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)

CD30 is a member of the tumor necrosis factor receptor family. Overexpression of CD30 on some neoplasms versus its limited expression on normal tissues makes this receptor a promising target for antibody-based therapy. Anaplastic large-cell lymphoma (ALCL) represents a heterogeneous group of aggressive non-Hodgkin lymphomas characterized by the strong expression of CD30. We investigated the therapeutic efficacy of HeFi-1, a mouse IgG1 monoclonal antibody, which recognizes the ligand-binding site on CD30, and humanized anti-Tac antibody (daclizumab), which recognizes CD25, in a murine model of human ALCL. The ALCL model was established by intravenous injection of karpas299 cells into nonobese diabetic/severe combined immuno-deficient (SCID/NOD) wild-type or SCID/NOD Fc receptor common gamma chain-deficient (FcRgamma(-/-)) mice. HeFi-1, given at a dose of 100 microg weekly for 4 weeks, significantly prolonged survival of the ALCL-bearing SCID/NOD wild-type and SCID/NOD FcRgamma(-/-) mice (P < .01) as compared with the control groups. In vitro studies showed that HeFi-1 inhibited the proliferation of karpas299 cells, whereas daclizumab did not inhibit cell proliferation. We demonstrated that the expression of FcRgamma on polymorphonuclear leukocytes and monocytes was not required for HeFi-1-mediated tumor growth inhibition in vivo, although it was required for daclizumab.
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PMID:Effective therapy for a murine model of human anaplastic large-cell lymphoma with the anti-CD30 monoclonal antibody, HeFi-1, does not require activating Fc receptors. 1655 68

Hodgkin lymphoma (HL) is characterized by the presence of a small number of tumor cells in a rich background of inflammatory cells, but the contribution of the abundant nontumor cells to HL pathogenesis is poorly understood. We showed that migratory CD4(+) cells induced by HL cells were hyporesponsive to T-cell receptor stimulation and suppressed the activation/proliferation of the effector CD4(+) T cells in an autologous setting. We further showed that HL cells in the affected lymph nodes were surrounded by a large number of lymphocytes expressing both CC chemokine receptor 4 (CCR4) and FOXP3. These findings indicate that the migratory cells induced by HL cells function as regulatory T (Treg) cells so that these cells create a favorable environment for the tumor cells to escape from host immune system. In addition, we showed that a chimeric anti-CCR4 monoclonal antibody (mAb) could deplete CCR4(+) T cells and inhibit the migration of CD4(+)CD25(+) T cells in vitro. Recognition of the importance of CCR4(+) Treg cells in the pathogenesis of HL will allow rational design of more effective treatments, such as use of an anti-CCR4 mAb, to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.
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PMID:Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. 1674 Jul 9

This phase II study evaluated the safety and efficacy of denileukin diftitox, an interleukin-2-diphtheria toxin fusion protein, in relapsed/refractory T-cell non-Hodgkin lymphoma (T-NHL), excluding cutaneous T-cell lymphoma. Eligible patients received denileukin diftitox 18 microg/kg/d x 5 d every 3 weeks for up to eight cycles. Tumour staging was performed every two cycles and the primary endpoint was the objective response rate [complete response (CR) + partial response (PR)]. For 27 patients enrolled, median age: 55 years (range 26-80 years), 70.4% male, and mean prior therapies: 2.5 (range 1-6). Objective responses (six CRs, seven PRs) were achieved in 13 patients (48.1%), stable disease in eight (29.6%) and six (22.2%) had progressive disease. An objective response was achieved in eight of 13 patients (61.5%) with CD25(+) tumours (four CR/four PR) and five of 11 patients (45.5%) with CD25(-) tumours (two CR/three PR). Median progression-free survival was 6 months (range, 1-38+ months). Most adverse reactions were grade 1/2 and transient. No grade 4-5 toxicities were reported. Denileukin diftitox had significant activity and was well tolerated in relapsed/refractory T-NHL, with responses observed in both CD25(+) and CD25(-) tumours. Further studies of denileukin diftitox in combination with other agents are warranted in previously untreated and relapsed/refractory T-NHL.
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PMID:Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma. 1723 46

Foxp3 expression was initially thought to be restricted to the CD4(+)CD25(+) regulatory T-cell population. However, recent studies suggest that forkhead box P3 (Foxp3) is expressed in CD4(+)CD25(-) T cells in aged mice. In the present study in B-cell non-Hodgkin lymphoma (NHL), we found that a subset of intratumoral but not peripheral blood CD4(+)CD25(-) T cells, comprising about 15% of intratumoral CD4(+) T cells, express Foxp3 and are capable of suppressing the proliferation of autologous infiltrating CD8(+) T cells. In vitro activation with OKT3/anti-CD28 antibody (Ab) or dendritic cells (DCs) induced Foxp3 expression in a subset of these CD4(+)CD25(-)Foxp3(-) T cells. We found that the presence of lymphoma B cells during activation augmented activation-induced Foxp3 expression in CD4(+)CD25(-) T cells. We also found that CD70(+) lymphoma B cells significantly contributed to the activation-induced Foxp3 expression in intratumoral CD4(+)CD25(-) T cells. Furthermore, the blockade of CD27-CD70 interaction by anti-CD70 Ab abrogated lymphoma B-cell-mediated induction of Foxp3 expression in intratumoral CD4(+)CD25(-) T cells. Taken together, these studies reveal a novel role for NHL B cells in the development of intratumoral regulatory T cells.
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PMID:CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells. 1761 91

Immunophenotypic analysis can identify protein epitopes in non-Hodgkin lymphomas (NHL) that may respond to targeted immunotherapies, such as anti-CD20 and anti-CD52. Recent studies suggest additional targets may provide therapeutic benefits in NHL. This study evaluated protein expression of CD25, CD52, CD74 and CD80 in paediatric NHL to determine possible targets for immune-based therapeutic approaches. Patient samples were derived from paediatric NHL clinical trials sponsored by the Children's Cancer Group (CCG, now the Children's Oncology Group, COG) and included Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), disseminated T- and B-cell lymphoblastic lymphoma (T-LBL and B-LBL) and anaplastic large cell (ALCL). Immunophenotypic studies were performed on formalin-fixed, paraffin-embedded diagnostic tissues. CD25 was expressed in 8% of T-LBL and 75% of ALCL cases, but not in BL, DLBCL, or B-LBL. CD52 was expressed in 99% of cases of paediatric NHL of all subtypes. CD74 was expressed in 100% of B-LBL, BL and DLBCL, but was absent in ALCL and T-LBL. CD80 was expressed in 12% of B-LBL, 6% of BL and 10% of DLBCL cases studied, but was not detected in T-cell NHL. These expression patterns suggest that CD25, CD52 and CD74 may represent potential new therapeutic targets in paediatric NHL.
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PMID:Immunophenotypic identification of possible therapeutic targets in paediatric non-Hodgkin lymphomas: a children's oncology group report. 1765 54

Leukaemic phase of non-Hodgkin lymphoma (NHL) is characterised by penetration of lymphoma cells from the originating tissues (lymph nodes, less commonly the spleen) into the peripheral blood and bone marrow. The diagnosis of leukaemic phase of Mantle zone lymphoma is established on the basis of histological findings of lymph node biopsy and, possibly, the spleen, peripheral blood smear, and characteristic membranous phenotype. A patient, aged 60, is reported with Mantle zone (intermediate lymphoma) in leukaemic phase. Physical examination revealed pallor of the skin, generalized lymphadenopathy, and hepatomegaly. WBC count in the peripheral blood was 22.5 x 109/l, and the smear revealed the presence of pleomorphic lymphoid cells, mainly medium sized, with irregular nucleus or nuclear notches. Immunophenotype studies of mononuclear cells of the peripheral blood showed characteristic membranous phenotype for Mantle zone lymphoma in leukaemic phase: Smlg+ (lambda light chain); HLA-DR+; CD19+; CD22+; CD5+; CD10-; CD25-. Pro-MACE-Cyta-bom protocol was applied resulting in a 13-month-lasting remission. The total survival was 20 months, suggesting poor prognosis of leukaemic phase of Mantle zone lymphoma.
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PMID:[Leukaemic phase of Mantle zone (intermediate) lymphoma--case report--]. 1797 26

Adult T cell leukaemia (ATL) is an aggressive clonal malignancy of mature activated T cells, caused by the human T cell lymphotropic virus type I (HTLV-I) infection. ATL continues to have a very bad prognosis because of the intrinsic resistance of leukaemic cells to conventional or even high-dose chemotherapy and because of the associated severe immunosuppression. Even though conventional chemotherapy remains the standard treatment in acute and lymphomatous types of the disease, the benefit of this intensive approach is not well established in chronic and smouldering ATL. Combination chemotherapy regimens, in particular those designed for the treatment of aggressive non-Hodgkin's lymphomas or acute lymphoblastic leukaemia, have little effect in the treatment of ATL. Different combination regimens of conventional chemotherapy have been investigated in Japan, and recent results of intensive induction therapy showed a complete remission (CR) rate of about 40% in the aggressive forms of the disease. However, most of the patients relapsed and eventually died. Allogeneic bone marrow transplantation has been used in the treatment of a very small number of patients with ATL. High toxicity and transplant-related mortality were observed in these immunocompromised patients. New cytotoxic agents have also been used in pilot phase II studies in refractory or relapsed ATL patients, but significant results have only been observed with deoxycoformycin. Recently, promising results have been obtained with anti-Tac monoclonal antibodies directed against the alpha-chain of the interleukin-2 receptor (CD25), which is highly expressed on ATL cells but not on normal resting lymphocytes. Promising results were also reported in 2 phase II studies with combination therapy comprising the antiretroviral agent zidovudine and interferon-alpha (IFNalpha). In previously untreated patients with acute ATL, high and rapid (usually within 2 weeks) response rates were reported. In contrast, in lymphomatous ATL, both studies suggested a milder and slower effect of zidovudine and IFNalpha. In this case, this combination may be used as maintenance therapy after a CR or good partial response induced by polychemotherapy. Since cross resistance between chemotherapy and zidovudine and IFNalpha does not seem to occur, a combination with best induction polychemotherapy is warranted.
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PMID:Adult T cell leukaemia: a review of established and new treatments. 1802 Jun 14

Previous studies have demonstrated an increase in T-regulatory cells in the involved lymph nodes and peripheral blood of patients with Hodgkin lymphoma. Our study examined whether the detection of T-regulatory cells by flow cytometry could distinguish classical Hodgkin lymphoma (CHL) from benign cases and B-cell non-Hodgkin lymphomas (B-NHL). We measured CD4, CD25, and CD152 in 14 CHLs, 2 nodular lymphocyte-predominant Hodgkin lymphomas, 31 B-NHLs, and 54 benign cases. All T-regulatory cell parameters, including percent lymphocytes CD4+/CD152+ and CD4+/CD25+/CD152+, and mean and median CD152 expression in CD4+/CD25+ lymphocytes, were higher in CHL than in B-NHL and benign. Mean CD152 in CD4+/CD25+ lymphocytes distinguished CHL from benign with 79% sensitivity and 100% specificity, and from B-NHL with 71% sensitivity and 90% specificity. Overall, our results show that T-regulatory cells are increased in CHL and their detection may be a useful tool in differentiating CHL from other entities.
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PMID:Detection of T-regulatory cells has a potential role in the diagnosis of classical Hodgkin lymphoma. 1827 Oct 19

Regulatory T (Treg) cells contribute to immune evasion by malignancies. To investigate their importance in non-Hodgkin lymphoma (NHL), we enumerated Treg cells in peripheral blood mononuclear cells (PBMCs) and involved tissues from 30 patients. CD25(+)FoxP3(+)CD127(low)CD4(+) Treg cells were increased markedly in PBMCs (median = 20.4% CD4 T cells, n = 20) versus healthy controls (median = 3.2%, n = 13, P < .001) regardless of lymphoma subtype, and correlated with disease stage and serum lactate dehydrogenase (R(s) = 0.79, P < .001). T-cell hyporesponsiveness was reversed by depleting CD25(+) cells, or by adding anti-CTLA-4, supporting the view that Treg cells explain the systemic immunosuppression seen in NHL. A high proportion of Treg cells was also present in involved tissues (median = 38.8% CD4 T cells, n = 15) versus reactive nodes (median = 11.6%, n = 2, P = .02). When autologous CD25(-) PBMC fractions were incubated with tumor cells from patients (n = 6) in vitro, there was consistent strong induction and then expansion of cells with the CD4(+)CD25(+)FoxP3(+) phenotype of classic "natural" Treg cells. This population was confirmed to be suppressive in function. Direct cell-cell interaction of tumor cells with CD25(-) PBMCs was important in Treg induction, although there was heterogeneity in the mechanisms responsible. We conclude that NHL cells are powerful inducers of Treg cells, which may represent a new therapeutic target.
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PMID:Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma. 1830 20

Little is known about the gene expression profile and significance of the rosetting CD4+CD26- T cells in classical Hodgkin's lymphoma (cHL). To characterize these T cells, CD4+CD26- and CD4+CD26+ T-cell populations were sorted from lymph node (LN) cell suspensions from nodular sclerosis HL (NSHL) and reactive LNs. mRNA profiles of stimulated and resting cell subsets were evaluated with quantitative RT-PCR for 46 genes. We observed a higher percentage of CD4+CD26- T cells in NSHL than in reactive LNs. The resting CD4+CD26- T cells in NSHL showed higher mRNA levels of CD25, CTLA4, OX40 and CCR4 compared with in LNs, supporting a regulatory T-cell (Treg) type, and this was validated by immunohistochemistry. Moreover, these cells showed low or no expression of the Th1- or Th2-related cytokines IL-2, IFN-gamma, IL-13, IL-12B, IL-4, and IL-5, and the chemoattractant receptor CRTH2. Besides Tregs, Th17 cells may exist in NSHL based on the significantly higher IL-17 mRNA level for both T-cell populations in NSHL. Upon stimulation in vitro, lack of upregulation of mRNA levels of most cytokine genes indicated an anergic character for the CD4+CD26- T-cell subset. Anergy fits with the Treg profile of these cells, probably explaining the immunosuppressive mechanism involved in NSHL.
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PMID:The CD4+CD26- T-cell population in classical Hodgkin's lymphoma displays a distinctive regulatory T-cell profile. 1836 7


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