Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have constructed two recombinant adenoviral vectors AdVIP-10 and AdVIL-18 expressing the functional chemokine IFN-gamma inducible protein (IP)-10 and cytokine interleukin (IL)-18, respectively. Injection of either AdVIP-10 or AdVIL-18 subcutaneously into tumor nodules derived from the J558 murine myeloma cell line delayed some tumor growth but it was not curative in all cases. Coinjection of these two vectors at the same tumor nodule not only significantly suppressed the tumor growth, but also cured established tumors in 8 of 10 (80% tumor free) mice. The latter treatment stimulated T-cell infiltration into tumors in association with tumor necrosis formation, induced a type 1 immune response and induced the activation of J558 tumor-specific cytotoxic T lymphocytes. Moreover, the antitumor activity of IP-10 and IL-18 combined gene therapy was significantly diminished in mice with depletion of either CD4(+) (50% tumor free) or CD8(+) (40% tumor free) T cells, and completely lost (0% tumor free) in T cell-deficient nude and IFN-gamma knockout mice, indicating the critical roles of T cells and IFN-gamma in this therapeutical model. Taken together, the findings of this study demonstrate that the combined use of two adenoviral vectors expressing IP-10 and IL-18, respectively, synergize to facilitate regression of established tumors. These observations also suggest the potential use of double-recombinant adenoviral vectors expressing chemokines and immunomodulatory cytokines in cancer gene therapy.
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PMID:Intratumoral coinjection of two adenoviral vectors expressing functional interleukin-18 and inducible protein-10, respectively, synergizes to facilitate regression of established tumors. 1203 64

Reconstitution of T-cell immunity after bone marrow transplantation (BMT) is often delayed, resulting in a prolonged period of immunodeficiency. Donor lymphocyte infusion (DLI) has been used to enhance graft-versus-leukemia activity after BMT, but the effects of DLI on immune reconstitution have not been established. We studied 9 patients with multiple myeloma who received myeloablative therapy and T-cell-depleted allogeneic BMT followed 6 months later by infusion of lymphocytes from the same donor. DLI consisted of 3 x 10(7) CD4(+) donor T cells per kilogram obtained after in vitro depletion of CD8(+) cells. Cell surface phenotype of peripheral lymphocytes, T-cell receptor (TCR) V beta repertoire, TCR rearrangement excision circles (TRECs), and hematopoietic chimerism were studied in the first 6 months after BMT and for 1 year after DLI. These studies were also performed in 7 patients who received similar myeloablative therapy and BMT but without DLI. Phenotypic reconstitution of T and natural killer cells was similar in both groups, but patients who received CD4(+) DLI developed increased numbers of CD20(+) B cells. TCR V beta repertoire complexity was decreased at 3 and 6 months after BMT but improved more rapidly in patients who received DLI (P =.01). CD4(+) DLI was also associated with increased numbers of TRECs in CD3(+) T cells (P <.001) and with conversion to complete donor hematopoiesis (P =.05). These results provide evidence that prophylactic infusion of CD4(+) donor lymphocytes 6 months after BMT enhances reconstitution of donor T cells and conversion to donor hematopoiesis as well as promoting antitumor immunity.
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PMID:Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma. 1203 95

CD40 ligand (CD40L) is a member of the tumor necrosis factor (TNF) superfamily and is expressed primarily on the activated CD4( )T lymphocytes. The CD40 molecule, the cognate receptor of CD40L presents on many immunocytes such as B lymphocytes, dendritic cells (DCs) as well as on some neoplastic cells. Triggering of CD40 through CD40L plays a central role in the initiation and regulation of the human immune response. In order to further investigate the possible biological roles of CD40 signaling triggered by CD40L, we subcloned the DNA fragment encoding the extracellular region of human CD40L into the pSK plasmid. After being sequenced, the target fragment was introduced into the pPICZalphaA plasmid to construct the pPICZalphaA-sCD40L expressing vector which was then transduced into Pichia pastoris GS115 cells by electroporation. The tansformant expressed sCD40L in culture supernatants with a maximum yield of about 35 mg/L. Furthermore, we found that the recombinant human soluble CD40 ligand (rhsCD40L) could effectively induced human peripheral blood monocytes(PBMCs) in vitro in the absence of TNFalpha into dendritic cells (DCs) with the typical morphology and special surface markers of dendritic cells including CD1a, CD80, CD83, and HLA-DR etc. To our surprise, the rhsCD40L also could inhibit directly in vitro proliferation of the CD40-positive multiple myeloma cell line XG-2 and the B lymphoma cell line Daudi significantly at an optimal concentration from 2.5 to 15.0 mg/L, while CD40 negative ovarian carcinoma cell lines, SKB and SKR, were not effected by either high or low concentration of rhsCD40L. Moreover, rhsCD40L had the same effects as CD40L-transfected cell in inducing XG2 cell apoptosis. Our results demonstrated that functional human soluble CD40L could be successfully expressed in the Pichia pastoris system and that the recombinant human soluble CD40L might be a potential immune adjuvant and a new powerful molecule for tumor bio-therapy.
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PMID:Expression of Human Soluble CD40 Ligand in Pichia pastoris and Its Effects on Dendritic Cells and Malignant B Cells. 1205 65

Because tumor-specific antigens have been identified in multiple myeloma (MM), immunotherapy might provide an additional treatment modality for the disease. Expression of CD40 ligand (CD40L) proximate to the MM cells might serve this purpose, either by increasing their capacity to present self-antigens by activation through their CD40 receptor or by the recruitment of professional antigen-presenting cells (APCs) able to take up and present tumor-associated antigens. To distinguish between these possibilities and predict whether human CD40(-) myeloma might respond to this approach, we examined 3 murine plasmacytoma cell lines, 2 (MPC-11 and S107) expressing the CD40 molecule and 1 (X-24) lacking such expression. Syngeneic BALB/CBYJ mice were inoculated subcutaneously with tumor cells mixed with CL7.1 fibroblasts, retrovirally transduced to express either the mCD40L or the neo gene. For all 3 plasmacytoma cell lines, coinjection with CL7.1/mCD40L significantly reduced local tumor growth compared with controls. This effect was mediated by a systemic antitumor immune response, since mice immunized with tumor and CL7.1/mCD40L were resistant to subsequent challenge with tumor, and tumor growth inhibition was abolished when CD8(+) or CD4(+) lymphocytes were depleted. Because expression of CD40L gave equivalent protection from CD40(+) and CD40(-) tumors and transgenic-CD40L failed to up-regulate costimulatory molecules in either tumor, the protective effects of CD40L probably resulted from recruitment/activation of professional APCs rather than from CD40 activation of plasmacytoma cells. As further support of this concept, we found that mice were also well protected if CL7.1 and CD40L were injected together with apoptotic plasmacytoma cells from these tumors. Hence, transgenic CD40L expression may produce an antimyeloma immune response against either CD40(+) or CD40(-) tumors and may be of therapeutic value for both types of myeloma in humans.
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PMID:Transgenic expression of CD40 ligand produces an in vivo antitumor immune response against both CD40(+) and CD40(-) plasmacytoma cells. 1207 28

The coexistence of multiple myeloma (MM) and mycosis fungoides (MF), and hence of both B- and T-cell neoplastic clones, is a rare event. We describe a case of plaque-stage MF associated with IgG lambda MM. The clinical onset of MF preceded that of MM, supporting the hypothesis that MF predisposed to the development of the B-cell proliferative disorder. The skin tumor cells were found to originate from CD4(+) T-lymphocytes, characterized by a V beta 8 receptor and no proviral human T-lymphotropic virus (HTLV)-I monoclonal integration. They also displayed a polarized Th1-type cytokine profile containing mRNAs for interleukin (IL)-2, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-beta, but not for IL-4, IL-5, or IL-10. The CD8(+)/CD57(+) suppressor-cytotoxic subpopulation was significantly increased in the peripheral blood and was associated with MM progression. Expression of p16INK4A, a gene from the INK family that inhibits cyclin-dependent kinases and regulates the cell cycle, was lacking in MF cells and bone marrow (BM) plasma cells. The p16INK4A gene was silenced by hypermethylation, suggesting that it plays a role in the early phase of the pathogenesis of both diseases. Thus, a lymphoid precursor cell presumably contains aberrations that induce the development of both clonal diseases in a multistep process.
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PMID:Multiple myeloma and mycosis fungoides in the same patient: clinical, immunologic, and molecular studies. 1210 63

We found that the ratio of CD4(+) to CD8(+) T cells (CD4/CD8 ratio) was decreased in patients with multiple myeloma (MM) and that this decrease was significantly related to an increase of human leukocyte antigen (HLA)-DR expression by CD8(+) (but not CD4(+)) T cells (P<0.005). In addition, the serum level of interleukin (IL)-16 was significantly higher in stage III MM patients than in healthy controls (P<0.001). The decrease of CD4(+) T cells in MM may be mediated by activation of CD8(+) T cells derived cytokine IL-16. In addition, these T cell phenotypic changes and the IL-16 level appear to be useful indicators of disease activity.
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PMID:Relationship between CD4(+)/CD8(+) T cell ratio and T cell activation in multiple myeloma: reference to IL-16. 1219 64

Plasma cell neoplasia occurs much less frequently than high-grade B-cell non-Hodgkins lymphoma in HIV-infected patients, but is nevertheless an AIDS-associated malignancy. In this report, we describe the fine-needle aspiration (FNA) findings of a mass in the left parotid region with plasmablastic features that occurred in a 41-yr-old HIV-infected homosexual man whom we diagnosed as having anaplastic myeloma. The patient had normochromic, normocytic anemia with a hematocrit of 21%, a white blood count of 2.2 x 10(9)/l with 76% neutrophils, and a CD4 count of 31%. He also had elevated levels of calcium (13.2 mg/dl), alkaline phosphatase (25,400 IU/l), blood urea nitrogen (2,600 mg/dl), and creatinine (2.5 mg/dl). Serum protein electrophoresis showed polyclonal hypergammaglobulinemia without any monoclonal component. A bone survey revealed multiple punched-out lytic lesions. FNA smears showed large plasmacytoid cells with eccentrically placed nuclei, prominent nucleoli, and moderate amounts of basophilic cytoplasm. By immunocytochemical staining, tumor cells were negative for CD19, CD20, and leukocyte-common antigen (LCA), but strongly positive for CD38 and kappa light chain. Anaplastic myeloma and plasmablastic lymphoma were considered in the differential diagnosis. Although the cytomorphologic and immunophenotypic findings of our case overlapped with those of plasmablastic lymphoma, the pattern of bone involvement with punched-out lytic lesions and absence of localization of the tumor to the mucosa of the oral cavity led us to a diagnosis of anaplastic myeloma. The patient initially received antiretroviral therapy followed by thalidomide and pulse dexamethasome therapy, but his response was poor. His HIV load increased, and his malignancy rapidly progressed with the development of multiple vertebral lesions, extraosseous extension, and eventually cord compression. He died of the disease less than 2 mo after presentation.
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PMID:Fine-needle aspiration cytology of a case of HIV-associated anaplastic myeloma. 1235 99

Recent studies in tumor immunology indicate that malignant cells frequently express normal testicular-specific proteins. Because these proteins show restricted normal tissue distribution, they are usually highly immunogenic and may be potential targets for immunotherapy. In the present study, we have used a pair of sequence-specific primers in reverse transcription-polymerase chain reaction (RT-PCR) and sequence analysis to demonstrate that the X-linked gene encoding SPAN-Xb is expressed in multiple myeloma and other hematologic malignancies such as chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML). RT-PCR analysis demonstrates that SPAN-Xb is a cancer/testis antigen and shows a restricted normal tissue expression. It is not expressed in any normal tissue except testis. SPAN-Xb recombinant protein was produced and used in enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. High-titer immunoglobulin G (IgG) antibodies, of IgG3 or IgG2 subclass, against SPAN-Xb were detectable in the sera of these patients. In contrast, SPAN-Xb mRNA or antibodies could not be detected in any of the healthy donors. There was a good correlation between SPAN-Xb gene expression and B-cell immune responses. These results suggest the in vivo immunogenicity of the SPAN-Xb protein. The presence of high-titer IgG responses suggests that the B-cell responses are likely to have been generated with CD4 T-cell cognitive help. Based on these data, we conclude that SPAN-Xb is a novel member of the family of cancer/testis antigens aberrantly expressed by, and capable of inducing, immune responses in patients with multiple myeloma and other hematologic malignancies.
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PMID:Gene expression and immunologic consequence of SPAN-Xb in myeloma and other hematologic malignancies. 1239 89

The lack of efficient T-cell infiltration of tumors is a major obstacle to successful adoptive T-cell therapy. We have previously shown that transplanted SP2/0 myeloma tumors engineered to express lymphotactin invariably induced tumor regress mediated by SP2/0 tumor-specific T cells. Herein, we further systemically characterize these activated T cells and investigate their therapeutic efficacy, either alone or with the chemokine interferon gamma (IFN-gamma)-inducible protein-10 (IP-10) gene therapy. Following stimulation with SP2/0 cells, these activated T cells were CD25(+)FasL(+) L-selectin(low), expressed CXCR3 receptor and were chemoattracted by IP-10 in vitro. They comprised 64% CD4(+) Th1 and 36% CD8(+) Tc1 cells, both of which expressed IFN-gamma, perforin, and TNF-alpha, but not IL-4. The activated T cells were strongly cytotoxic for SP2/0 tumor cells (79% specific killing; E:T ratio, 50), mainly via perforin-mediated pathway. Cell tracking using labeled T cells confirmed that these T cells infiltrated better into the IP-10-expressing tumors than non-IP-10-expressing ones. In vivo, combined intratumoral IP-10 gene transfer and adoptive T-cell immunotherapy for well-established SP2/0 tumors eradicated the tumors in 7 of the 8 mice. Control or IP-10 adenoviral treatments by themselves neither alter the lethal outcome for tumor-bearing mice nor did T-cell therapy by itself, although the latter two treatments did slow its time-frame. Taken together, our data provide solid evidence of a potent synergy between adoptive T-cell therapy and IP-10 gene transfer into tumor tissues, which culminated in the eradication of well-established tumor masses.
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PMID:Synergistic effect of adoptive T-cell therapy and intratumoral interferon gamma-inducible protein-10 transgene expression in treatment of established tumors. 1242 97

The MAL mRNA was initially identified during T-cell development and was later found in myelin-forming cells and certain polarized epithelial cell lines. It encodes a proteolipid believed to participate in membrane microdomains stabilization, transport machinery and signal transduction. Using a differential display reverse-transcription approach, we identified MAL as a distinct molecular marker of primary mediastinal large B-cell lymphoma compared with nonmediastinal diffuse large B-cell lymphomas. In the present study, we used immunohistochemistry to extend MAL expression analysis to normal lymphoid tissues; to 185 lymphomas representing most B, T, and Hodgkin lymphoma entities; and to the primary mediastinal large B-cell lymphoma derived B-cell line MedB-1. In addition, B and T cells from peripheral blood, tonsil, and spleen were analyzed by flow cytometry. Our results show that MAL is highly expressed in thymocytes, in a large percentage of peripheral CD4 T cells, and in a lower proportion of CD8 peripheral T cells. In the normal B-cell compartment, MAL expression appears to be restricted to a minor subpopulation of thymic medullary B cells and to occasional mature plasma cells located in the interfollicular areas of tonsil and lymph nodes. Among B-cell lymphomas (n = 110), MAL expression in tumor cells was observed in 21/33 primary mediastinal large B-cell lymphomas (70%) and in 3/5 plasmacytoma/myeloma, but not in all other B-cell lymphomas with the exception of 1/33 nonmediastinal diffuse large B-cell lymphomas. The MedB-1 B-cell line was also MAL positive. Among T-cell neoplasms, MAL was highly expressed in lymphoblastic tumors (5/6), whereas mature T-cell lymphomas were essentially MAL negative (27/28). Among 41 Hodgkin lymphomas, 3 nodular-sclerosing cases with mediastinal involvement showed MAL-positive Reed Sternberg cells. In conclusion, this study further supports thymic B cells as the putative normal counterpart of primary mediastinal large B-cell lymphomas and supports MAL as a distinct molecular marker of this lymphoma subtype among diffuse large B-cell lymphomas.
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PMID:MAL expression in lymphoid cells: further evidence for MAL as a distinct molecular marker of primary mediastinal large B-cell lymphomas. 1242 96


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