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

In the present study, we examined the effect of soluble CD4 (sCD4) on host resistance and delayed-type hypersensitivity (DTH) response to Cryptococcus neoformans using a novel mutant mouse that exhibits a defect in the expression of membrane-bound CD4 but secretes high levels of sCD4 in the serum. In these mice, host resistance to this pathogen was impaired as indicated by an increased number of live pathogens in the lung. To elucidate the mechanism of immunodeficiency, three different sets of experiments were conducted. First, administration of anti-CD4 mAb restored the attenuated host defense. Second, in CD4 gene-disrupted (CD4KO) mice, host resistance was not attenuated compared to control mice. Third, implantation of sCD4 gene-transfected myeloma cells rendered the CD4KO mice susceptible to this infection, while similar treatment with mock-transfected cells did not show such an effect. These results indicated that immunodeficiency in the mutant mice was attributed to the circulating sCD4 rather than to the lack of CD4+ T cells. In addition, DTH response to C. neoformans evaluated by footpad swelling was reduced in the mutant mice compared to that in the control, and the reduced response was restored by the administration of anti-CD4 mAb. Finally, serum levels of IFN-gamma, IL-12 and IL-18 in the mutant mice were significantly reduced, while there was no difference in Th2 cytokines, such as IL-4 and IL-10. Considered collectively, our results demonstrated that sCD4 could directly prevent host resistance and DTH response to C. neoformans through interference with the production of Th1-type cytokines.
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PMID:Circulating soluble CD4 directly prevents host resistance and delayed-type hypersensitivity response to Cryptococcus neoformans in mice. 1122 Jun 77

In this study we compared the lymphocyte reconstitution in 13 multiple myeloma (MM), nine acute myeloid leukemia (AML) and 10 chronic myeloid leukemia (CML) patients after allogeneic G-CSF-mobilized PBSC transplantation from HLA-identical siblings. Conditioning regimens included standard total body irradiation + cyclophosphamide (CY), or busulphan + CY, whereas VP-16 was added in patients with advanced disease. Overall comparable numbers of mononuclear cells, CD34+ cells and CD3+ T cells were infused in each group. A significantly higher CD3+ T cell number was observed in MM and AML than in CML patients 1 month after transplant. However, MM patients showed a faster and better recovery of CD4+ T cells than both AML and CML patients at 3 months (P = 0.01 and P = 0.01, respectively) and 12 months (P = 0.01 vs AML, while P = NS vs CML) after transplant, and had a CD4:CD8 ratio > 1 with a median CD4+ T cell value > 400/microl 1 year after transplant. Development of acute graft-versus-host disease (GVHD) did not affect CD4:CD8 ratios but patients who experienced acute GVHD > grade I had lower CD4+ and CD8+ T cell numbers at all time points. However, after excluding patients with GVHD > grade I, MM patients still showed a significantly higher CD4+ T cell value than patients with myeloproliferative diseases 1 year after transplant. These findings suggest that although allogeneic PBSC transplantation induces rapid immune reconstitution, different kinetics may occur among patients with hematological malignancies. In particular, the rapid reconstitution of CD4+ T cells in MM patients may contribute to the low transplant-related mortality achieved in this disease.
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PMID:Different immune reconstitution in multiple myeloma, chronic myeloid leukemia and acute myeloid leukemia patients after allogeneic transplantation of peripheral blood stem cells. 1122 73

Cytokine flow cytometry (CFC) is a simple and powerful method for measuring antigen-specific T-cell responses by detection of intracellular cytokine staining. We applied this method to the detection of CD4 T-cell responses to tumor vaccines. Patients with multiple myeloma were immunized against their autologous tumor immunoglobulin idiotype, using antigen-pulsed dendritic cell vaccination. Blood samples were drawn before and after vaccination, and CFC and proliferation assays were performed. For CFC, whole blood was incubated overnight with antigen in the presence of costimulatory antibodies to CD28 and CD49d. The blood was then treated with EDTA, erythrocytes were lysed, and leukocytes were fixed, permeabilized, and stained for intracellular cytokines [tumor necrosis factor-alpha (TNF-alpha) or IFN-gamma], CD4, and CD69. Cells were analyzed by flow cytometry and cytokine-producing CD69+ cells enumerated as a percentage of CD4 cells. Of nine patients analyzed, three demonstrated detectable CFC responses to tumor immunoglobulin and/or keyhole limpet hemocyanin (KLH) after vaccination. One of these patients responded only to KLH, whereas the other two responded to both tumor immunoglobulin and KLH. Most responses were detected with both TNF-alpha and IFN-gamma, but one patient's KLH response was detected only with TNF-alpha. There was a positive, but not strong, correlation of cytokine responses with proliferative responses to KLH. Although further follow-up and correlation with clinical outcome is needed, CFC may represent a simple yet detailed assessment of T-cell frequencies and subsets responding to cancer vaccines.
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PMID:Detection of CD4 T-cell responses to a tumor vaccine by cytokine flow cytometry. 1130 Apr 90

Previously, it was reported that patients with multiple myeloma (MM) who have higher baseline levels of blood CD4(+) or CD19(+) cells have longer survival. This article extends the analysis of immune cell levels and survival in a large cohort (N = 504) of patients with MM entered on Eastern Cooperative Oncology Group (ECOG) phase 3 trial (9486). Newly diagnosed patients with MM received 2 cycles of vincristine, bischloroethylnitrosourea, melphalan, cytoxan, prednisone (VBMCP) and were treated on one of 3 randomized arms: VBMCP with either interferon or high-dose cyclophosphamide, or VBMCP alone. Blood immune cell levels were studied at trial entry (baseline), after 2 cycles of chemotherapy, after 2 years of therapy, and at relapse. Baseline CD3(+), CD4(+), CD8(+), CD19(+), and CD4(+) subset cell levels were all positively associated with survival (P =.0087 to P <.0001). A multivariate analysis incorporating CD4(+) and CD19(+) cell levels defined 3 separate groups of patients with MM to survival outcome. Higher CD19(+) blood levels were positively associated with MM-patient survival at entry to the study, at year 2, and at relapse (P <.0001 at all 3 timepoints). Patients with MM had evidence of immune cell reconstitution after 2 years of therapy, but the rate and extent of recovery was greater for CD8(+), which was greater than CD4(+), which was greater than CD19(+). This latter data affirms the positive relationship between the quantitative status of the blood immune system in MM and survival. In addition, the importance of the CD19(+) blood cells to survival is evident throughout the course of MM. Therapeutic efforts to maintain an intact immune system may be crucial in maximizing chemotherapeutic and/or immunotherapy efforts in this disease.
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PMID:Blood levels of immune cells predict survival in myeloma patients: results of an Eastern Cooperative Oncology Group phase 3 trial for newly diagnosed multiple myeloma patients. 1141 58

The C chemokine lymphotactin has been characterized as a T cell chemoattractant both in vitro and in vivo. To determine whether lymphotactin expression within tumors could influence tumor growth, we transfected an expression vector for lymphotactin into SP2/0 myeloma cells and tested their ability to form tumors in BALB/c and nude mice. Transfection did not alter cell growth in vitro. Whereas SP2/0 cells gave rise to a 100% tumor incidence, lymphotactin-expressing SP2/0-Lptn tumors invariably regressed in BALB/c mice and became infiltrated with CD4(+) and CD8(+) T cells and neutrophils. Regression of the SP2/0-Lptn tumors was associated with a type 1 cytokine response and dependent on both CD4(+) and CD8(+) T cells, but not NK cells. Both SP2/0 and SP2/0-Lptn tumors grew in nude mice, but growth of the latter tumors was retarded and associated with heavy neutrophil responses; this retardation of SP2/0-Lptn tumor growth was reversed by neutrophil depletion of the mice. Our data also indicate that mouse neutrophils express the lymphotactin receptor XCR1 and that lymphotactin specifically chemoattracts these cells in vitro. Thus, lymphotactin has natural adjuvant activities that may augment antitumor responses via effects on both T cells and neutrophils and thereby could be important in gene transfer immunotherapies for some cancers.
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PMID:Lymphotactin expression by engineered myeloma cells drives tumor regression: mediation by CD4+ and CD8+ T cells and neutrophils expressing XCR1 receptor. 1141 32

Previous trials of allogeneic bone marrow transplantation (BMT) in patients with multiple myeloma (MM) have demonstrated high response rates but also high transplantation-related mortality (TRM) and high relapse rates. Exploitation of this strategy remains of interest because donor lymphocyte infusions (DLIs) can induce a potent graft-versus-myeloma (GVM) effect. CD6 T-cell--depleted allogeneic BMT was combined with prophylactic CD4(+) DLI administered 6 to 9 months after BMT in an effort to reduce TRM and to induce a GVM response after BMT. Twenty-four patients with matched sibling donors and chemotherapy-sensitive disease underwent BMT. CD6 T-cell depletion of donor bone marrow was the sole method of graft-versus-host disease (GVHD) prophylaxis. GVHD after BMT was minimal, 1 (4%) grade III and 4 (17%) grade II GVHD. Fourteen patients received DLI, 3 in complete response and 11 with persistent disease after BMT. Significant GVM responses were noted after DLI in 10 patients with persistent disease, resulting in 6 complete responses and 4 partial responses. After DLI, 50% of patients developed acute (> or = II) or extensive chronic GVHD. Two-year estimated overall survival and current progression-free survival (PFS) for all 24 patients is 55% and 42%, respectively. The 14 patients receiving DLI had an improved 2-year current PFS (65%) when compared with a historical cohort of MM patients who underwent CD6-depleted BMT survived 6 months with no GVHD and did not receive DLI (41%) (P =.13). Although this study suggests that prophylactic DLI induces significant GVM responses after allogeneic BMT, only 58% of patients were able to receive DLI despite T-cell--depleted BMT. Therefore, less toxic transplantation strategies are needed to allow a higher proportion of patients to receive DLI and the benefit from the GVM effect after transplantation. (Blood. 2001;98:934-939)
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PMID:T-cell--depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. 1149 35

IL-18 is a novel cytokine that stimulates T and NK cell activity and has potent antitumor effects. In this study, a mouse IL-18 gene was transfected into the mouse myeloma cell line J558. Our data demonstrated that (i) inoculation of 0.5x10(6) engineered tumor cells J558/IL-18 into syngeneic mice induced a Th1 dominant immune response and resulted in tumor regression in all 8/8 mice; (ii) the IL-18 antitumor effect was significantly decreased in mice depleted of either the CD4(+), or CD8(+), or NK cell subset, respectively but was completely abrogated in mice depleted of both CD4(+) and CD8(+) T cells; (iii) in vivo neutralization of IFN-gamma was accompanied by the growth of J558/IL-18 tumor in all the mice; and (iv) the J558/IL-18 tumor regression further induced protective immunity against a subsequent challenge by the parental J558 tumor, which is mediated by CD8(+) T cells as examined in the cytotoxicity assay in vitro and in the animal study in vivo. Taken together, our findings indicate that: (i) IL-18 can induce antitumor immune responses mediated by both CD4(+)/CD8(+) T cells and NK cells; and (ii) it is associated with IFN-gamma production. This study thus highlights the potential utility of IL-18 as an antitumor agent, a role that it can fulfil alone or in combination with other immunomodulatory cytokines such as IL-12.
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PMID:Regression of engineered myeloma cells secreting interferon-gamma-inducing factor is mediated by both CD4(+)/CD8(+) T and natural killer cells. 1153 25

A start was made on explorations into hybridoma technologies at the N. N. Blokhin Russian Cancer Research Center in the late 1970s. ICO series monoclonal antibodies (MAb) against different human differentiation leukocyte antigens have been designed in a short period of time. MAb to antigens CD25, CD8, CDw50, CD5, CD4, CD7, CD3, CD71, CD34, CD45, CD38, CD11b, CD16, and CD95 have gained worldwide recognition at International HDLA Workshop Conferences. Today, the collection of hybridomas at the Center includes more than 200 samples. MAb are used for immunophenotypic assays of blood and bone marrow cells, for classification of lymphomas and leukemias, for assessment of human immunity for immunophenotypic diagnosis of minimal residual tumor in multiple myeloma. New prognostic markers in various nosological entities and MAb biological activity are under study. MAb have been used to develop ELISA diagnostic kits. They are employed as vectors for immunotoxin design, for immunomagnetic separation, many MAb-based drugs have been designed. A start has been made on the promising development of a new line of biopharmacy, namely design of new immunoliposomal dosage forms of doxorubicin and betulinic acids.
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PMID:[Monoclonal antibodies in oncology]. 1167 47

Keyhole limpet hemocyanin (KLH) has been used as an immune potentiator to enhance antigen-specific responses against haptens and weak antigens including self-antigens. In the present study, we describe the optimization of the intracellular cytokine response to KLH in peripheral blood mononuclear cells (PBMC) of lymphoma and myeloma patients that were vaccinated with tumor-specific immunoglobulin (Id) conjugated to KLH. Addition of anti-CD28 antibody significantly enhanced cytokine-producing CD4-T cells. While fresh PBMC showed maximal cytokine response 14 h after antigen stimulation, the frozen PBMC showed maximal cytokine responses by 24 h. Supplementation of the culture medium with fetal bovine serum gave a better signal-to-noise ratio than human AB serum in the intracellular detection of cytokines. The intracellular cytokine responses correlated with the cytokine measurements by enzyme-linked immunosorbent assay (ELISA). Together these results indicate that the intracellular cytokine assay is very helpful to measure antigen-specific immune responses, and in subsequent studies, we have utilized this sensitive technique to detect immune responses against tumor antigens such as idiotype.
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PMID:Detection of keyhole limpet hemocyanin (KLH)-specific immune responses by intracellular cytokine assay in patients vaccinated with idiotype-KLH vaccine. 1176 19

The idiotype protein, secreted by myeloma plasma cells, is a tumor-specific but weak antigen. Idiotype-based immunotherapy has been explored in myeloma patients with disappointing results. It is conceivable that myeloma cells contain a multitude of tumor antigens that can more effectively stimulate antitumor T cells. To explore the possibility of using whole myeloma cells as a source of tumor antigens for immunotherapy, the current study was undertaken to generate and examine the function of myeloma-specific cytotoxic T lymphocytes (CTLs) by using dendritic cells (DCs) pulsed with myeloma cell lysates as stimulating cells. After repeated stimulation, specific CTL lines, containing CD4(+) and CD8(+) T cells, were generated from myeloma patients. Our results show that these T cells not only recognized and lysed autologous myeloma protein-pulsed DCs, they also killed autologous primary myeloma cells. Occasionally, CTLs responded to autologous idiotype-pulsed DCs and to allogeneic primary myeloma cells. No cytolytic activity, however, was detected against autologous lymphocytes including B cells, suggesting that the T cells acted specifically against myeloma cells. Cytotoxicity against target cells was major histocompatibility complex class 1 and, to a lesser extent, class 2 restricted and was dependent mainly on the perforin-mediated pathway. CTLs secreted predominantly interferon-gamma and tumor necrosis factor-alpha on antigenic stimulation, indicating a type 1 T-cell subset. These findings represent the first demonstration that tumor cell lysate-primed CTLs kill only myeloma cells, not autologous lymphocytes. This provides a rationale for myeloma cell-based immunotherapy in multiple myeloma.
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PMID:Tumor lysate-specific cytotoxic T lymphocytes in multiple myeloma: promising effector cells for immunotherapy. 1196 94


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