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)

Patients with Hodgkin's disease, either untreated or in remission, exhibit a persistent defect in cellular immunity. This cellular immune defect appears to be the result of increased sensitivity to suppressor monocytes and T-suppressor cells, in addition to abnormal Interleukin-2 production. T-lymphocyte function is abnormal in patients with advanced disease. The precise origin of Reed-Sternberg and Hodgkin's cells is unknown. Reed-Sternberg cells function as antigen-presenting cells and as accessory cells in mitogen-induced T-cell proliferation. They have properties in common with dendritic cells and activated lymphocytes. L428 cells express a transformation-associated phosphorylated transmembrane protein, with properties of a growth factor receptor, that may play a role in tumorigenic transformation.
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PMID:Immunology and cellular biology of Hodgkin's disease. 266 23

CD40 is a transmembrane protein that belongs to a superfamily of proteins related to nerve growth factor receptor. CD40 is expressed on B cells and some B cell malignancies. It appears to be involved in B cell proliferation and the prevention of apoptosis in germinal center cells, which is accompanied by expression of bcl-2. Its expression is up-regulated by the EBV protein latent membrane protein-1 and cytokines interleukin-4 and interferon-gamma. The expression of CD40 in 37 cases of Hodgkin's disease and 23 cases of non-Hodgkin's lymphoma (11 T cell lymphomas and 12 B cell lymphomas) was examined by paraffin section immunohistochemistry using the BB-20 monoclonal antibody. In 26 of 37 cases of Hodgkin's disease the Reed-Sternberg cells showed strong membrane or cytoplasmic expression of CD40. Only 3 of 23 non-Hodgkin's lymphomas showed any expression of CD40 and then only weakly. There was no correlation between expression of bcl-2 or latent membrane protein-1 with CD40 expression. These results show that there is probable hyperexpression of CD40 in Hodgkin's disease and suggest that dysregulation of CD40 expression may play a role in the pathogenesis of Hodgkin's disease.
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PMID:CD40 expression in Hodgkin's disease. 753 45

The CD34 antigen is a glycosilated transmembrane protein with a molecular weight of 105-120 kDs, whose molecular function is still unknown. At present different epitopes of this antigen are recognized by more than 20 monoclonal antibodies. By flow cytometry is quite simple to identify and enumerate the CD34+ cells, present in physiological conditions on 1-3% of normal bone marrow, 0,1-0,5% of cord blood and 0,001-0,01% of peripheral blood cells. The concomitant expression of other monoclonal antibodies allows the identification of different subsets, lineage negative or already lineage "committed", so that CD34+ cells represent an heterogeneous population with only a small number of undifferentiated progenitors. The number of circulating progenitors has highly increased in peripheral blood for few hours during the fast hematopoietic recovery after high dose chemotherapy. Growth factors are able to mobilize CD34+ cells if used alone in a short treatment schedule and the effect is amplified by combining growth factors with chemotherapy. With this treatment CD34+ cells can increase in peripheral blood up to 100-1000 fold the baseline concentration. Collection of large scale of peripheral stem cells is now possible using different models of continuous-flow blood cell separators. The vast majority of the cells harvested by apheresis are constituted by "committed" elements, myeloid peroxidase positive cells (40%), T lymphocytes (30%), monocytes (20%), B lymphocytes (1-2%), the CD34+ representing not more than 3-4% of the total cells collected. The main biological characteristic of the CD34+ cells is the capacity to reconstitute the myelo and lymphopoietic system after a myeloablative treatment. For this reason in the last few years there has been an increasing interest in using these particular stem cells in many clinical settings. Peripheral blood autografting is widely used in a large number of trials for the treatment of chemosensitive tumors. At present peripheral blood allogeneic transplants have been done in a number of patients sufficient to conclude that it is safe and able to give rise to a sustained marrow engraftment. Moreover, due to the fact that circulating stem cells are a mixture of indifferentiated progenitors and "committed" cells, the hematopoietic recovery is significantly faster both in autologous and allogeneic transplant setting. The increasing use of peripheral blood stem cells for autografting has raised the problem of tumoral contamination. The role of reinfused tumoral cells in promoting the relapse had been proved in the past. Attempts to "purge" the bone marrow of patients affected by low-grade non-Hodgkin lymphoma were done several years ago at Dana Farber Institute, strongly suggesting the importance of tumor cells left in the inoculum in modifying the prognosis. In certain tumors, such as myeloma for example, using a PCR based method, the contamination was found in all the aphereses tested. Similar data were found in samples derived from advanced breast cancer or small-cell lung cancer patients. These findings have brought to the development of different systems of stem cell "purging" or CD34+ positive selection. At present at least two or three different methods are available on the market for small and large scale bone marrow or peripheral blood stem cell processing. The ongoing trials will clarify the clinical utility. In the end the availability of large amount of enriched CD34+ cells have suggested to several investigators a possible target for gene therapy. The first data seem to suggest this is a good way to pursue, even if a clinical application remains still far from being satisfying.
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PMID:[CD34+ cells: biological aspects]. 892 36

The 150-kd transmembrane protein CD100 is the first semaphorin protein shown to be expressed in lymphoid tissue. CD100 is present in the interfollicular T cell zones and is also expressed by B cells in the germinal centers of secondary lymphoid follicles, but not in the mantle zones. The CD100 molecule was recently cloned, and CD100 transfectants were shown to induce homotypic aggregation of human B cells and improve their viability in vitro, suggesting that CD100 may play a role in lymphocyte aggregation and germinal center formation. We studied the expression of CD100 in 138 clinical cases representing a range of lymphoproliferative disorders, to determine whether this molecule is expressed in these neoplastic processes. In general, we found CD100 expression to be common in peripheral T-cell non-Hodgkin's lymphomas but rare in B-cell non-Hodgkin's lymphomas. CD100 expression was not detectable in low-grade B-cell non-Hodgkin's lymphomas, including cases of small lymphocytic lymphoma (18 cases), marginal zone lymphoma (10 cases), and mantle cell lymphoma (10 cases), as might be expected for these neoplasms that are not of follicular center cell origin. Surprisingly, we found that the vast majority of follicular lymphomas (37 of 40 cases) as well as diffuse large-cell lymphomas of B-cell type (35 cases) did not express CD100. The neoplastic cells in 3 of 11 cases of predominantly large-cell-type follicular lymphoma did express CD100. In contrast, all five cases of high-grade, small non-cleaved (Burkitt-like) B-cell lymphoma were immunoreactive for CD100 expression, as were 18 of 20 cases (90%) of malignant T cell neoplasms. Northern blot analysis of CD100 expression correlated with immunohistochemical findings. Absence of expression of CD100 by neoplastic follicular center B cells is a common feature in follicular lymphomas, but expression of CD100 by T cells is maintained in T-cell lymphoproliferative disorders.
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PMID:The leukocyte semaphorin CD100 is expressed in most T-cell, but few B-cell, non-Hodgkin's lymphomas. 966 86

Epstein-Barr virus (EBV) causes lymphoproliferative diseases in immunocompromised patients and is associated with endemic Burkitt lymphoma, nasopharyngeal carcinoma and some cases of Hodgkin disease. The latent membrane protein 1 (LMP1) of EBV is a transmembrane protein that is essential for the transformation of B lymphocytes. LMP1-mediated up-regulation of Bcl-2 is thought to be an important element in this process. As an approach to explore novel treatments for EBV-associated lymphomas, we constructed a single-chain antibody (sFv) directed against LMP1 to achieve functional inhibition of this oncoprotein in EBV-transformed B lymphocytes. We demonstrated that intracellular expression of an endoplasmic reticulum (ER)-targeted form of this sFv markedly reduced LMP1 protein levels. We also observed a decrease in intracellular level of this protein which correlated with a marked reduction of Bcl-2 expression in EBV-transformed B lymphocytes. We further demonstrated that anti-LMP1 sFv-mediated reduction of Bcl-2 correlated with increased sensitivity of these cells to drug-induced cell death. Therefore, these data suggest that an anti-LMP1 sFv used in combination with conventional chemotherapy may be useful for gene therapy of EBV-associated lymphomas in immunocompromised patients.
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PMID:Phenotypic knock-out of the latent membrane protein 1 of Epstein-Barr virus by an intracellular single-chain antibody. 993 Mar 17

Apoptosis via CD95 and its ligand is an important mechanism that prevents uncontrolled proliferation of activated lymphocytes and regulates lymphocyte homeostasis. The apoptosis receptor CD95 is a transmembrane protein with an intracellular domain well conserved between CD95 and tumor necrosis factor receptor I, another apoptosis-inducing protein. Because of its functional importance, this domain was designated the death domain. We describe the molecular analysis of the CD95 death domain in a family with autoimmune lymphoproliferative syndrome (Canale-Smith syndrome), T-cell lymphoma, and Hodgkin's disease. A functional defect in apoptosis was detected in cells from the index patient, a 5-year-old girl suffering from Canale-Smith syndrome and a T-cell lymphoma, as well as in her father, who had a history of splenomegaly and mild hemolysis, and her paternal uncle who had been cured of Hodgkin's disease (HD). Expansion of double-negative T cells (CD4-CD8-) was only seen in the index patient. All family members with a functional defect in apoptosis were heterozygous for a point mutation in the death domain of CD95 (A1009G, E256G). We conclude that, within the same family, a defect in apoptosis due to a mutation in the CD95 death domain can be associated with diverse clinical phenotypes, including mild, reversible symptoms and different malignancies.
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PMID:Defective apoptosis due to a point mutation in the death domain of CD95 associated with autoimmune lymphoproliferative syndrome, T-cell lymphoma, and Hodgkin's disease. 1034 Apr 3

CD30 is a transmembrane protein selectively overexpressed on many human lymphoma cells and therefore an interesting target for antibody-based immunotherapy. However, binding of therapeutic antibodies stimulates a juxtamembrane cleavage of CD30 leading to a loss of target antigen and an enhanced release of the soluble ectodomain of CD30 (sCD30). Here, we show that sCD30 binds to CD30 ligand (CD153)-expressing non-target cells. Because antibodies bind to sCD30, this results in unwanted antibody binding to these cells via sCD30 bridging. To overcome shedding-dependent damage of normal cells in CD30-specific immunotherapy, we analyzed the mechanism involved in the release. Shedding of CD30 can be enhanced by protein kinase C (PKC) activation, implicating the disintegrin metalloproteinase ADAM17 but not free cytoplasmic calcium. However, antibody-induced CD30 shedding is calcium dependent and PKC independent. This shedding involved the related metalloproteinase ADAM10 as shown by the use of the preferential ADAM10 inhibitor GI254023X and by an ADAM10-deficient cell line generated from embryonically lethal ADAM10(-/-) mouse. In coculture experiments, the antibody-induced transfer of sCD30 from the human Hodgkin's lymphoma cell line L540 to the CD30-negative but CD153-expressing human mast cell line HMC-1 was inhibited by GI254023X. These findings suggest that selective metalloproteinase inhibitors blocking antibody-induced shedding of target antigens could be of therapeutic value to increase the specificity and reduce side effects of immunotherapy with monoclonal antibodies.
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PMID:ADAM10 inhibition of human CD30 shedding increases specificity of targeted immunotherapy in vitro. 1721 Jul 15

The treatment of non-Hodgkin lymphoma (NHL) has changed dramatically since the introduction of rituximab, a monoclonal antibody that binds to the B-cell transmembrane protein CD20 and causes lysis of the lymphoma cells. Since then, a number of additional antibodies have been tested against other B-cell targets, resulting in variable efficacies. The goal of these newer agents is to achieve similar or better response rates as seen with rituximab, and perhaps demonstrate activity in rituximab-refractory disease. Several of the antibodies have been investigated in combination with each other as well as with conventional chemotherapeutic regimens. Approval of such antibodies by regulatory committees and their eventual integration into clinical practice will likely depend on positive results from randomized trials.
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PMID:Beyond rituximab: the future of monoclonal antibodies in B-cell non-Hodgkin lymphoma. 1870 70

Rituximab is a chimeric monoclonal antibody currently used for the treatment of non-Hodgkin lymphoma that targets the transmembrane protein CD20 of B cells. Recently it has also been used for the treatment of several autoimmune diseases, including skin disorders such as Paraneoplastic Pemphigus, Pemphigus Vulgaris, Pemphigus Foliaceus, Mucosal pemphigoid, Bullous pemphigoid, Epidermolysis bullosa acquisita, Systemic lupus erythematous and Dermatomyositis. Frequently all these conditions required intolerably high doses of corticosteroids and additional immunosoppressants, which can increase the risk of severe adverse events. Therefore, new therapeutic options are needed for such patients. The intent of the authors in this review is to provide the reader with a panoramic view of the studies reported to date.
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PMID:Rituximab in dermatological diseases. 1975 55

The treatment of non-Hodgkin lymphoma (NHL) has changed dramatically since the introduction of rituximab, a monoclonal antibody that binds to the B-cell transmembrane protein CD20 and causes lysis of the lymphoma cells. Since then, a number of additional antibodies have been tested against other B-cell targets, resulting in variable efficacies. The goal of these newer agents is to achieve similar or better response rates as seen with rituximab and perhaps demonstrate activity in rituximab-refractory disease. Several of the antibodies have been investigated in combination with each other as well as with conventional chemotherapeutic regimens. Approval of such antibodies by regulatory committees and their eventual integration into clinical practice will likely depend on positive results from randomized trials.
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PMID:Beyond rituximab: The future of monoclonal antibodies in B-cell non-Hodgkin lymphoma. 2042 65


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