Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epstein-Barr virus (EBV) establishes a life-long persistent infection in most of the human population. In the peripheral blood, EBV is restricted to memory B cells that are resting and express limited genetic information. We have proposed that these memory cells are the site of long-term persistent infection. We now show that memory cells in the tonsil express the genes for EBV nuclear antigen 1 (EBNA1) (from the Qp promoter), latent membrane protein 1 (LMP1), and LMP2a but do not express EBNA2 or the EBNA3s. This pattern of latent gene expression has only been seen previously in EBV-associated tumors such as nasopharyngeal carcinoma, Hodgkin's disease (HD), and T/NK lymphomas. Normal circulating memory B cells frequently reenter secondary lymphoid tissue, where they receive signals essential for their survival. Specifically they require signals from antigen-specific T helper cells and from antigen itself. LMP1 and LMP2 are known to be able to generate these signals in a ligand-independent fashion. We suggest, therefore, that the transcription pattern we have found in latently infected, tonsillar, memory B cells is used because it allows for the expression of LMP1, LMP2a, and EBNA1 in the absence of the immunogenic and growth-promoting EBNA2 and EBNA3 molecules. LMP1 and LMP2a are produced to provide the surrogate rescue and survival signals needed to allow latently infected memory cells to persist, and EBNA1 is produced to allow replication of the viral episome.
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PMID:Tonsillar memory B cells, latently infected with Epstein-Barr virus, express the restricted pattern of latent genes previously found only in Epstein-Barr virus-associated tumors. 1103 74

The Type II EBV malignancies nasopharyngeal carcinoma and EBV(+) Hodgkin's disease express three subdominant antigens, latency membrane protein (LMP) 1, LMP2, and EBNA-1. While adoptive immunotherapy with T cell lines for Type III EBV malignancy (such as posttransplant lymphoma, PTLD, which expresses the immunodominant EBNA-3 antigens) has been used to prevent and treat PTLD, the generation of class I MHC-restricted CTL suitable for the immunotherapy of Type II EBV malignancy is difficult. This is primarily due to the lack of anti-LMP or EBNA-1 CTL activity in many healthy volunteers. We have engineered, by retroviral transduction of the TCR, CTL that have the potential to recognize subdominant EBV latency antigens. Using the SAMEN retroviral vector we demonstrate the ability to transfer CTL activity from a LMP2 peptide-specific CTL clone to a stimulated PBMC population. TCR-transduced PBMC also secrete IFN-gamma upon coculture with LMP2 targets and maintain expression of the transduced TCR during subsequent mitogenic expansion.
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PMID:Retroviral transduction of a T cell receptor specific for an Epstein-Barr virus-encoded peptide. 1116 78

Based upon the success of using polyclonal, Epstein-Barr virus (EBV)-specific CTL lines for the prophylaxis and treatment of patients with post-transplant lymphoproliferative disease (PTLPD), there is now considerable incentive to develop CTL directed against the sub-dominant EBV antigens EBNA1, LMP1 and LMP2, which are expressed by the tumor cells of Hodgkin disease and nasopharyngeal carcinoma. To develop a system for generating LMP2a-specific CTL in vitro, we transfected autologous immature dendritic cells (DC), which had been grown in the absence of serum, with LMP2a RNA in the presence of the cationic lipid DOTAP. This transfection method did not adversely affect the DC in terms of immunophenotyping and they expressed high levels of HLA class I and II and critical costimulatory molecules. These LMP2a(+) DC, as compared to DC which had been transfected with irrelevant RNA, were shown to be highly immunostimulatory in autologous mixed lymphocyte reactions and, importantly, could stimulate the generation of CD8(+) and CD4(+) CTL which exclusively recognized LMP2a-expressing targets. This specific cytotoxicity was confirmed using antibody blocking experiments and cytotoxicity assays of the separated T cell subsets. Using this DC-based system we could also reactivate LMP2a-specific memory in EBV-seropositive donors whose polyclonal CTL response to LCL stimulation did not contain a LMP2a-specific component.
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PMID:The generation of LMP2a-specific cytotoxic T lymphocytes for the treatment of patients with Epstein-Barr virus-positive Hodgkin disease. 1124

Epstein-Barr virus (EBV) is associated with several human malignancies that each show different viral gene expression profiles. In malignancies such as Hodgkin's disease and nasopharyngeal carcinoma only Epstein-Barr nuclear antigen 1 (EBNA1) and varying levels of latent membrane proteins 1 and 2 (LMP1 and -2) are expressed. Since endogenously expressed EBNA1 is protected from CTL recognition, LMP1 and LMP2 are the most likely target antigens for anti-tumor immunotherapy. Therefore, we sought to identify in a systematic way CD8(+) T-cell responses directed against eptitopes derived from LMP1 and LMP2. Using IFNgamma-ELISPOT assays of interferon-gamma release, peripheral blood mononuclear cells (PBMC) of healthy donors were screened with peptide panels (15 mer overlapping by 10) spanning the LMP1 and LMP2 sequences of the prototype EBV strain B95.8. When positive responses were found, CD4(+) or CD8(+) T cells were depleted from donor PBMC to determine the origin of the responder population. We detected CD8(+) T-cell responses to LMP1 in 9/50(18%) donors and to LMP2 in 15/28 (54%) donors. In addition to the already described epitopes, 3 new LMP1- and 5 new LMP2-derived CD8(+) epitopes were identified. In most donors LMP1- and LMP2-specific CD8(+) precursor frequencies were low compared with precursors against immunodominant EBV epitopes from latent (EBNA3A, -3B and -3C) and lytic cycle antigens. These results demonstrate that CD8(+) memory T cell responses to LMP1 and especially to LMP2 do exist in Caucasians, albeit at low levels and could potentially be exploited for therapeutic use.
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PMID:Identification and prevalence of CD8(+) T-cell responses directed against Epstein-Barr virus-encoded latent membrane protein 1 and latent membrane protein 2. 1194 98

Hodgkin's lymphoma (HL) is unusual among human malignancies in that the epidemiology suggests an infectious aetiology. The Epstein-Barr virus (EBV) is associated with a proportion of cases and this association is believed to be causal. In these cases the Hodgkin and Reed-Sternberg (HRS) cells express the EBV-encoded proteins LMP1 and LMP2, which can mimic CD40 and the B cell receptor, respectively, and therefore may play a critical role in facilitating the survival of HRS cells. EBV-associated and non-EBV-associated HL cases have different epidemiological features and recent data suggest that delayed exposure to EBV is a risk factor for the development of EBV-associated HL in young adults. We suggest that HL can be divided into four entities on the basis of EBV status and age at presentation, with three groups of EBV-associated cases and a single group of EBV-negative cases. The aetiology of the latter cases is obscure although involvement of an infectious agent(s) is suspected.
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PMID:Viruses and Hodgkin's lymphoma. 1207 98

Development of an epitope-based vaccination strategy designed to enhance Epstein-Barr virus (EBV)-specific CD8(+) cytotoxic T lymphocytes (CTLs) is increasingly being considered as a preferred approach for the treatment of EBV-associated relapsed Hodgkin disease (HD) and nasopharyngeal carcinoma (NPC). EBV-encoded latent membrane proteins, LMP1 and LMP2, are the only target antigens available for therapeutic augmentation of CTL responses in patients with HD and NPC. Here, we describe preclinical studies using a recombinant poxvirus vaccine that encodes a polyepitope protein comprising 6 HLA A2-restricted epitopes derived from LMP1. Human cells infected with this recombinant polyepitope construct were efficiently recognized by LMP1-specific CTL lines from HLA A2 healthy individuals. Furthermore, immunization of HLA A2/K(b) mice with this polyepitope vaccine consistently generated strong LMP1-specific CTL responses to 5 of the 6 epitopes, which were readily detected by both ex vivo and in vitro assays. More important, this polyepitope vaccine successfully reversed the outgrowth of LMP1-expressing tumors in HLA A2/K(b) mice. These studies provide an important platform for the development of an LMP-based polyepitope vaccine as an immunotherapeutic tool for the treatment of EBV-associated HD and NPC.
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PMID:Therapeutic LMP1 polyepitope vaccine for EBV-associated Hodgkin disease and nasopharyngeal carcinoma. 1246 25

EBV proteins present in the malignant Hodgkin Reed-Sternberg (HR-S) cells of about 40% of patients with Hodgkin's Disease (HD) provide targets for immunotherapy with virus-specific cytotoxic T lymphocytes (CTL). However, Hodgkin tumors use multiple strategies to avoid CTL, including down-regulation of immunodominant EBV antigens, and secretion of cytokines and chemokines such as TGF-beta, that inhibit the activation of CTL and professional antigen-presenting cells (APC). To be effective against this tumor, CTL must resist some or all of these strategies. Thirteen patients with multiply-relapsed HD received EBV-specific CTL, generated ex vivo using the autologous EBV-transformed B cells (LCL) as stimulator cells. After CTL infusion, EBV-specific immunity increased, virus load decreased, CTL homed to sites of malignancy and persisted for up to ten months. Clinically, CTL produced resolution of B symptoms and mixed tumor responses including one complete remission of residual disease remaining after autologous bone marrow transplant. However, no complete remission of bulky disease was achieved. Although LMP2-specific CTL activity could be detected in some of the infused CTL lines, they were present in low frequency. In pre-clinical studies, LMP1 and LMP2-specific CTL could be produced by stimulating PBMC from patients and normal donors with autologous dendritic cells expressing LMP1 or LMP2 from adenoviral vectors. Further, CTL could be rendered resistant to the devastating effects of TGF-beta by transduction with a retrovirus vector expressing a dominant-negative TGF-beta receptor, while transgenic IL-12 could increase the expression of Th1 and decrease that of Th2 cytokines. Future clinical studies will test the efficacy of CTL with improved antigen-specificity and resistance to Hodgkin immune evasion strategies.
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PMID:Immunotherapy for Hodgkin's disease. 1261 Oct 71

Cellular adoptive immunotherapy for virus-associated malignant disease is an attractive strategy, since viral antigens provide targets for specific T lymphocytes. In Epstein-Barr virus (EBV)-positive Hodgkin disease (HD), a limited number of EBV-encoded antigens such as the latent membrane antigens (LMP) 1 and 2 are expressed on the malignant Reed-Sternberg cells. The authors aimed to generate cytotoxic T lymphocytes (CTLs) from patients with relapsed HD by specifically targeting LMP2A. Patients with relapsed HD have highly immunosuppressive tumors and have been heavily pretreated with cytotoxic agents. As a result, monocytes and lymphocytes are numerically reduced and functionally impaired. Approaches using dendritic cells (DCs) as the sole antigen-presenting cell to expand LMP2-specific CTL lines in vitro have proved impractical. The authors now show how small amounts of patient peripheral blood can be used to produce DCs expressing LMP2 after Ad5F35 transduction, and how an initial reactivation of LMP2-specific CTLs can be followed by stimulation with lymphoblastoid cell lines overexpressing LMP2 from the same vector. Large numbers of LMP2-specific cytotoxic lymphocytes are produced that contain both CD4+ and CD8+ T cells (favoring long-term persistence in vivo) and recognize multiple LMP2 epitopes (minimizing the risk of tumor antigen loss variants). This approach is being used in a current clinical trial.
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PMID:The generation and characterization of LMP2-specific CTLs for use as adoptive transfer from patients with relapsed EBV-positive Hodgkin disease. 1523 93

Epstein-Barr virus (EBV) seems to use B cell normal differentiation pathways to establish and maintain a persistent infection. This process is effectively controlled by the immune system through the action of EBV-specific T lymphocytes, so that the lifelong chronic infection is free of complications for most individuals. EBV is, however, associated with several malignancies. 30-50% of Hodgkin's lymphomas (HL) are EBV-associated. In EBV-positive HL, the virus is localized to the tumor cells and is clonal. HL is characterized by a type II form of latency with viral antigen expression limited to EBNA1, LMP1 and LMP2. EBV-positive HL is more frequent in childhood, in older patients and in mixed cellularity cases. EBV association may represent a poor prognosis factor in the elderly. The true contribution of EBV to the pathogenesis of HL remains uncertain, but EBV may provide to abnormal B cells survival signals protecting them from apoptosis. Finally, whatever the role that EBV plays in tumor development, the presence of viral antigens in the malignant cells may represent a target for new therapeutic strategies.
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PMID:[Hodgkin's disease and Epstein-Barr virus]. 1556 22

Epstein Barr virus (EBV)+ Hodgkin's disease (HD) expresses clearly identified tumor antigens derived from the virus and could, in principle, be a target for adoptive immunotherapy with viral antigen-specific T cells. However, like most tumor-associated antigens in immunocompetent hosts, these potential targets are only weakly immunogenic, consisting primarily of the latent membrane protein (LMP)1 and LMP2 antigens. Moreover, Hodgkin tumors possess a range of tumor evasion strategies. Therefore, the likely value of immunotherapy with EBV-specific cytotoxic effector cells has been questioned. We have now used a combination of gene marking, tetramer, and functional analyses to track the fate and assess the activity of EBV cytotoxic T lymphocyte (CTL) lines administered to 14 patients treated for relapsed EBV+ HD. Gene marking studies showed that infused effector cells could further expand by several logs in vivo, contribute to the memory pool (persisting up to 12 mo), and traffic to tumor sites. Tetramer and functional analyses showed that T cells reactive with the tumor-associated antigen LMP2 were present in the infused lines, expanded in peripheral blood after infusion, and also entered tumor. Viral load decreased, demonstrating the biologic activity of the infused CTLs. Clinically, EBV CTLs were well tolerated, could control type B symptoms (fever, night sweats, and weight loss), and had antitumor activity. After CTL infusion, five patients were in complete remission at up to 40 mo, two of whom had clearly measurable tumor at the time of treatment. One additional patient had a partial response, and five had stable disease. The performance and fate of these human tumor antigen-specific T cells in vivo suggests that they might be of value for the treatment of EBV+ Hodgkin lymphoma.
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PMID:Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's disease. 1561 Dec 90


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