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)

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.
 ...
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)
 ...
PMID:Expression pattern of T-cell-associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma. 1088 35

The malignant Hodgkin and Reed-Sternberg (H/RS) cells of Hodgkin disease (HD) express several members of the tumor necrosis factor (TNF) receptor family, including CD30 and CD40, and secrete several cytokines and chemokines. However, little is known about what regulates cytokine and chemokine secretion in H/RS cells. Although H/RS cells are predominantly of B-cell origin, they frequently share phenotypic and functional features with dendritic cells (DCs). Previous studies reported that receptor activator of nuclear factor kappaB (NF-kappaB) (RANK), a member of the TNF receptor family, is expressed on DCs, and that RANK ligand (RANKL) enhances DC survival and induces them to secrete cytokines. This study reports that, similar to DCs, cultured H/RS cells expressed RANK. However, unlike DCs, H/RS cells also expressed RANKL. Soluble RANKL activated NF-kappaB and induced messenger RNA expression of interferon-gamma, interleukin-8 (IL-8), IL-13, IL-9, IL-15, and RANTES, in addition to the receptors for IL-9, IL-13, IL-15, and CCR4. RANKL increased IL-8 and IL-13 levels in the supernatants of H/RS cell lines, an effect that was blocked by soluble RANK. Furthermore, soluble RANK decreased the basal level of IL-8 in one cell line, suggesting that IL-8 was induced by an autocrine RANKL/RANK loop. RANKL had no effect on H/RS cell survival in culture, and it did not modulate the expression of bcl-2, bcl-xL, bax, or inhibitors of apoptosis proteins. These data provide evidence of further functional similarities between DCs and H/RS cells. The coexpression of RANK and RANKL in H/RS cells suggests that they may regulate cytokine and chemokine secretion in H/RS cells by an autocrine mechanism.
 ...
PMID:Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines. 1200 8

Hodgkin disease (HD) is characterized by the presence of Hodgkin and Reed-Sternberg cells (H&RS) and a prominent lymphocytic infiltration. Various CXC and CC chemokines [e.g., interferon-gamma-inducible protein-10 (IP10), monokine induced by interferon-gamma (MIG) and TARC] are expressed on H&RS cells. Our study was designed to investigate the expression of MIG, IP10 and TARC on H&RS cells and their relations on lymphocyte infiltration. Immunohistochemical staining was performed using antibodies for CXCR3 (a specific receptor for IP10 and MIG), which is characteristic of Th1 helper phenotype and CCR3, CCR4 and ST2, which are features of Th2 cells. We studied 15 cases of HD [lymphocyte predominance (LP) type, 2; mixed cellularity (MC) type, 6; and nodular sclerosis (NS) type, 7]. All 6 MC cases contained TARC-, IP10- and MIG-expressing H&RS cells, however only 2 of 5 NS cases contained TARC-expressing H&RS cells, 3 of 7 NS contained MIG-expressing H&RS cells and only 1 of 7 NS contained IP10-expressing H&RS cells. Neither of the 2 LP cases contained HR&S cells that expressed these chemokines. The chemokines were more frequently expressed by MC than by NS and LP types. IP10-, MIG- and TARC-positive HD cases contained higher numbers of Th2 lymphocytes (ST2- CCR3- or CCR4-positive lymphocytes), compared to IP10-, MIG- and TARC-negative HD cases (p < 0.05 or <0.5). The number of CXCR3 (MIG and IP10 receptor)-positive lymphocytes (Th1 lymphocytes) was not different between MIG- and IP10-positive and -negative HD. Lymphocytes surrounding MIG- and IP10-positive H&RS cells were more frequently CXCR3-positive, however, compared to MIG- and IP10-negative cases. The CCR4 (TARC receptor)-positive lymphocytes, surrounding H&RS cells, were minority and the surrounding lymphocytes were not different between TARC-positive and negative cases. Our results indicate that MIG, IP10 and TARC chemokines influenced the response of Th2 cells in HD. It is possible, however, that IP10 and MIG may locally influence Th1 cells via cell migration.
 ...
PMID:Infiltration of Th1 and Th2 lymphocytes around Hodgkin and Reed-Sternberg (H&RS) cells in Hodgkin disease: Relation with expression of CXC and CC chemokines on H&RS cells. 1192 Jun 17

We performed an immunohistochemical analysis of CXCR4/CD184 expression in frozen and paraffin-embedded sections of human peripheral T-cell lymphomas that exhibit a composite Th1 T-cell-like or Th2 T-cell-like immunophenotype, based on expression of Th1-associated markers (CXCR3, OX40/CD134, and CD69) and Th2-associated markers (CD30 and CCR4). In 66 cases examined, CXCR4/CD184 expression correlated significantly with immunoreactivity for other markers of Th2 differentiation (P < .0001). Anaplastic large cell lymphoma, which typically expresses markers of Th2 differentiation, was immunoreactive for CXCR4/CD184 in 22 (88%) of 25 cases. Tumors previously identified as exhibiting a composite Th1-like immunophenotype, which include angioimmunoblastic lymphoma, lymphoepithelioid lymphoma, and other peripheral T-cell lymphomas now termed unspecified, were positive for CXCR4/CD184 in 7 (17%) of 41 cases. These results are consistent with previous findings that a subset of peripheral T-cell lymphomas can be divided into Th1-like and Th2-like categories based on immunoreactivity with a limited set of markers. Our findings also suggest that CXCR4/CD184, which is expressed by a number of malignant neoplasms and may have a role in tumor metastasis, may have a similar function in CXCR4+ T-cell non-Hodgkin lymphomas.
 ...
PMID:CXCR4/CD184 immunoreactivity in T-cell non-Hodgkin lymphomas with an overall Th1- Th2+ immunophenotype. 1264 45

Chemokine receptors mediate the migration of lymphocytes through the binding of ligands, and the expression is differentially regulated in lymphocyte subsets. CXCR3 is usually expressed in Th1 T cells, however, recently is reported to be expressed in B cell chronic lymphocytic leukemia, mucosa-associated lymphoid tissue type lymphoma (MALT) (extranodal marginal zone lymphoma), and other B cell non-Hodgkin lymphomas. Our study was designed to investigate the expression of CXCR3 and its ligand Mig, and their relationships in MALT using immunohistochemistry. In addition, CCR4, which is characteristic Th2 helper phenotype, and its ligand thymus and activation-regulated chemokine (TARC), were compared with CXCR3, as Th1 phenotype. We studied 14 cases of gastric B cell lymphoma [low-grade MALT, 5 cases; high-grade MALT, 5 cases; and diffuse large (DL), 4 cases] and 16 cases of thyroid B cell lymphoma [low-grade MALT, 4 cases; high-grade MALT, 5 cases; and DL, 7 cases]. CXCR3-expressing lymphoid cells were detected in all cases. In double immunostaining (CXCR3-CD20), gastric and thyroid low/high MALT showed CXCR3-positive neoplastic B cells, but DL, except two cases, did not. In DL, CXCR3-positive lymphoid cells were mainly reactive T-cells (CD3-positive cells). Mig was expressed mainly in stromal cells (histiocytes, macrophages, fibroblasts, and endothelial cells). In gastric lymphoma, low-grade MALT contained abundant Mig-strongly expressing cells, while staining in high-grade MALT and DL was mild. In thyroid lymphoma, staining was strong in low- and high-grade MALT, but moderate in DL. In double-staining, CXCR3-Mig-coexpressing lymphoma cells were abundant in high MALT of the stomach and thyroid, but rare in other subtypes. TARC-positive cells and CCR4-positive cells were rarely encountered in all cases. Our results indicate a tendency for low-grade MALT to contain CXCR3(+)Mig- lymphoma cells, high-grade to contain CXCR3(+)Mig+ and DL to contain CRCR3(-)Mig- lymphoma cells. We speculate that CXCR3 is associated with migration of lymphoma cells in low-grade MALT, and autocrine function in high-grade MALT, and not associated with any function in DL.
 ...
PMID:Expression of chemokine receptor CXCR3 and its ligand, mig, in gastric and thyroid marginal zone lymphomas. Possible migration and autocrine mechanism. 1268 53

Most non-Hodgkin lymphomas (NHLs) are of B-cell origin, but the tumor tissue can be variably infiltrated with T cells. In the present study, we have identified a subset of CD4(+)CD25(+) T cells with high levels of CTLA-4 and Foxp3 (intratumoral T(reg) cells) that are overrepresented in biopsy specimens of B-cell NHL (median of 17% in lymphoma biopsies, 12% in inflammatory tonsil, and 6% in tumor-free lymph nodes; P = .001). We found that these CD4(+)CD25(+) T cells suppressed the proliferation and cytokine (IFN-gamma and IL-4) production of infiltrating CD4(+)CD25(-) T cells in response to PHA stimulation. PD-1 was found to be constitutively and exclusively expressed on a subset of infiltrating CD4(+)CD25(-) T cells, and B7-H1 could be induced on intratumoral CD4(+)CD25(+) T cells in B-cell NHL. Anti-B7-H1 antibody or PD-1 fusion protein partly restored the proliferation of infiltrating CD4(+)CD25(-) T cells when cocultured with intratumoral T(reg) cells. Finally, we found that CCL22 secreted by lymphoma B cells is involved in the chemotaxis and migration of intratumoral T(reg) cells that express CCR4, but not CCR8. Taken together, our results suggest that T(reg) cells are highly represented in the area of B-cell NHL and that malignant B cells are involved in the recruitment of these cells into the area of lymphoma.
 ...
PMID:Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. 1640 12

The chemokine receptor CXCR4 is widely expressed on different cell types, is involved in leukocyte chemotaxis, and is a co-receptor for HIV. AMD3100 has been shown to be a CXCR4 receptor antagonist, and to block HIV infection of T-tropic, X4-using, virus in vitro and in vivo. AMD3100 is an effective mobilizer of hematopoietic stem cells and is being investigated in clinical trials in multiple myeloma and non-Hodgkins lymphoma patients. Using the CCRF-CEM T-cell line that constitutively expresses CXCR4 we confirmed that AMD3100 was an antagonist of SDF-1/CXCL12 ligand binding (IC50=651+/-37 nM). We have also shown that AMD3100 inhibits SDF-1 mediated GTP-binding (IC50=27+/-2.2 nM), SDF-1 mediated calcium flux (IC50=572+/-190 nM), and SDF-1 stimulated chemotaxis (IC50=51+/-17 nM). AMD3100 did not inhibit calcium flux against cells expressing CXCR3, CCR1, CCR2b, CCR4, CCR5 or CCR7 when stimulated with their cognate ligands, nor did it inhibit receptor binding of LTB4. AMD3100 did not, on its own, induce a calcium flux in the CCRF-CEM cells, which express multiple GPCRs including CXCR4, CCR4 and CCR7. Furthermore, AMD3100 neither stimulated GTP-binding, an assay for GPCR activation, in CEM cell membranes; nor chemotaxis of CCRF-CEM cells. These data therefore demonstrate that AMD3100 is a specific antagonist of CXCR4, is not cross-reactive with other chemokine receptors, and is not an agonist of CXCR4.
 ...
PMID:Characterization of the molecular pharmacology of AMD3100: a specific antagonist of the G-protein coupled chemokine receptor, CXCR4. 1681 9

Whereas regulatory T (Treg) cells play an important role in the prevention of autoimmunity, increasing evidence suggests that their down-regulatory properties negatively affect immune responses directed against tumors. Treg cells selectively express chemokine receptors CCR4 and CCR8, and specific migration occurs following the release of various chemokines. Neoplastic meningitis (NM) resulting from leptomeningeal spread of systemic non-Hodgkin lymphoma (NHL) or carcinoma has a poor prognosis. We hypothesized that Treg-cell accumulation within the subarachnoid space as a result of interfering with tumor immunity may be relevant for survival of neoplastic cells. We collected cerebrospinal fluid (CSF) from 101 patients diagnosed with lymphomatous/carcinomatous NM and various inflammatory diseases (IDs) and noninflammatory neurologic disorders (NIDs). CSF Treg- cell counts were determined by flow cytometry, Treg cell-specific chemokines by enzyme-linked immunosorbent assay (ELISA), and Treg-cell trafficking by chemotaxis assay. Both frequencies of Treg-cell and Treg cell-specific chemotactic activities were significantly elevated in CSF samples of patients with NM. Local Treg-cell accumulation occurred without concomitant rise of conventional T (Tconv) cells, coincided with elevated concentrations of Treg cell-attracting chemokines CCL17 and CCL22 and correlated with numbers of atypical CSF cells. We conclude that Treg cells are specifically recruited into the CSF of patients with NM, suggesting that the presence of Treg cells within the subarachnoid space generates a microenvironment that may favor survival and growth of malignant cells.
 ...
PMID:Specific recruitment of regulatory T cells into the CSF in lymphomatous and carcinomatous meningitis. 1796 42

Age-related Epstein-Barr virus-positive (EBV(+)) B-cell lymphoproliferative disorder (ALPD) is a disease entity identified from a large-scale re-survey of cases diagnosed as diffuse large B-cell lymphoma. ALPD is a group of EBV(+) polymorphic B-cell lymphoma typically seen in elderly patients. An age-associated decline in host immunity against EBV might be partly responsible for the pathogenesis of ALPD. Histologically, ALPD is often characterized by a minor proportion of EBV-encoded RNA-positive tumor cells in a background of extensive cellular infiltration, similar to that of classical Hodgkin's lymphoma. In contrast to Hodgkin and Reed-Sternberg cells, ALPD tumor cells are clearly positive for B cell markers CD20 and/or CD79a. Hodgkin and Reed-Sternberg cells produce various chemokines, including CCL17 and CCL22, that attract chemokine receptor CCR4-expressing Th2 cells and regulatory T cells. Previously, we have shown that EBV-immortalized B cells also produce CCL17 and CCL22 through latent membrane protein 1 (LMP1)-mediated activation of nuclear factor kappaB. Here we examined expression of CCL17 and CCL22 in ALPD. ALPD tumor cells were often heterogeneous in size in accordance with the differential expression of EBV latent genes at the single cell level. LMP1-expressing tumor cells were typically large in size and selectively positive for CCL17 and CCL22. CCR4(+) cells and forkhead box protein 3(+) regulatory T cells were abundantly present, and the majority of forkhead box protein 3(+) cells were CCR4(+). Collectively, our data show production of CCL17 and CCL22 by LMP1(+) large-sized tumor cells and accumulation of CCR4-expressing cells including regulatory T cells in ALPD.
 ...
PMID:Expression of CCL17 and CCL22 by latent membrane protein 1-positive tumor cells in age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorder. 1827 28


1 2 Next >>