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)

We have previously reported that specific anti-tumour cytotoxic T cells (CTL) can be differentiated from tumour-infiltrating lymphocytes (TIL) in non-Hodgkin's lymphoma. We found that the combination of interleukin (IL)-1, IL-2 and IL-12 was very efficient for expansion of CD8+ T-cell receptor (TCR)alphabeta+ T cells and for development of their ability to specifically lyse tumour cells. In this study, we investigated whether anti-tumour T cells could be generated from the peripheral blood of patients using the culture protocol developed for TIL. Autologous T cells and tumour B cells from five patients were included in this study. It was found that polyclonal anti-tumour cytotoxic effector cells were generated when cultured in the presence of IL-1beta, IL-2 and IL-12. Interestingly, tumour cells were lysed by perforin/granzyme-mediated cytolysis and not by CD95-mediated apoptosis. By performing inhibition experiments, it was observed that both CD8+ and CD4+ T cells were responsible for the cytotoxic effect and that they were able to recognize malignant B cells by either a major histocompatibility complex (MHC)-restricted or MHC-non-restricted mechanism. Intriguingly, in addition to interferon-gamma and tumour necrosis factor-alpha, IL-10 was secreted continuously during culture. The source of patient T cells used for the generation of anti-tumour CTL should be based on the results obtained with peripheral blood lymphocytes and TIL.
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PMID:Differentiation of anti-tumour cytotoxic T lymphocytes from autologous peripheral blood lymphocytes in non-Hodgkin's lymphomas. 1240 81

Immunotherapy with high-dose interleukin (IL) 2 has been shown to successfully treat tumors in animal models and cause dramatic tumor regressions in some patients with metastatic melanoma, renal cell carcinoma, and non-Hodgkin's lymphoma. However, toxicity associated with IL-2 administration has compromised its widespread use in the clinic. IL-21 is a more recently discovered cytokine produced by activated CD4(+) T cells that shares significant sequence homology to IL-2, IL-4, and IL-15. Because IL-21 and IL-2 and their receptors share significant sequence similarities and both cytokines can stimulate T and natural killer (NK) cells, we sought to study whether IL-21, like IL-2, exhibits antitumor effects in vivo. In this study, we treated established s.c. tumor in mice by systemically administering plasmid DNA encoding murine IL-21 using a hydrodynamics-based gene delivery technique. Administration of IL-21 plasmid DNA resulted in high levels of circulating IL-21 in vivo. Treatment of tumor-bearing mice with IL-21 plasmid DNA significantly inhibited the growth of B16 melanoma and MCA205 fibrosarcoma in a dose-dependent manner without significant toxicity and increased the survival rate, compared with mice treated with control plasmid DNA. In vivo depletion of either CD4(+) or CD8(+) T cells did not affect IL-21-mediated antitumor activity. However, depletion of NK cells completely abolished IL-21-induced tumor inhibition. Consistent with this, the antitumor activity of IL-21 seemed to be mediated through enhanced cytolytic activity of NK cells. Our study suggests that IL-21 has significant antitumor activity and may have therapeutic potentials as an antitumor agent in the clinic.
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PMID:In vivo antitumor activity of interleukin 21 mediated by natural killer cells. 1469 20

T lymphocytes play a central role in controlling adaptive immune responses. IL-2 critically regulates both T cell growth and death and is involved in maintaining peripheral tolerance, but the molecules involved in these and other IL-2 actions are only partially known. We now provide a comprehensive compendium of the genes expressed in T cells and of those regulated by IL-2 based on a combination of DNA microarrays and serial analysis of gene expression (SAGE). The newly identified IL-2 target genes include many genes previously linked to apoptosis in other cellular systems that may contribute to IL-2-dependent survival functions. We also studied the mRNA expression of known regulators of signaling pathways for their induction in response to IL-2 in order to identify potential novel positive and/or negative feedback regulators of IL-2 signaling. We show that IL-2 regulates only a limited number of these genes. These include suppressors of cytokine signaling (SOCS) 1, SOCS2, dual-specificity phosphatase (DUSP) 5, DUSP6 and non-receptor type phosphatase-7 (PTPN7). Additionally, we provide evidence that many genes expressed in T cells locate in chromosomal clusters, and that select IL-2-regulated genes are located in at least two clusters, one at 5q31, a known cytokine gene cluster, and the other at 6p21.3, a region that contains genes encoding the tumor necrosis factor (TNF) superfamily members TNF, LT-alpha and LT-beta.
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PMID:Global analysis of IL-2 target genes: identification of chromosomal clusters of expressed genes. 1598 98

Denileukin diftitox (DAB(389)IL-2 or Ontak) is a synthetic fusion protein with demonstrated efficacy in a number of lymphoproliferative disorders, including non-Hodgkin's lymphoma. We report the case of a 45-year-old man with progressive follicular large cell lymphoma following an autologous stem cell transplant treated with denileukin diftitox who developed a fatal skin rash associated with extensive erythema, edema and large bullae involving his entire body. The clinical features and pathology were compatible with toxic epidermal necrolysis. This is the first reported case of toxic epidermal necrolysis in the literature associated with denileukin diftitox.
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PMID:Toxic epidermal necrolysis associated with denileukin diftitox (DAB389IL-2) administration in a patient with follicular large cell lymphoma. 1626 85

The conditioning regimens for autologous SCT (auto-SCT) lead to impairment of the immune system and concomitant increase in susceptibility to infections. We studied the recovery of cellular immunity by in vitro analysis of T-cell proliferation and cytokine production profiles during the first 15 months after auto-SCT in patients with multiple myeloma and non-Hodgkin's lymphoma. PBMC were collected at 6, 9 and 15 months after transplantation and stimulated with a combination of CD2 and CD28 monoclonal antibodies, with PHA or with tetanus toxoid as recall antigen. A multiplex enzyme linked immunoassay was used to determine levels of Th1 cytokines IL-2, IFN-gamma and tumour-necrosis factor-alpha (TNF-alpha), Th2 cytokines IL-4, IL-5 and IL-13, the regulatory cytokine IL-10 and the proinflammatory cytokines IL-1alpha, IL-1beta, IL-6 and the chemokine IL-8. T-cell proliferation progressively increased from 6 to 15 months after auto-SCT. Overall, cytokine production increased after auto-SCT. Production of Th2 cytokines IL-5 and IL-13 was superior to production of Th1 cytokines IFN-gamma and TNF-alpha. We hypothesize that prolonged impairment of IFN-gamma production might contribute to the relatively high incidence of viral infections after auto-SCT.
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PMID:Development of T cell-mediated immunity after autologous stem cell transplantation: prolonged impairment of antigen-stimulated production of gamma-interferon. 1756 37

In sequential studies, we compared immune reconstitution following high-dose chemotherapy (HDT) and stem cell transplantation (SCT) using intact mobilized peripheral blood stem cell (PSC) in intermediate grade non-Hodgkin's lymphoma (NHL) patients and CD34(+), lineage-negative (Lin(-)), Thy-1(lo) (CD34(+)Lin(-)Thy-1(lo)) stem cells in low-grade NHL patients. Cytokine expression and cellular phenotype and function were used as the basis of comparison. Despite differences in cellular composition of the stem cell grafts, immune reconstitution in both groups was similar. Significantly higher levels of type 1- and 2-associated cytokine messenger ribonucleic acid (mRNA) were observed both prior to and following transplant in the peripheral blood (PB) of both cohorts as compared to normal individuals. Similar levels of interleukin (IL)-4, IL-10, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) messenger ribonucleic acid (mRNA) were seen in PB mononuclear cells following transplant with either product. In contrast, patients receiving isolated CD34(+)Lin(-)Thy-1(lo) cells expressed significantly higher IL-2 levels at all times examined post-transplant. Despite the high levels of cytokine gene expression and rapid restoration to pretransplant levels of CD3 cell number by day 30, T cell function and CD4:CD8 and CD4(+)CD45RA:CD4(+)CD45RO(+) ratios were significantly depressed in both cohorts compared to normal donors, and significantly lower in patients transplanted with CD34(+)Lin(-)Thy-1(lo) compared to patients receiving an intact PSC product. These data suggest that the peripheral tolerance in patients receiving HDT and an autologous SCT occurs independent of graft composition, although immune function and CD4 recovery are better facilitated by transplantation of an intact product.
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PMID:Immune reconstitution after autologous hematopoietic transplantation with Lin-, CD34+, Thy-1lo selected or intact stem cell products. 1757 Mar 20

Interleukin (IL)-2 is a glycoprotein lymphokine which induces proliferation of all subclasses of T-lymphocytes, natural killer cells and lymphokine activated killer cells, differentiation of cytotoxic cells and secretion of other cytokines, especially interferon-gamma. A fundamental property of IL-2 activated effector cells is to selectively lyse freshly isolated tumour cells. Work carried out on animal tumour models and application in human therapeutics has suggested the potential value of an immunotherapeutic approach in haematological malignancies, especially in the setting of minimal residual disease. Extensive phase I/II trials have been conducted in all haematological diseases, but the most interesting results have been obtained in acute myeloid leukaemia and non-Hodgkin's lymphoma, where the possibility of achieving partial and complete responses in patients with advanced disease has been reported. The feasibility and immunomodulatory effects of IL-2 treatment in patients with minimal residual disease after high-dose chemotherapy have also been explored. However, the heterogeneity of cases treated and administration schedules used does not allow definitive conclusions to be drawn about the true impact of IL-2 treatment on the prognosis of these patients. The clearly encouraging results reported in the literature deserve further investigation from a biological and clinical point of view; until the role of IL-2 in haematological malignancies has been identified, it should be used only in the investigative setting of clinical trials.
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PMID:Use of interleukin-2 in the management of haematological malignancies: focus on minimal residual disease. 1803 Nov 61

Using biopsy specimens from patients with B-cell non-Hodgkin's lymphoma, we observed a significantly low frequency of T(H)17 cells, including several samples with no detectable amount of interleukin (IL)-17-producing cells present in the tumor microenvironment. We found that, in the absence of lymphoma B cells, treatment with IL-1beta/IL-6 or lipopolysaccharide (LPS) enhanced IL-17 expression in CD4(+) T cells and this enhancement was attenuated when CD4(+) T cells were cocultured with lymphoma B cells. Blockade of CD27-CD70 or CD28-CD80/86 interactions by anti-CD70 or anti-CD80/86 antibodies restored LPS-mediated induction of IL-17 expression in CD4(+) T cells cocultured with lymphoma B cells. Because a subset of lymphoma B cells express IL-2 and given that IL-2 signaling is critically important in the development of regulatory T (T(reg)) cells, we tested the role of IL-2 signaling in T(H)17 cell development. We found that treatment with anti-IL-2 antibody to interrupt IL-2 signaling significantly inhibited Foxp3 expression in CD4(+) T cells. In contrast, interruption of IL-2 signaling up-regulated IL-17 expression in CD4(+) T cells and restored lymphoma-mediated down-regulation of IL-17-producing cells. Furthermore, the reversal of T(reg) cell activity by LPS or CpG-A resulted in an enhancement of IL-17-producing cells. Taken together, our study indicated that lymphoma B cells play an important role in skewing the balance between T(reg) and T(H)17 cells resulting in the establishment of a profoundly inhibitory tumor microenvironment.
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PMID:Malignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkin's lymphoma. 1950 24

Therapeutic vaccination holds great potential as complementary treatment for non-Hodgkin's lymphoma. Here, we report that a therapeutic whole cell vaccine formulated with IL-2 adsorbed onto aluminum hydroxide as cytokine-depot formulation elicits potent antitumor immunity and induces delayed tumor growth, control of tumor dissemination and longer survival in mice challenged with A20-lymphoma. Therapeutic vaccination induced higher numbers of tumor's infiltrating lymphocytes (CD4(+) and CD8(+) T cells and NK cells), and the production of IFN-gamma and IL-4 by intratumoral CD4(+) T cells. Further, strong tumor antigen-specific cellular responses were detected at systemic level. Both the A20-derived antigenic material and the IL-2 depot formulation were required for induction of an effective immune response that impacted on cancer progression. All mice receiving any form of IL-2, either as part of the vaccine or alone as control, showed higher numbers of CD4(+)CD25(+/high)Foxp3(+) regulatory T cells (Treg) in the tumor, which might have a role in tumor progression in these animals. Nevertheless, for those animals that received the cytokine as part of the vaccine formulation, the overall effect was improved immune response and less disseminated disease, suggesting that therapeutic vaccination overcomes the potential detrimental effect of intratumoral Treg cells. Overall, the results presented here show that a simple vaccine formulation, that can be easily prepared under GMP conditions, is a promising strategy to be used in B-cell lymphoma and may have enough merit to be tested in clinical trials.
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PMID:A B-cell lymphoma vaccine using a depot formulation of interleukin-2 induces potent antitumor immunity despite increased numbers of intratumoral regulatory T cells. 1976 58

This study was aimed to investigate the killing activity of cytokine-induced killer (CIK) cells after being incubated with autologous tumor cell lysate-pulsed dendritic cells (DC) and to evaluate the clinical efficacy and side effect of autologous tumor cell lysate-loaded DC in combination with CIK on relapsed or refractory non-Hodgkin's lymphoma (NHL). Peripheral blood mononuclear cells (PBMNC) were isolated from 9 patients with NHL, and cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) to produce DC. The DC were pulsed with autologous tumor cell lysate. T lymphocytes from PBMNC were cultured with interferon-gamma (IFN-gamma), IL-2, CD3-moAb, and IL-1alpha to prepare CIK. After receiving the immunotherapy of DC and CIK, immunologic and clinical responses were evaluated. The results showed that the AgNOR, CD3(+)CD8(+) and CD3(+)CD56(+) ratio were markedly improved after the immunotherapy (p < 0.01); IFN-gamma and IL-12 levels in supernatant of DC-CIK group were higher than that in CIK group (p < 0.01); Tumor size were significantly decreased after the immunotherapy (p < 0.05). Except transient fever and chill, no remarkable adverse event happened during or after the treatment. It is concluded that the autologous tumor cell lysate-pulsed DC in combination with CIK show ability to specifically kill the lymphoma cells, obviously increases the IS value of Ag-NOR in peripheral lymphocytes, secretes cytokines higher than CIK cells alone. This combination displays the short-term satisfied efficacy on NHL through inducing specific antitumor immunity, and can be used as an effective adjuvant measure for the routine therapy of NHL.
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PMID:[Therapy of relapsed or refractory non-Hodgkin's lymphoma by antigen specific dendritic cells-activated lymphocytes]. 2013 51


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