The relationships between Epstein-Barr virus latent membrane protein 1 and regulatory T cells in Hodgkin's lymphoma

Marshall, Neil A.; Culligan, Dominic; Tighe, Jane; Johnston, Peter; Barker, Robert N.; Vickers, Mark A.

doi:10.1016/j.exphem.2007.01.030

Cited by 41 publications

(37 citation statements)

References 43 publications

(57 reference statements)

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“…In contrast, T cells of CD4 ϩ CD25 ϩ regulatory phenotype were not apparently increased ( Figure 2B right), whereas they are reported to play an important role in the pathogenesis of HL. [17][18][19][20][21] We evaluated PD-1 and Foxp3 expression concurrently in 9 other HL patients ( Figure 2C), and they were shown to be mostly independent of each other. This result is similar to the result of tumor-infiltrating T cells studied in B-NHL.…”

Section: Resultsmentioning

confidence: 99%

PD-1–PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma

Yamamoto

Nishikori

Kitawaki

et al. 2008

Blood

356

238

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IntroductionProgrammed death-1 (PD-1), a member of the CD28 costimulatory receptor superfamily, inhibits T-cell activity by providing a second signal to T cells in conjunction with signaling through the T-cell receptor. 1 To date, B7-H1 and B7-DC have been identified as ligands for PD-1 (PD-Ls). During chronic viral infection, PD-1 is selectively up-regulated by the exhausted T cells, and blockade of this pathway restores CD8 ϩ T-cell function and reduces viral load. 2 This signaling system has been recently highlighted in the research of human immunodeficiency virus (HIV) infection. [3][4][5][6] In addition, PD-1 is indicated to be involved in the evasion of tumor immunity. [7][8][9][10] Hodgkin lymphoma (HL) is characterized by massive reactive infiltrates surrounding Hodgkin/Reed-Sternberg (H/RS) cells. HL patients are well recognized as having defective cellular immunity; they are susceptible to bacterial, fungal, and viral infections, and in vitro studies show depressed T-cell proliferation and reduced synthesis of Th1 cytokines. 11 We report here that PD-1-PD-L signaling system is operative in patients with HL, and tumor-infiltrating T cells around H/RS cells seem to be kept in balance by this inhibitory signaling. Our findings illuminate the mechanism for deficient cellular immunity observed in HL patients, and propose a potentially effective immunologic strategy for the treatment of HL. Methods Cell lines and clinical sample preparationThe following cell lines were described previously 12,13 : HL cell lines KM-H2, L428, and HDLM-2; anaplastic large cell lymphoma (ALCL) cell line DEL; follicular lymphoma cell line FL-218; diffuse large B-cell lymphoma (DLBCL) cell line KIS-1; Burkitt lymphoma cell lines Daudi, Raji, Middle 91, Tree 92, and Ramos; adult T-cell leukemia/lymphoma cell line HUT 102; and acute T-cell leukemia cell line Jurkat. LCL-OHN is an Epstein-Barr virus (EBV)-transformed lymphoblastoid B-cell line (LCL). Peripheral blood samples were collected from 19 HL patients, 12 B-NHL patients, and 11 healthy volunteers after informed consent was obtained in accordance with the Declaration of Helsinki. This study is approved by the institutional review board of Kyoto University. After removing red blood cells using ACK lysis buffer, leukocytes were subjected to flow cytometry. For immunohistochemistry, tissue specimens were snap-frozen in OCT compound (TissueTek, Tokyo, Japan) and stored at Ϫ80°C. Reverse transcription-polymerase chain reaction, flow cytometry, and immunohistochemistryTotal RNA was isolated from cells with Trizol (Invitrogen, Carlsbad, CA), and cDNA was synthesized using MultiScribe Reverse Transcriptase (Applied Biosystems, Foster City, CA). PCR assays were performed by the conventional method using Taq polymerase (TaKaRa Biotechnology, Shiga, Japan). For flow cytometry, cells were analyzed on a FACScan (Becton Dickinson, Mansfield, MS). The following antibodies were used: PEconjugated B7-H1 and B7-DC (eBioscience, San Diego, CA), FITC-PD-1 (BD Pharmingen, San Diego, CA), PC5-CD4 a...

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Section: Resultsmentioning

confidence: 99%

PD-1–PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma

Yamamoto

Nishikori

Kitawaki

et al. 2008

Blood

356

238

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“…Notably, amplification of the PD-L1 and PD-L2 genes at 9p24 is common in nodular sclerosis HL (Green et al 2010), while the PD-L1 gene can also be deregulated as a result of a reciprocal translocation involving CIITA in a proportion of classical HL cases (Steidl et al 2011). In the context of EBV-positive HL, EBV upregulates the expression of numerous immunosuppressive factors, including IL10, galectin-1 and TGFβ, all of which can inhibit cytotoxic T-cell responses (Marshall et al 2007;Juszczynski et al 2007;Gandhi et al 2007), while LMP1 has also been reported to induce Interactions between EBV and cellular environment in HL. LMP1 contributes to the highly suppressive immune environment of HL through several different mechanisms.…”

Section: Ebv and The Hl Microenvironmentmentioning

confidence: 98%

Contribution of the Epstein-Barr Virus to the Pathogenesis of Hodgkin Lymphoma

Murray

Bell

2015

Current Topics in Microbiology and Immunology

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The morphology of the pathognomonic Hodgkin and Reed-Sternberg cells (HRS) of Hodgkin lymphoma was described over a century ago, yet it was only relatively recently that the B-cell origin of these cells was identified. In a proportion of cases, HRS cells harbour monoclonal forms of the B lymphotropic Epstein-Barr virus (EBV). This review summarises current knowledge of the pathogenesis of Hodgkin lymphoma with a particular emphasis on the contribution of EBV.

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“…Moreover, NPC cells by expressing FasL or IL-10, and the malignant Reed-Stenberg cells in HL lesions by producing IL-10, TGFb, and CCL17 (TARC), create an environment that promotes Th2 at the expense of Th1 responses [45]. Furthermore, it has been demonstrated in vitro that T lymphocytes infiltrating HL are capable of suppressing PBMC activity through IL-10 release, cell-to-cell interaction and CTLA-4 expression [46]. In the attempt to overcome the inhibitory barriers for their action, T cells have been genetically modified to produce IL-12, a cytokine promoting the Th1 anti-tumor response, or to express a TGFb receptor dominant negative mutant [47,48].…”

Section: Moving Towards All Ebv-associated Diseasesmentioning

confidence: 98%

Immunotherapy for EBV-associated malignancies

et al. 2011

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Since 1995 to date, more than 250 patients with EBV-related diseases received virus-specific CTL. Cell therapy proved to be safe and effective, and achieved some complete remissions also in patients who failed all previous standard treatments. The first clinical results with EBV-specific CTL were obtained for both prophylaxis and treatment of post-transplant lymphoproliferative disease arising in stem cell transplant or solid organ transplant recipients. Based on such encouraging results, the same approach was then extended to other EBV-related diseases, namely Hodgkin's lymphoma, nasopharyngeal carcinoma, and chronic active infection. Nowadays, the modification of the CTL generation protocols and the introduction of new specificities into EBV-specific CTL lines by chimeric antigen receptor transfer allow targeting other viral infections and also non-EBV related malignancies. Aim of this review is to summarize clinical results obtained thus far in adoptive cell therapy approaches with EBV-specific CTL. Moreover, by analyzing ongoing clinical trials, we also provide some insights on the potential future of a successful and paradigmatic history.

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The relationships between Epstein-Barr virus latent membrane protein 1 and regulatory T cells in Hodgkin's lymphoma

Cited by 41 publications

References 43 publications

PD-1–PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma

PD-1–PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma

Contribution of the Epstein-Barr Virus to the Pathogenesis of Hodgkin Lymphoma

Immunotherapy for EBV-associated malignancies

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