nonisotopically labeled EBER probe showed a phenotype of mature B lymphocytes and a polyclonal composition for a large proportion of the EBER+ small cells. However, in contrast to noninfected cells, CD20 expression was not detectable in many of these cells, which may indicate downregulation of certain differentiation antigens in latently EBV-infected small lymphoid cells in vivo.

scholarly journals Frequent expression of interleukin-10 by Epstein-Barr virus-harboring tumor cells of Hodgkin's disease

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2918-2929 ◽  
Author(s):  
H Herbst ◽  
HD Foss ◽  
J Samol ◽  
I Araujo ◽  
H Klotzbach ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Hodgkin's Disease ◽  
Epstein Barr Virus ◽  
Hodgkin’S Disease ◽  
Interleukin 10 ◽  
Cell Mediated Immunity ◽  
Barr Virus ◽  
Ebv Infection ◽  
Infected Cells ◽  
Epstein Barr

Tumor cells of Epstein-Barr virus (EBV)-associated Hodgkin's disease (HD) express the viral protein, latent infection membrane protein-1 (LMP1), but evade cytotoxic responses normally directed at this antigen. We tested whether local production of the immunoregulatory interleukins (IL)-4 and -10 may have a role in this process. IL-4 RNA was not detectable in any of the HD cases. By contrast, isotopic in situ hybridization and correlation with the presence of EBV gene products showed significantly higher proportions of cases with IL-10 expressing tumor cells in LMP1-positive (17 of 26, 66%) as compared with LMP1-negative HD cases (six of 37, 16%). Absence of EBV BCRF1 RNA indicated that the transcripts originated from the cellular IL-10 gene. Similarly, an association between IL-10 expression and EBV-infection of tumor cells was found in AIDS-related malignant non-Hodgkin lymphomas (ARL). Very small proportions of EBV-infected cells, mainly blasts, expressed IL-10 in infectious mononucleosis tonsils. Thus, although not entirely exclusive to EBV-positive cases, IL-10 expression is frequently associated with EBV-infection in HD and ARL and appears to be upregulated by EBV, most likely through LMP1. In view of the established inhibitory effects of IL-10 on cell mediated immunity, it is suggested that IL-10 expression may contribute to evasion of LMP1- positive cells from cytotoxicity directed at viral antigens.

scholarly journals Epstein-Barr virus (EBV)-associated lymphoproliferations in severe combined immunodeficient mice transplanted with Hodgkin's disease lymph nodes: implications of EBV-positive bystander B lymphocytes rather than EBV-infected Reed-Sternberg cells

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2435-2442 ◽  
Author(s):  
F Meggetto ◽  
C Muller ◽  
S Henry ◽  
J Selves ◽  
B Mariame ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
B Lymphocytes ◽  
Hodgkin's Disease ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
Hodgkin’S Disease ◽  
Scid Mice ◽  
Barr Virus ◽  
Epstein Barr

To establish an in vivo model for the study of Hodgkin's disease and Reed-Sternberg (RS) cells, 25 lymph node tissue samples involved by Hodgkin's disease were grafted into severe combined immunodeficiency (SCID) mice. Ten Epstein-Barr virus (EBV)-associated tumors were obtained in SCID mice. EBV-positive tumors growing in SCID mice were correlated with the presence of EBV-positive nonneoplastic B cells in patient tumors (90% v 26.6%; P>.01) and was independent of the EBV status of RS cells. Our results suggested that EBV-positive tumors growing in SCID mice originated from normal EBV-positive small lymphocytes (bystander B lymphocytes). We also compared the characteristics of these tumors with those obtained after transplantation of 15 non-Hodgkin's lymphoma and four reactive lymph nodes. The latent period to observe a growing tumor in SCID mice was similar between the two groups (12.86 +/- 5.59 weeks for Hodgkin's disease v 13.6 +/- 5.36 weeks for non-Hodgkin's lymphoma and reactive lymph nodes). The relatively high number of EBV-positive small lymphocytes detected in Hodgkin's disease and T-cell lymphoma compared with B-cell lymphoma may account for the greater percentage of EBV- positive tumors obtained in SCID mice. Our results show that SCID mice do not provide the growth conditions that are required for in vivo growth of RS cells. We noted in some SCID tumors, the presence of binucleated and/or multinucleated giant cells resembling RS cells. However, the presence of such cells was not restricted to mice grafted with lymph nodes involved by Hodgkin's disease. We postulate that in previous reports, cells resembling RS cells were just binucleated EBV- positive lymphoma blastoid cells rather than actual RS cells.

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