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

Hodgkin's lymphoma is characterized by the combination of Reed-Sternberg (R-S) cells and a prominent inflammatory cell infiltrate. One of the intriguing questions regarding this disease is what is causing the influx of T lymphocytes into the involved tissues. We applied the serial analysis of gene expression (SAGE) technique on the Hodgkin's lymphoma-derived cell line L428 and on an Epstein-Barr virus (EBV)-transformed lymphoblastoid B-cell line. A frequently expressed tag in L428 corresponded to the T-cell-directed CC chemokine TARC. Reverse transcription polymerase chain reaction analyses demonstrated expression of TARC in nodular sclerosis (NS) and mixed cellularity (MC) classical Hodgkin's lymphomas but not in NLP Hodgkin's lymphoma, anaplastic large-cell lymphomas, and large-B-cell lymphomas with CD30 positivity. Two of five cases of T-cell-rich B-cell lymphoma (TCRBCL) were TARC positive. RNA in situ hybridization (ISH) showed a strong signal for TARC in the cytoplasm of R-S cells, and immunohistochemical staining confirmed the presence of the TARC protein in the R-S cells of NS and MC Hodgkin's lymphomas. The lymphocytic and histiocytic (L&H)-type cells of nodular lymphocyte predominance Hodgkin's lymphoma and the neoplastic cells of non-Hodgkin's lymphomas with the exception of two cases of TCRBCL did not stain for TARC. TARC is known to bind to the CCR4 receptor, which is expressed on activated Th2 lymphocytes. The immunophenotype of lymphocytes surrounding R-S cells is indeed Th2-like, and by RNA ISH these lymphocytes showed a positive signal for the chemokine receptor CCR4. The findings suggest that production of TARC by the R-S cells may explain the characteristic T-cell infiltrate in classical Hodgkin's lymphoma.
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PMID:High expression of the CC chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltratein Hodgkin's lymphoma. 1036 93

Chemokine receptors mediate the migration of lymphocytes through the binding of soluble ligands, and their expression is differentially regulated in lymphocyte subsets. The pattern of chemokine receptor expression in T-cell non-Hodgkin lymphoma has not been previously studied. Using a panel of mouse monoclonal antibodies, we studied the immunohistochemical expression of the Th1-associated chemokine receptor CXCR3 in 141 patients with T-cell lymphoma, and we studied the receptors CCR4 and CCR5 and some of their ligands in a subset of these tumors. Expression of CXCR3 was typical of the smaller T cells in angioimmunoblastic lymphoma (15 of 18 patients), angiocentric lymphoma (3 of 3 patients), histiocyte-rich tumors (4 of 5 patients), and unspecified T-cell lymphomas (17 of 39 patients). CXCR3 expression was seen in only 1 of 15 patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma. In contrast, all ALK-positive tumors showed diffuse reactivity for the Th2-associated receptor CCR4 (5 of 5 patients). CCR4 expression was also a consistent feature of the large-cell transformation of mycosis fungoides. CCR5 expression showed no consistent association with any T-cell tumor type. The chemokines Mig (CXCR3 ligand), TARC (CCR4 ligand), and MCP-2 (CCR5 ligand) were detected in intratumoral blood vessels and histiocytes. Mig was also coexpressed by a subset of CXCR3-positive tumor cells in 6 of 20 lymphomas. MCP-2 was highly expressed in stromal cells in 3 patients with nodal involvement by cutaneous T-cell lymphoma. As with normal T-cell subsets, we demonstrated that there is frequent differential expression of chemokine receptors in T-cell tumors, which may explain, in part, the distinctive patterns of spread in different tumor subtypes. (Blood. 2000;96:685-690)
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PMID:Expression pattern of T-cell-associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma. 1088 35

Chemokines are a family of 8-10 kDa proteins with a wide range of biological activities including the regulation of leukocyte trafficking, modulation of haemopoietic cell proliferation and adhesion to extracellular matrix molecules. Using a panel of chemokine receptor-specific monoclonal antibodies (MoAb) in a multicolour flow cytometry approach we analysed the expression of the lymphocyte-associated chemokine receptors CXCR4, CXCR5, CCR5 and CCR6 in B cell acute lymphoblastic leukaemia (precursor B-ALL; six cases), B cell chronic lymphocytic leukaemia (B-CLL; 31 cases), multiple myeloma (10 cases), mantle cell lymphoma (MCL, four cases), follicular lymphoma (FL, three cases) and hairy cell leukaemia (HCL, five cases). We demonstrate that CXCR4, CXCR5 and CCR6 are differentially expressed in these B lymphoproliferative disorders depending on the maturational stage of the malignant B cell population investigated. In particular, we found that CXCR4 is strongly expressed on immature ALL blasts whereas no surface immunoreactivity for CXCR5, CCR5 and CCR6 was observed. By contrast, non-Hodgkin's lymphomas (NHLs) corresponding to more mature peripheral B cell subsets (ie B-CLL and MCL) exhibited high expression levels of CXCR4 and CXCR5. Analysis of terminally differentiated myeloma cells revealed a down-regulation of CXCR4, CXCR5 and CCR6. CCR5, which is not expressed in normal B cells, was also absent from the majority of NHLs. However, CCR5 staining was seen in three of five cases of HCL, representing the first example of cross-lineage aberrant chemokine receptor expression in malignant haemopoietic cells.
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PMID:Differential expression of chemokine receptors in B cell malignancies. 1136 35

Chemokines and chemokine receptors are key mediators for regulating cell traffic and positioning in both homeostatic and inflammatory conditions. It is also presumed that chemokines and their receptors are likely to play a critical role in the localization of malignant hematopoietic cells in their target organs. This study analyzed chemokine and chemokine receptor expression in several Hodgkin disease (HD)-derived cell lines and in HD tumors. All HD-derived cell lines expressed functional CCR7 and CXCR4 receptors. CCR7 up-regulation was mediated by constitutive NF-kappaB activity. Lymphoid tissues in HD revealed differential expression levels of CCR7, CXCR4, and CXCR5, depending on the distinct subtypes of HD. HD of the classical subtypes, predominantly located in the interfollicular zone, showed strong CCR7 and CXCR4 expression and moderate CXCR5 expression. In contrast, the nodular lymphocyte-predominant HD (NLP) subtype, regularly associated with follicular structures, exhibited no CCR7 reactivity but abundant CXCR4 staining. Their respective chemokine ligands showed marked expression by reactive cells within the tumors of classical HD and outside of the tumor nodules in NLPHD. Functionally, such differential chemokine receptor expression might contribute to specific localization and confinement of neoplastic cells within the target organs in the distinct HD entities.
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PMID:Up-regulation of the chemokine receptor CCR7 in classical but not in lymphocyte-predominant Hodgkin disease correlates with distinct dissemination of neoplastic cells in lymphoid organs. 1183 Apr 55

Several recent studies have revealed important contributions of chemokines and their receptors to the development and progression of both hematopoietic and nonhematopoietic neoplasms. The chemokine receptor CCR6 is unusual in that it mediates leukocyte chemotaxis in response to a single chemokine, CCL20 (macrophage inhibitory factor-3alpha), as well as in response to a family of antimicrobial peptides termed "beta-defensins." CCR6 is critical for mucosal immunity, and expression of the receptor is tightly regulated on hematopoietic cells. Here we characterize the expression of CCR6 on B cells and B-cell non-Hodgkin's lymphomas. We demonstrate that CCR6 expression is limited to cells comprising the mantle and marginal zones of the secondary lymphoid tissues and serves to identify the majority of mantle cell, marginal zone, and mucosa-associated lymphoid tissue lymphomas. Furthermore, we show that CCR6 serves as a functional chemokine receptor when expressed by neoplastic cells. Finally, we establish that the cognate ligand for CCR6 is present on mucosal epithelium infiltrated by neoplastic cells in select extranodal lymphomas. Thus, CCR6 is a useful new marker identifying a subset of B-cell non-Hodgkin's lymphomas and likely contributes to the localization of select extranodal lymphomas at mucosal sites.
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PMID:CCR6 is a functional chemokine receptor that serves to identify select B-cell non-Hodgkin's lymphomas. 1251 92

Chemokines regulate both homeostatic leukocyte recirculation and trafficking to sites of infection and inflammation. Apart from the well-established physiological functions, chemokines receive growing interest for their role in pathophysiological processes such as autoimmune diseases, cancer, and allograft rejection. The chemokine receptor CCR7, which is responsible for directing T cells, B cells, and dendritic cells (DCs) into secondary lymphoid organs and their precise positioning therein, has already been implicated in lymphoid organ infiltration by neoplastic cells and the localization of metastasis formation. We have shown that the differential expression of CCR7 by neoplastic cells in two entities of Hodgkin's disease (HD), classic HD (cHD) and the nodular lymphocyte predominant HD (NLPHD), may account for the differences observed in tumor cell dissemination within the affected lymph nodes. Because of the prominent role of the chemokine receptors CCR7 and CXCR5 in lymphocyte homing to secondary lymphoid organs, we hypothesized that they may also be involved in the action of FTY720, a synthetic immunosuppressant inducing lymphopenia. By using CXCR5 and CCR7 knockout mice, we have tested for a possible function of these receptors in the FTY720-induced migration of lymphocytes into Peyer's patches (PPs) and peripheral lymph nodes (PLNs). Lymphopenia is noticeably delayed in mice lacking CCR7, whereas CXCR5 knockout mice show a significant reduction of lymphocyte accumulation in secondary lymphoid organs that are infrequently present in these mice. However, FTY720-induced lymphocyte sequestration appears to be essentially independent of CCR7 and CXCR5.
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PMID:Role of homeostatic chemokine and sphingosine-1-phosphate receptors in the organization of lymphoid tissue. 1272 29

Classical Hodgkin lymphoma (HL) is characterized by the presence of Hodgkin and Reed-Sternberg cells (H&RS) and a prominent lymphocytic infiltration. We previously reported Hodgkin-like adult T-cell leukemia/lymphoma (HL-like ATLL) (new WHO classification). Various CXC and CC chemokines are expressed on H&RS cells and the relationships between chemokines and the chemokine receptor (R) are thought to be important for selectivity of local immunity of Th1 and Th2 T cells. To clarify the role of T-cell immunity in classical HL and Hodgkin-like ATLL, we performed gene expression profiling (chemokine, chemokine R and cytokine DNA chips) in 12 cases [classical HL, 8 cases [mixed cellularity (MC) type, 4; nodular sclerosis (NS) type, 4]; Hodgkin-like ATLL, 4 cases] and immunohistochemical staining in 29 cases (MC, 10; NS, 10; Hodgkin-like ATLL, 9). EBV-infected H&RS cells were detected in 9 of 10 cases of HL MC, 5 of 9 of HL-like ATLL and 2 of 10 HL NS. T-cell-directed chemokine thymus- and activation-regulated chemokine (TARC)- and/or macrophage-derived chemokine (MDC)-positive H&RS cells were detected in all 20 cases of HL MC and HL NS but only in 5 of 9 cases of HL-like ATLL. Interferon-gamma-inducible protein-10 (IP10)- and monokine induced by interferon-gamma (MIG)-positive H&RS cells were detected in all 10 HL MC but only in 5 of 10 cases of HL NS and 2 of 9 cases of HL-like ATLL. However, 2 of 5 cases of HL-like ATLL with EBV infection and 2 of 2 HL NS with EBV had IP10/MIG-positive H&RS cells. The chemokine expressions in H&RS cells seemed to be associated with EBV infection rather than histologic subtypes. In the DNA chip expression analysis, classical HL and HL-like ATLL had a mixed Th1/Th2-type profile, and HL MC (EBV-positive) and HL NS (EBV-negative) were differentially clustered. However, 2 cases of HL-like ATLL clustered with HL MS and the other 2 cases of HL-like ATLL clustered with HL NS. The former HL-like ATLL had EBV infection in H&RS cells, whereas the latter did not have EBV infection. This finding also suggests that EBV might influence local expression of chemokines rather than HL subtypes. Our results indicate that local immunologic disorder or imbalance appears to influence the formation of H&RS cells and that in HL-like ATLL, HTLV-1 infection might not be necessary for H&RS cell formation.
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PMID:Imbalances of chemokines, chemokine receptors and cytokines in Hodgkin lymphoma: classical Hodgkin lymphoma vs. Hodgkin-like ATLL. 1286 30

T cell immunity plays an important role in the clinicopathology of Epstein-Barr virus (EBV)-associated diseases. Acute EBV-induced infectious mononucleosis (IM) is a common self-limiting disease, however, other EBV-associated diseases, including chronic active EBV infection (CAEBV), NK cell lymphoma (NKL), and Hodgkin's lymphoma (HL), exhibit distinct clinical features. Chemokines are members of a family of small-secreted proteins. The relationships between chemokines and the chemokine receptor (R) are thought to be important for selectivity of local immunity. Some chemokines, chemokine R and cytokines closely associate with the T cell subtypes, Th1 and Th2 T cells and cytotoxic cells. To clarify the role of T cell immunity in EBV-associated diseases, we conducted gene expression profiling, using chemokine, chemokine R and cytokine DNA chips. Compared to EBV negative non-specific lymphadenitis, CAEBV and NKL exhibited diffuse down- and up-regulation, respectively, of these gene profiles. IM had a predominantly Th1-type profile, whereas HL had a mixed Th1/Th2-type profile. Reduction of the Th1-type cytokine interferon gamma (IFN-gamma) in CAEBV was confirmed by Reverse transcriptase-polymerase chain reaction, whereas IFN-gamma expression was markedly enhanced in NKL, and moderately enhanced in IM. Compared to IM, CAEBV showed slight elevation of "regulated upon activation, normal T expressed and secreted" (RANTES), but almost all other genes assayed were down-regulated. NKL exhibited elevated expression of numerous genes, particularly IFN-gamma-inducible-10 (IP-10) and monokine induced by IFN-gamma (MIG). HL showed variable elevated and reduced expression of various genes, with increased expression of IL-13 receptor and MIG. Our study demonstrated the enormous potential of gene expression profiling for clarifying the pathogenesis of EBV-associated diseases.
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PMID:Differential chemokine, chemokine receptor and cytokine expression in Epstein-Barr virus-associated lymphoproliferative diseases. 1295 31

Hodgkin lymphoma (HL) and nasopharyngeal carcinoma (NPC) are characterized by their association with Epstein-Barr virus (EBV) and an abundant infiltrate of reactive lymphoid cells. The presence of this lymphoid stroma may influence the effect of anti-viral immunotherapy. The interferon-inducible chemokine IP-10 has anti-neoplastic effects in several model systems mediated by T-cells expressing the CXCR3 chemokine receptor. Using in situ hybridization, it is shown that IP-10 is expressed in neoplastic cells of HL and correlates both with the mixed cellularity histotype and with EBV infection. IP-10 expression was also detected in tumour cells of most NPCs as well as in EBV-negative squamous cell carcinomas of the tongue. Thus, in carcinomas, IP-10 expression showed no correlation with EBV infection. Numerous CXCR3-positive lymphocytes were detected in the lymphoid stroma of HL and NPC, raising the possibility of a Th1-predominant immune response in these cases. In view of the proposed anti-neoplastic functions of IP-10 and CXCR3-positive lymphocytes, these findings are unexpected and raise the possibility that endogenous IP-10 expression in the context of human tumours may not exert the anti-tumour effects ascribed to it by in vitro experiments.
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PMID:Expression of the interferon-inducible chemokine IP-10 (CXCL10), a chemokine with proposed anti-neoplastic functions, in Hodgkin lymphoma and nasopharyngeal carcinoma. 1575 Oct 51

Plerixafor [Mozobil, AMD 3100, JM 3100, SDZ SID 791] is a bicyclam derivative that acts as a stem cell mobiliser by blocking the CXCR4 chemokine receptor. Plerixafor was synthesised by Johnson Matthey (AnorMED) in collaboration with the Rega Institute of Leuven, Belgium. Plerixafor is in phase III clinical trials in stem cell transplantation among cancer patients. Plerixafor blocks CXCR4, which triggers the rapid movement of stem cells out of the bone marrow and into circulating blood. These cells can then be collected and used in stem cell transplant procedures. Plerixafor had been available for partnering in Europe. However, decisions concerning partnering arrangements were deferred by AnorMED until top-line clinical data became available (expected in 2007). In November 2006, Genzyme Corporation completed its acquisition of AnorMED. Genzyme intends to commercialise plerixafor in >50 countries throughout the world using its existing transplant business. Evotec OAI was selected by AnorMED to support it in the chemical development of plerixafor. Evotec OAI will use EVOdevelop, its integrated chemical and pharmaceutical development platform, to complete the full validation of the process to plerixafor, including process research and development, cGMP manufacturing and analytical work. Evotec OAI will also be responsible for producing the relevant Chemical Manufacturing Control (CMC) documentation for regulatory filings. Top line results from the phase III studies are expected in the second quarter of 2007 and, assuming these are successful, the marketing submissions are planned for the US in 2007 (launch in 2008), and for Canada and Europe in 2008. Plerixafor has orphan drug status for stem cell transplantation in cancer patients in the US and the EU. AnorMED (now Genzyme) decided to pursue a full Marketing Authorisation Application (MAA) in Europe for plerixafor in stem cell transplant. Previously, the company had been planning on filing a CMA (Conditional Marketing Authorisation) in this region. The change in strategy requires additional phase II trials in the five major EU markets. Multicentre phase II trials with plerixafor have begun in Canada and Germany in approximately 50 patients with non-Hodgkin's lymphoma and multiple myeloma (studies EU21 and C201). Enrolment has been completed in a US-based, multicentre, phase II trial (study 2105) of plerixafor plus G-CSF in patients with multiple myeloma and non-Hodgkin's lymphoma. This study is designed to optimise the administration schedule of this combination therapy regimen. Plerixafor has completed a phase II study (study 2104) in multiple myeloma and NHL patients in combination with chemotherapy. A US-based phase II pilot study (study 2108) with plerixafor as a single mobilising agent in multiple myeloma patients undergoing stem cell transplant is underway. Another US-based phase II pilot study (study 2106) is evaluating plerixafor in combination with the standard mobilisation regimen, G-CSF, in patients with Hodgkin's disease undergoing stem cell transplant. AnorMED completed a phase II study (study 2101) evaluating the potential of plerixafor in combination with G-CSF as a therapy for stem cell transplantation compared to G-CSF therapy alone. The study involved patients with multiple myeloma and patients with NHL. Results indicated that the combination regimen was significantly superior to G-CSF treatment alone in stem cell mobilisation. Further trials are planned for plerixafor, to expand its use in transplant and in other indications including one to investigate the potential of plerixafor to improve the effectiveness of chemotherapy in patients with leukaemia. Phase I trials have been completed.
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PMID:Plerixafor: AMD 3100, AMD3100, JM 3100, SDZ SID 791. 1732 9


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