Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 56-year-old man with refractory B-cell lymphocytic non-Hodgkin's lymphoma was treated in a Phase II study with interleukin-2 (IL-2) (Roussel-Uclaf, Romainville, France). The patient had involvement of multiple lymph nodes and medullary and peripheral blood (3.6 x 10(9) monoclonal CD19-positive [CD19+] B-lymphocytes/l). After a 5-day cycle of IL-2 treatment, an eightfold increase of the monoclonal CD19+ population was observed (27 x 10(9) monoclonal CD19+ cells). The lymphocytosis decreased dramatically during the second cycle (days 15 to 19) of IL-2 treatment, resulting in 6 x 10(9)/l peripheral lymphocytes, with 5.5 x 10(9) B-lymphocytes. As soon as day 20, peripheral B-cells again increased considerably, with 32 x 10(9) CD19+ cells/l at day 27. The CD19+ population remained monoclonal as assessed by kappa/lambda cell-surface phenotyping and kappa gene rearrangement evaluation. Kinetics of the monoclonal B-lymphocyte response to IL-2 paralleled the natural killer/lymphokine-activated killer and T-cell response, with a 4-day latency period, suggesting an indirect enhancing effect of IL-2. Before and during IL-2 treatment, peripheral B-lymphocytes never expressed detectable levels of the p55 IL-2 receptor. However, the p75 IL-2 receptor was expressed significantly in the IL-2-responsive monoclonal B-cell population. Tumor necrosis factor alpha, a known (in vitro) B-cell tumor growth factor, reached high serum levels during IL-2 treatment. Response evaluation at day 45 showed stability of the lymph node involvement and the marrow lymphocyte infiltrate. At day 45, peripheral B-cell lymphocytosis was 7.5 x 10(9)/l. To the knowledge of the authors, this is the first report of an in vivo IL-2-induced reversible increase of peripheral monoclonal B-cell lymphocytosis.
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PMID:Interleukin-2-induced increase of a monoclonal B-cell lymphocytosis. A novel in vivo interleukin-2 effect? 156 83

Ten patients with high-grade non-Hodgkin's lymphoma (HG-NHL) entered a subcutaneous (s.c.) recombinant interleukin 2 (rIL2) trial within 2 months of undergoing autologous bone marrow transplantation (ABMT). Immunological studies, consisting in T- and natural killer (NK)-cell subset assessment, together with functional assays, such as NK activity and CD16-mediated redirected killing assay, were performed before therapy, after 2 weeks, and then monthly. Phenotypic analysis showed a significant increase (p = 0.01) of CD16 and CD56 NK cells, from 12% to 28% and from 17% to 37%, respectively. In particular, the CD56bright NK cell population showed a tenfold increase, while CD56dim NK cells remained unmodified compared with pretreatment values. The expression of IL2 receptors was also studied and a significant increase (p = 0.01) of CD122 (p75)-positive cells from 8% to 30% was found, while no significant increase was observed in CD25 (p55)-positive cells. Furthermore, rIL2 administration led to an increase of NK activity even at the lowest effectors:target ratio and to an increase of CD16-mediated redirected killing assay. These phenotypic and functional modifications lasted throughout the duration of rIL2 therapy and remained after completion of therapy. In addition, none of the ten patients relapsed, and two of them who started IL2 treatment while still showing residual disease experienced a complete disappearance of the disease after 10 and 7 months of therapy, respectively. Our data suggest that infusion of rIL2 s.c. after ABMT is safe, can selectively increase NK cell number and function, and may have a beneficial effect on the minimal residual disease.
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PMID:Low doses of rIL2 after autologous bone marrow transplantation induce a "prolonged" immunostimulation of NK compartment in high-grade non-Hodgkin's lymphomas. 757 23

Lymphotoxin (LT) is a cytokine related to TNF, found in human systems in both secreted and membrane bound forms. The well characterized secreted form is a trimer of a single protein, LT-alpha, whereas the surface form is composed of a complex between two related molecules, LT-alpha and LT-beta. Because there is a distinct receptor for the complex, the membrane form is believed to signal via events different from those elicited by TNF and secreted LT-alpha. By using a battery of anti-LT-alpha and LT-beta mAbs, it is clear that two LT surface forms exist on the surface of PMA-activated II-23 cells, a human T cell hybridoma. Assuming that these surface forms are trimers, a minor form appears early after induction having an apparent stoichiometry of LT-alpha 2/beta 1 and is recognized by one group of anti-LT-alpha mAbs and the p55-TNF receptor. The second and predominant form has an apparent LT-alpha 1/beta 2 composition and is recognized by a second group of pantrophic anti-LT-alpha mAbs and the LT-beta receptor. Neither of the heteromeric forms nor a putative LT-beta homotrimeric form were found to be secreted. The properties of surface LT on the II-23 cell system were similar to those of the surface LT forms on Chinese hamster ovary cells transfected with both LT-alpha and LT-beta genes and a number of lymphoid tumor lines. These experiments point toward the LT-alpha 1/beta 2 complex as the predominant membrane form of LT on the lymphocyte surface, and this complex is the primary ligand for the LT-beta receptor.
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PMID:Characterization of surface lymphotoxin forms. Use of specific monoclonal antibodies and soluble receptors. 799 52

Enhanced concentrations of soluble forms of the receptor for tumour necrosis factor (TNF)-alpha have been detected in the serum of cancer patients. We determined serum concentrations of soluble TNF receptor p55 (sTNF-R55) in patients with haematological neoplasias, 50 patients suffering from non-Hodgkin's lymphoma (n = 35), Hodgkin's disease (n = 10) and multiple myeloma (n = 5). Compared with healthy controls and with patients with potential thyroid disease, significantly elevated concentrations of sTNF-R55 were found (mean +/- standard error: 2.68 +/- 0.22 vs. 1.23 +/- 0.21 ng/ml, P < 0.0001 and 2.18 +/- 0.32 ng/ml, P = 0.03). Likewise, neopterin concentrations were raised (19.6 +/- 3.66 vs. 5.3 +/- 0.25 nmol/l in controls, P < 0.0001). We found a significant correlation between sTNF-R55 and neopterin concentrations (Rs = 0.544, P < 0.001). Patients with weight loss showed higher sTNF-R55 concentrations than patients with stable weight. Our results confirm the relevance of sTNF-R55 concentrations in serum of patients with cancer.
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PMID:Serum soluble tumour necrosis factor receptor 55 is increased in patients with haematological neoplasias and is associated with immune activation and weight loss. 811 Apr 91

The cell line described here was established for a 50-year-old male patient with rapidly progressive non-Hodgkin's lymphoma whose marrow was diffusely infiltrated with large granular lymphocytes (LGL). Immunophenotyping of marrow blasts and peripheral lymphocytes was positive for CD56, CD2 and CD7, and negative for CD3. Cytotoxicity of peripheral blood mononuclear cells at an effector: target (E:T) cell ratio of 50:1 was 79% against K562 cells and 48% against Daudi cells. To establish the line, cells from the peripheral blood were placed into enriched alpha medium containing 12.5% fetal calf serum, 12.5% horse serum, 10(-4) M beta-mercaptoethanol and 10(-6) M hydrocortisone. Growth of the line (termed NK-92) is dependent on the presence of recombinant IL-2 and a dose as low as 10 U/ml is sufficient to maintain proliferation. Conversely, cells die within 72 h when deprived of IL-2; IL-7 and IL-12 do not maintain long-term growth, although IL-7 induces short-term proliferation measured by 3H-thymidine incorporation. None of the other cytokines tested (IL-1 alpha, IL-6, TNF-alpha, IFN-alpha, IFN-gamma) supported growth of NK-92 cells which have the following characteristics: surface marker positive for CD2, CD7, CD11a, CD28, CD45, CD54, CD56bright; surface marker negative for CD1, CD3, CD4, CD5, CD8, CD10, CD14, CD16, CD19, CD20, CD23, CD34, HLA-DR. DNA analysis showed germline configuration for T-cell receptor beta and gamma genes. CD25 (p55 IL-2 receptor) is expressed on about 50% of all cells when tested at 100 U/ml of IL-2 and its expression correlates inversely with the IL-2 concentration. The p75 IL-2 receptor is expressed on about half of the cells at low density irrespective of the IL-2 concentration. NK-92 cells kill both K562 and Daudi cells very effectively in a 4 h51-chromium release assay (84 and 86% respectively, at an E:T cell ratio of 5:1). The cell line described here thus displays characteristics of activated NK-cells and could be a valuable tool to study their biology.
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PMID:Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. 815 60

Lymphotoxin alpha (LT-alpha) may form secreted homotrimers binding to p55 and p75 tumor necrosis factor (TNF) receptors or cell surface-bound heterotrimers with LT-beta that interact with the LT-beta receptor. Genetic ablation of LT-alpha revealed that mutant mice have no detectable lymph nodes or Peyer's patches and that the organization of the splenic white pulp in T and B cell areas is disturbed. In this report we describe a novel function for the p55 TNF receptor during ontogeny and demonstrate that mice deficient for p55 completely lack organized Peyer's patches. In contrast, lymph nodes and spleen are present in p55-deficient mice and lymphocytes segregate normally into B and T cell areas in these organs. Lamina propria and intraepithelial lymphocytes of the small intestine were detected in normal number and distribution in p55 mutant mice. Lymphocytes and endothelial cells from p55-deficient mice express normal levels of adhesion molecules considered important for lymphocyte migration to mucosal organs; this indicates that the lack of Peyer's patches does not result from a defect in lymphocyte homing. In summary, the p55 receptor for TNF selectively mediates organogenesis of Peyer's patches throughout ontogeny, suggesting that the effects of LT-alpha on the development of lymphoid organs may be mediated by distinct receptors, each functioning in an organ-specific context.
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PMID:Defective Peyer's patch organogenesis in mice lacking the 55-kD receptor for tumor necrosis factor. 869 Nov 40

In order to induce a therapeutic immunomodulatory activity, 11 patients with high-grade non-Hodgkin's lymphoma (HG-NHL) at a median of 42 days after autologous bone marrow transplantation (ABMT) received recombinant interleukin-2 (rIL-2) subcutaneously at a dose of 2 international megaunits (IMU)/m2 every other day for 2 weeks and then 3 IMU/m2 twice a week for 1 year. Immunological studies, including T and natural killer (NK) cell subset assessment, together with functional assay, such as NK and CD16-mediated cytotoxic activities, were performed before therapy, after 2 weeks and then monthly. Phenotypic analyses showed a significant and persistant (P = 0.001) increase in the proportion and absolute number of total lymphocytes and, particularly of both CD16 and CD56 NK cells, from pre-treatment values of 14 and 18% to 30 and 38% respectively, recorded after 6 months of therapy. No changes were observed in CD25 (p55)-positive cells, while a significant increase from 13 to 33% (after 6 months) was observed in CD122-positive cells. Furthermore, rIL-2 administration led to an enhancement of NK activity even at the lowest effector:target ratio and of CD16-mediated cytotoxic activity. Clinical tolerance was acceptable with moderate fever and fluid retention observed only at the onset of rIL-2 treatment. None of the patients have progressed with a median follow-up of 22 months (range 10-42 months) after starting therapy. In addition, two patients with a residual disease after ABMT, one in the liver and the second in the lymph nodes, obtained a complete response after 10 and 7 months of rIL-2 therapy, respectively. These preliminary data suggest that the infusion of low-dose rIL-2 s.c. after ABMT is safe and well tolerated and can selectively increase the NK cell number and function. Additional patients are needed in order to assess the impact of these immunological changes on relapse-free survival after ABMT for HG-NHL.
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PMID:Immunologic and clinical modifications following low-dose subcutaneous administration of rIL-2 in non-Hodgkin's lymphoma patients after autologous bone marrow transplantation. 883 99

CD30 ligand (CD30L) is a type-II membrane glycoprotein capable of transducing signals leading to either cell death or proliferation through its specific counterstructure CD30. Although several lines of evidence indicate that CD30L plays a key role as a paracrine- or autocrine-acting surface molecule in the deregulated cytokine cascade of Hodgkin's disease, little is known regarding its distribution and biologic significance in other human hematopoietic malignancies. By analyzing tumor cells from 181 patients with RNA studies and immunostaining by the anti-CD30L monoclonal antibody M80, we were able to show that human hematopoietic malignancies of different lineage and maturation stage display a frequent and broad expression of the ligand. CD30L mRNA and surface protein were detected in 60% of acute myeloid leukemias (AMLs), 54% of B-lineage acute lymphoblastic leukemias (ALLs), and in a consistent fraction (68%) of B-cell lymphoproliferative disorders. In this latter group, hairy cell leukemia and high-grade B-cell non-Hodgkin's lymphoma (B-NHL) expressed a higher surface density of CD30L as compared with B-cell chronic lymphocytic leukemia and low-grade B-NHL. Purified plasmacells from a fraction of multiple myeloma patients also displayed CD30L mRNA and protein. A more restricted expression of CD30L was found in T-cell tumors that was mainly confined to neoplasms with an activated peripheral T-cell phenotype, such as T-cell prolymphocytic leukemia, peripheral T-NHL, and adult T-cell leukemia/lymphoma. In contrast, none of the T-lineage ALLs analyzed expressed the ligand. In AML, a high cellular density of CD30L was detected in French-American-British M3, M4, and M5 phenotypes, which are directly associated with the presence on tumor cells of certain surface structures, including the p55 interleukin-2 receptor alpha-chain, the alpha(M) (CD11b) chain of beta2 integrins, and the intercellular adhesion molecule-1 (CD54). Analysis of normal hematopoietic cells evidenced that, in addition to circulating and tonsil B cells, a fraction of bone marrow myeloid precursors, erythroblasts, and subsets of megakaryocytes also express CD30L. Finally, we have shown that native CD30L expressed on primary leukemic cells is functionally active by triggering both mitogenic and antiproliferative signals on CD30+ target cells. As opposed to CD30L, only 10 of 181 primary tumors expressed CD30 mRNA or protein, rendering therefore unlikely a CD30-CD30L autocrine loop in human hematopoietic neoplasms. Taken together, our data indicate that CD30L is widely expressed from early to late stages of human hematopoiesis and suggest a regulatory role for this molecule in the interactions of normal and malignant hematopoietic cells with CD30+ immune effectors and/or microenvironmental accessory cells.
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PMID:CD30 ligand is frequently expressed in human hematopoietic malignancies of myeloid and lymphoid origin. 905 27

Targeted inactivation of genes in the tumor necrosis factor (TNF)/lymphotoxin (LT) ligand and receptor system has recently revealed essential roles for these molecules in lymphoid tissue development and organization. Lymphotoxin-alphabeta (LTalphabeta)/lymphotoxin-beta receptor (LTbeta-R) signaling is critical for the organogenesis of lymph nodes and Peyer's patches and for the structural compartmentalization of the splenic white pulp into distinct B and T cell areas and marginal zones. Moreover, an essential role has been demonstrated for TNF/p55 tumor necrosis factor receptor (p55TNF-R) signaling in the formation of splenic B lymphocyte follicles, follicular dendritic cell networks, and germinal centers. In contrast to a previously described essential role for the p55TNF-R in Peyer's patch organogenesis, we show in this report that Peyer's patches are present in both TNF and p55TNF-R knockout mice, demonstrating that these molecules are not essential for the organogenesis of this lymphoid organ. Furthermore, we show that in the absence of TNF/p55TNF-R signaling, lymphocytes segregate normally into T and B cell areas and a normal content and localization of dendritic cells is observed in both lymph nodes and Peyer's patches. However, although B cells are found to home normally within Peyer's patches and in the outer cortex area of lymph nodes, organized follicular structures and follicular dendritic cell networks fail to form. These results show that in contrast to LTalphabeta signaling, TNF signaling through the p55TNF-R is not essential for lymphoid organogenesis but rather for interactions that determine the cellular and structural organization of B cell follicles in all secondary lymphoid tissues.
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PMID:Peyer's patch organogenesis is intact yet formation of B lymphocyte follicles is defective in peripheral lymphoid organs of mice deficient for tumor necrosis factor and its 55-kDa receptor. 917 15

Targeted inactivation of genes in the tumor necrosis factor (TNF)/lymphotoxin (LT) ligand and receptor system has recently revealed essential roles forthese molecules in lymphoid tissue development and organization. Lymphotoxin-alpha beta (LT alpha beta)/lymphotoxin-beta receptor (LT beta-R) signaling is critical for the organogenesis of lymph nodes and Peyer's patches and for the structural compartmentalization of the splenic white pulp into distinct B and T cell areas and marginal zones. Moreover, an essential role has been demonstrated for TNF/p55 tumor necrosis factor receptor (p55TNF-R) signaling in the formation of splenic B lymphocyte follicles, follicular dendritic cell networks, and germinal centers. In contrast to a previously described essential role for the p55TNF-R in Peyer's patch organogenesis, we show in this report that Peyer's patches are present in both TNF and p55TNF-R knockout mice, demonstrating that these molecules are not essential for the organogenesis of this lymphoid organ. Furthermore, we show that in the absence of TNF/p55TNF-R signaling, lymphocytes segregate normally into T and B cell areas and a normal content and localization of dendritic cells is observed in both lymph nodes and Peyer's patches. However, although B cells are found to home normally within Peyer's patches and in the outer cortex area of lymph nodes, organized follicular structures and follicular dendritic cell networks fail to form. These results show that in contrast to LT alpha beta signaling, TNF signaling through the p55TNF-R is not essential for lymphoid organogenesis but rather for interactions that determine the cellular and structural organization of B cell follicles in all secondary lymphoid tissues.
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PMID:Peyer's patch organogenesis--cytokines rule, OK? 941 84


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