transforming-growth-factor-beta and Lymphoma--Non-Hodgkin

Advances in understanding of the immune microenvironment have highlighted the role of immunosuppressive T cell, myeloid, dendritic and monocytic sub-populations in inhibition of the anti-tumor immune response. The role of B cells in modulating the immune response to solid tumors as well as lymphoid malignancies is less well understood. Murine models of autoimmune disease have defined B regulatory cell (Breg) subsets with immune suppressive activity, including B cell subsets that express IL-10, and transforming growth factor-β, which can facilitate T regulatory cell recruitment and expansion. Multiple murine tumor models point to the existence of similar immune suppressive B cell sub-populations that can migrate into tumor deposits and acquire an immune suppressive phenotype, which then leads to attenuation of the local anti-tumor immune response. Other murine models of viral or chemically induced skin carcinogenesis have identified a pivotal role for B cells in promoting inflammation and carcinogenesis. While many human solid tumors demonstrate significant B cell infiltration and/or tertiary lymphoid structure formation, the functional properties of tumor-infiltrating B cells and their effects on immunity are poorly understood. Recent successes in early Phase I/II trials using anti-checkpoint inhibitor antibodies such as nivolumab or pidilizumab directed against PD-1 in the setting of Hodgkin's and non-Hodgkin's lymphomas validate the therapeutic utility of reversing B cell-mediated immune suppression. Further studies to define Breg subsets, and mechanisms of suppression, may provide new avenues for modulation of the immune response and meaningful therapeutic intervention in both lymphoid and solid tumors.

Topics: Animals; Autoimmune Diseases; B-Lymphocytes, Regulatory; Cell Lineage; Clinical Trials as Topic; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Hodgkin Disease; Humans; Immune Tolerance; Interleukin-10; Lymphoma, Non-Hodgkin; Mice; Signal Transduction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tumor Microenvironment

Allogeneic blood stem-cell donors demonstrate more vigorous mobilization of CD34(+) cells to the circulation in response to cytokine administration than do autologous donors. Transforming growth factor (TGF-beta1) has been implicated as a mobilization inhibitor. A study was designed to determine whether plasma TGF-beta1 levels are elevated in cytokine-mobilized autologous cancer donors compared with cytokine-mobilized normal donors.. Plasma collected from 29 autologous cancer donors and 33 normal allogeneic stem-cell donors following administration of mobilizing cytokines just prior to the first collection was assayed for TGF-beta1 using a sandwich-type ELISA. Plasma from three volunteers not treated with cytokine was also analyzed. Comparisons were made using the Student's t test on log-transformed data.. Average TGF-beta1 levels in the plasma of cancer patients were significantly higher than in allogeneic stem-cell donors (4.4 ng/mL versus 7.2 ng/mL; p = 0.038). The allogeneic donors required fewer collections to harvest greater numbers of CD34(+) cells and colony-forming unit granulocyte-macrophage (CFU-GM) than autologous donors. Plasma from three untreated volunteers had mean TGF-beta1 levels of 0.36 ng/mL, with all three levels below the 25th percentile for allogeneic donors and the 5th percentile for cancer patients.. Cytokine administration was associated with increased plasma TGF-beta1 levels. The levels were higher in cancer patients being mobilized for stem-cell collection than in allogeneic blood stem-cell donors. These differences could underlie the increased number of apheresis procedures required to harvest autologous graft products from cancer patients.

Topics: Antigens, CD34; Blood Donors; Breast Neoplasms; Enzyme-Linked Immunosorbent Assay; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Humans; Lymphoma, Non-Hodgkin; Neoplasms; Transforming Growth Factor beta; Transplantation, Autologous; Transplantation, Homologous

Nyctanthes arbor-tristis Linn. is native to Indo-Pak sub-continent and has high medicinal values in Ayureda. This plant has been used traditionally for the treatment of sciatica, rheumatism, chronic fever, diabetes, snakebite, dysentery, cachexia and cancer. Studies have shown many pharmacological properties such as anti-cancer efficacy against Dalton's ascetic lymphoma, cytotoxicity against T-cell leukemia, anti-inflammatory, anti-diabetic and anti-oxidant effects.. Aim of the study was to explore the anti-inflammatory and anti-proliferative potential of N. arbor-tristis.. Ethanol extract of fresh and uncrushed aerial parts of N. arbor-tristis was used in the present study. A new compound nyctanthesin A was isolated following a bioactivity-guided fractionation and chromatographic separations. Its chemical structure was elucidated through spectral studies including 1D, 2D-NMR experiments and HREIMS. The intracellular reactive oxygen species (ROS) and nitric oxide (NO) generation from phagocytes were detected by chemiluminescence technique and Griess method, respectively. TNF-α and TGF-β production was quantified by ELISA. Anti-lymphoma and cytotoxic activities were assessed by alamar blue and MTT assays, respectively. The transcription and protein expression level of Bcl-2, COX-2, p38 MAPK, PDL-1, NF-κB, c-Myc and PNF-κB was performed by qRT-PCR and protein blot assays, respectively.. Petroleum ether insoluble fraction of the ethanol extract of fresh and uncrushed aerial parts of N. arbor-tristis revealed anti-inflammatory potential by inhibiting ROS. A previously undescribed compound nyctanthesin A was isolated from this fraction and characterized by UV, IR, NMR and HREIMS. It showed significant anti-inflammatory property by inhibiting ROS, NO and TNF-α production. The strong anti-proliferative effects on B- cell lymphoma cells, DOHH2 and Raji, revealed its anti-lymphoma potential along with non-toxic profile against BJ and NIH-3T3 fibroblast cells of normal origin. The qRT-PCR results showed marked inhibition of Bcl-2, COX-2, p38 MAPK, PDL-1, c-Myc, NF-κB, and PNF-κB at transcription level in DOHH2 cells with comparatively lesser but significant effects in Raji cells, where the expression of Bcl-2 gene was not affected. The protein expression of PNF-κB in DOHH2 cells was inhibited by 66% (P < 0.05) and COX-2 in both cell lines was inhibited by 50% (P < 0.05) at 60 μg/mL. A moderate non-significant inhibition of TGF-β (∼20%) was observed in both cell lines at 100 μg/mL CONCLUSIONS: Scientific evidences reported here validate the anti-inflammatory and anti-cancer potential of the plant.

Topics: Anti-Inflammatory Agents; Cyclooxygenase 2; Ethanol; Humans; Lipopolysaccharides; Lymphoma, Non-Hodgkin; NF-kappa B; Nitric Oxide; Oleaceae; p38 Mitogen-Activated Protein Kinases; Plant Extracts; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

We aimed to investigate any association between hepatitis C virus (HCV) infection and non-Hodgkin’s\ lymphoma (NHL) in the view of cytokines that control inflammation/angiogenesis and their correlation with\ certain CD markers. NHL patients with or without HCV infection were studied. CD5, CD30, CD3, CD20 and\ CD45 were immunohistochemically evaluated. Plasma levels of vascular endothelial and platelet derived growth\ factors (VEGF, and PDGF), tumor necrosis factor (TNF-α), transforming growth factor (TGF-β), interleukin-6\ (IL-6), IL-8, IL-4, IL-12 and interferon gamma (IFN-γ) were detected by enzyme-linked immunosorbent assay\ (ELISA). HCV+ve NHL patients showed a significant reduction in VEGF, PDGF, IFN-γ, CD5 and CD45 and a\ significant increase in IL-12 and IL-8. In conclusion, there was a significant change in cytokine secretion and\ expression of CD markers in HCV+ve NHL patients. Based on our results, HCV infection in NHL patients\ requires more in-depth investigations to explore any role in lymphoma progression.

Topics: Adolescent; Adult; Aged; Antigens, CD; Biomarkers, Tumor; Female; Hepacivirus; Hepatitis C; Humans; Inflammation; Interferon-gamma; Interleukin-12; Interleukin-4; Interleukin-6; Interleukin-8; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neovascularization, Pathologic; Platelet-Derived Growth Factor; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Young Adult

While the effect of TGF-β on malignant B cells in non-Hodgkin lymphoma (NHL) has been previously evaluated, studies to specifically define the role of TGF-β in tumor immunity in B-cell NHL are limited. We found that soluble TGF-β, secreted by both lymphoma cells and intratumoral T cells, is present in the serum of patients with B-cell NHL. Soluble TGF-β promoted regulatory T (T(reg)) cells by enhancing expression of Foxp3 in CD4(+) T cells and suppressed effector helper T (T(H)) cells by inhibiting expression of IFN-γ and IL-17. Blockade of the IL-2 signaling pathway diminished the effect of soluble TGF-β on T cell differentiation. Furthermore, we found that membrane-bound TGF-β is expressed specifically on the surface of malignant B cells in B-cell NHL. TGF-β was able to bind to the surface of lymphoma B cells through an interaction with heparan sulfate (HS) but not through the TGF-β receptor. We showed that pretreatment of lymphoma B cells with TGF-β significantly inhibits the proliferation and cytokine production of intratumoral T cells. Taken together, these results suggest that tumor-associated soluble and membrane-bound TGF-β are involved in the regulation of intratumoral T cell differentiation and function in B-cell NHL.

Topics: B-Lymphocytes; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Gene Expression Regulation, Neoplastic; Humans; Interleukin-2; Lymphoma, Non-Hodgkin; Signal Transduction; Solubility; T-Lymphocytes; Transforming Growth Factor beta; Tumor Microenvironment

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.

Topics: B-Lymphocytes; Biopsy; CD4-Positive T-Lymphocytes; Cytokines; Flow Cytometry; Forkhead Transcription Factors; Humans; Interleukin-17; Interleukin-2; Interleukin-23; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Mesenchymal stem cells (MSCs) have received much attention because of their capabilities of differentiating into multiple mesenchymal lineages and supporting hematopoiesis. Recently, MSCs have gained further interests after the demonstration of an immunosuppressive role. However, it's still unclear whether the immunosuppressive capability of MSCs will be altered with disease state. In this study, our results showed that MSCs derived from patients with lymphoblastic leukemia (ALL), Hodgkin disease (HD), and non-Hodgkin lymphoma (NHL) capable of suppressing the proliferation of T-lymphocyte stimulated in a mixed-lymphocyte reaction (MLR). The immunosuppressive effect of MSCs derived from ALL, HD and NHL on T-cell proliferation was dose-dependent. The supernatants of MSCs derived from ALL, HD and NHL had effect on T-cell proliferation. By using neutralising monoclonal antibodies, we found that transforming growth factor beta1 (TGFbeta1) and hepatocyte growth factor were major mediators of T-cell suppression by MSCs derived from ALL, HD and NHL. Although MSCs derived from patients with myelodysplastics syndromes (MDS) could inhibit T-cell proliferation stimulated with mitogen or in MLR, the inhibitory effect of MDS-MSCs was impaired. However, adherent cells derived from patients with acute myeloid leukemia (AML) showed abnormal immunomodulatory functions. Adherent cells derived from AML failed to suppress the proliferation of T-cell stimulated in MLR.

Topics: Bone Marrow Cells; Hematologic Neoplasms; Hepatocyte Growth Factor; Hodgkin Disease; Humans; Immunologic Factors; Immunosuppression Therapy; Lymphocyte Culture Test, Mixed; Lymphoma, Non-Hodgkin; Mesenchymal Stem Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Transforming Growth Factor beta

We report 3 cases of reduced cardiac function with complications in non-Hodgkin's lymphoma patients who were treated with rituximab. Patients experienced reduced cardiac functions after the administration of rituximab; there was no evidence of any preceding infusion reactions. Reticulin fiber was observed diffusely in cardiac muscles. Transforming growth factor-beta levels were elevated after the administration of rituximab. We believe that continuous elevation of transforming growth factor-beta may promote the growth of reticulin fiber in cardiac muscles. Reduction in cardiac functions is a severe complication that must be considered when rituximab is administered.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Drug Hypersensitivity; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Myocardium; Reticulin; Rituximab; Transforming Growth Factor beta; Ventricular Dysfunction, Left

Non-Hodgkin's lymphomas (NHL) constitute a heterogenous group of mainly B-cell lymphoproliferative diseases with different patterns of clinical behaviour. Biological mechanisms leading to development of NHL are not clearly understood. Transforming growth factor-beta1 (TGF-beta1) influences B cell growth and development. The present study aimed to determine whether there is an association between the polymorphic features located within the TGF-beta1 gene in NHL patients and progression of the disease. Two single nucleotide polymorphisms at positions 869 T/C (Leu10Pro) and 915 G/C (Arg25Pro) in the precursor region of the TGF-beta1 gene were determined in 55 NHL patients and 50 healthy individuals by PCR-SSP technique using commercial primers. In univariate analysis the presence of TGF-beta1 high producer genotypes (T/T G/G or T/C G/G) was found to significantly associate with an increased number of extranodal sites (11/30 vs 3/25, p=0.035 for two or more extranodal sites in patients having or lacking the TGF-beta1 high producer genotype, respectively). TGF-beta1 high producer genotype together with other clinical and biological factors (patient sex and age, stage and aggressiveness of the disease, presence of B symptoms, serum LDH level) were subjected to multivariate logistic regression analyses for the number of extranodal sites. Multivariate analysis confirmed the role of TGF-beta1 high producer genotype as a risk factor of NHL manifestation in two or more extranodal sites (OR=7.217, p=0.043) in addition to histological aggressiveness of the disease (OR=4.302, p=0.057). TGF-beta1 gene polymorphisms were found to associate with the course of the disease in NHL patients. TGF-beta1 high producer genotype appeared as an independent risk factor of extranodal manifestation of the disease.

Topics: Alleles; Disease Progression; Female; Genotype; Humans; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Polymorphism, Genetic; Risk Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

An ascitic lymphosarcoma (LS-A) of Swiss mice that regressed spontaneously on subcutaneous (s.c.) transplantation was investigated for the mechanism of its progressive growth and host mortality on intraperitoneal (i.p.) transplantation. In vitro studies indicated significant inhibition of LS-A proliferation seeded at higher cell density (>10(4)/ml). Culture supernatants of LS-A caused bi-modal growth effects, the early supernatants (24 h) caused stimulation and the late (72 h) supernatants inhibited LS-A proliferation. The 72-h supernatants also suppressed T and B cell response to mitogens in a dose-dependent manner. Pan anti-transforming growth factor-beta antibody abrogated the inhibitory effects of supernatants. The supernatants contained both latent as well as bio-active form of transforming growth factor-beta1 (TGF-beta1) as determined by ELISA. Mice bearing i.p. ascites tumor had elevated serum TGF-beta1, hemoglobulinemia, splenic lymphopenia, impaired response of the T cells to mitogen and reduced expression of transferrin receptor (CD71) on the bone marrow cells. However, mice which rejected s.c. transplants, did not show significant changes in these parameters. Our studies indicated profound influence of site of tumor growth on tumor progression and host immune system mediated by tumor-derived TGF-beta1. It is possible that human tumors which secrete TGF-beta1 may exhibit similar patho-physiological effects in the host depending on the anatomical site of the tumor.

Topics: Anemia; Animals; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Ascites; Cell Proliferation; Disease Progression; Hemoglobins; Humans; Injections, Intraperitoneal; Injections, Subcutaneous; Lymphoma, Non-Hodgkin; Lymphopenia; Male; Mice; Mitogens; Receptors, Transferrin; Sarcoma, Experimental; Spleen; T-Lymphocytes; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Cells, Cultured

Transforming growth factor beta (TGF ) is involved in a variety of important cellular functions. The lack of TGF -dependent cell-growth control might be related to oncogenesis, as it has been shown in lung, breast, and colon carcinomas. Current observations have revealed that TGF is rather an inhibiting, not a stimulating, factor as far as malignant tumor development is concerned. Recently, however, there has been a growing number of reports on increased expression of TGF genes in certain tumors. In patients with a diagnosis of non-small-cell lung carcinoma, the tumors expressing high levels of TGF were the ones that had a higher proliferation and metastasis capability, whereas more promising were the cases with lower levels of TGF expression.. A pilot study of 14 patients was conducted comprising 8 patients with a low-grade lymphoma and 6 patients with a high-grade lymphoma. The QRT-PCR method was employed to assess the activity of TGF 1 and of its receptor types I, II, and III.. The expression values for TGF 1 and its receptors I, II, and III were twice as high in the group of patients with a diagnosis of high-grade lymphomas as in the group of patients diagnosed with low-grade lymphomas.. Results showed a clear difference in TGF 1 expression in patients with NHL depending on the subtype of the lymphoma, suggesting its significant role in the pathomechanism of this group of malignant diseases as well as its potential value as a prognostic factor.

Topics: Activin Receptors, Type I; Aged; Base Sequence; DNA Primers; Female; Gene Expression; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Pilot Projects; Protein Serine-Threonine Kinases; Proteoglycans; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

We assessed mRNA for chosen pro- and anti-inflammatory cytokines in T-lymphocytes of peripheral blood in paediatric patients with leukemias and lymphomas. Levels of four different cytokine mRNAs (IFN-gamma, IL-10, IL-4, TGF-beta) were determined by the real-time PCR technique. In the whole examined group, at the time of diagnosis, we noted lower amounts of mRNA for TGF-beta1, comparing to respective values in the control patients. In the ALL group, we observed the following: 1) at the time of diagnosis: lower amounts of mRNA for IL-4 and for TGF-beta1, comparing to respective values in the control group; 2) lower amounts of mRNA for IL-10 after remission induction, comparing to the time of diagnosis. In our opinion, "immunedysregulation" in lymphoproliferative diseases in children is not caused by IFN-gamma deficiency. The deficit of anti-inflammatory cytokines, i.e., IL-4, TGF-beta, with higher amounts of IL-10, suggests their role in cancer development.

Topics: CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Hodgkin Disease; Humans; Interleukin-10; Lymphoma; Lymphoma, Non-Hodgkin; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; RNA, Messenger; T-Lymphocytes; Transforming Growth Factor beta

Angiogenic cytokines regulate B-cell lymphopoiesis and are related to prognosis in B-cell lymphoproliferative disorders. Transforming growth factor-beta (TGF-beta) inhibits mature B-cell proliferation and immunoglobulin production. Increased levels of serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are associated with poor prognosis in non-Hodgkin lymphoma (NHL). To understand the expression of angiogenic cytokines at different stages of B-cell differentiation in lymph nodes, we examined the immunohistochemical expression of TGF-beta, VEGF, bFGF, and their receptors in five patients with reactive benign lymphadenopathy and 12 patients with B-cell NHL (mantle cell lymphoma, 4; small cleaved cell follicular lymphoma, 5; lymphoplasmacytic lymphoma, 3). In benign lymph nodes, TGF-beta1, TGF-beta2, and TGFbetaRII were positive in prefollicular mantle cells, follicular center cells, and postfollicular plasma cells. Basic FGF, FGF-R1, and FGF-R4 were positive in large follicular center cells and postfollicular plasma cells. Vascular endothelial growth factor was positive in large follicular center cells and postfollicular plasma cells. In NHL, TGF-beta and its receptors were weakly positive in small cleaved cell follicular lymphoma; VEGF was strongly positive in lymphoplasmacytic lymphoma and weakly positive in mantle cell lymphoma. Basic FGF and its receptors were negative in NHL; however, FGF-R4 was positive in some cases of small cleaved cell follicular lymphoma. Our findings suggest that TGF-beta, bFGF, and their receptors have opposite roles in B-cell differentiation and maturation in benign lymph nodes. Transforming growth factor-beta and its receptors have an important role in germinal center development; loss of their activity could be associated with abnormal clonal proliferation of NHL.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Cytokines; Endothelial Growth Factors; Female; Fibroblast Growth Factor 2; Humans; Immunoenzyme Techniques; Intercellular Signaling Peptides and Proteins; Lymph Nodes; Lymphokines; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neovascularization, Pathologic; Receptors, Cytokine; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The cyclin-dependent kinase inhibitor p27Kip1 is a key regulator of the G1/S transition, and an inverse relationship between p27Kip1 protein expression and proliferation index has been reported in malignant lymphomas. However, a subset of aggressive B-cell lymphomas demonstrates high p27Kip1 expression despite a high proliferation index. The aim of this study was to determine potential mechanisms by which lymphoma cells abrogate the growth inhibitory effect of high p27Kip1. The effect of transforming growth factor-beta (TGF-beta) and serum stimulation on p27Kip1 expression and cyclin E/cdk2 activity was investigated in four lymphoma cell lines, Jurkat, CEM-6, OCI-Ly1 and Nalm-6. Reactive lymphocytes responded to growth inhibitory TGF-beta by inducing p27Kip1 expression, with subsequent accumulation of cells in G0/G1. In contrast, TGF-beta did not alter the level of p27Kip1 in Jurkat, CEM-6 and OCI-Ly1 cells with no change in cyclin E/cdk2-kinase activity. Serum stimulation also did not result in a significant change in p27Kip1 expression. Western blot analysis of subcellular fractions demonstrated cytoplasmic p27Kip1, corroborated by immunocytochemistry in a subset of the lymphoma cells. Sequestration of p27Kip1 by cyclin D3 was observed in the nuclear and cytoplasmic fractions of Nalm-6, OCI-Ly-1 and NCEB cells. These results indicate that multiple mechanisms contribute to the abrogation of growth regulation by unscheduled high p27Kip1 protein expression including deficient response to TGF-beta and serum, sequestration by cyclin D3 and cytoplasmic displacement.

Topics: Blotting, Western; Cell Cycle Proteins; Cell Division; Cyclin D3; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Humans; Immunoblotting; Lymphoma, Non-Hodgkin; Transforming Growth Factor beta; Tumor Cells, Cultured; Tumor Suppressor Proteins

Marrow stromal cells of patients treated by autologous bone marrow transplantation (ABMT) for malignancies have been assessed for their ability to secrete granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), stem cell factor (SCF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), transforming growth factor beta1 (TGFbeta1) and macrophage inflammatory protein-1alpha. (MIP-1alpha). Long-term marrow cultures were established from 10 patients prior to and 3 months after ABMT, from 7 patients 1 yr after ABMT and from 11 controls. Cytokines in culture supernatants of stromal layers (SL) were evaluated by enzyme-linked immunosorbent assay (ELISA). Significant differences between patient groups and controls were apparent in baseline production of GM-CSF, SCF, MIP-1alpha and TGFbeta1. After IL-1beta addition in cultures, G-CSF production was reduced in pretransplant and post-transplant patients compared to controls. The production of TGFbeta1, LIF, IL-6 and more particularly SCF were reduced in post-transplant patients, while elevated levels of GM-CSF and MIP-1alpha were observed in these patients only when the values were corrected for the number of cells growing in the SL. These results indicate a prolonged stromal defect in growth factor production following ABMT for the early-stage acting cytokines IL-6, LIF and SCF as well as for G-CSF, but not for GM-CSF, while the production of the 2 inhibitors shows different pathways.

Topics: Adult; Bone Marrow Cells; Bone Marrow Transplantation; Cell Count; Chemokine CCL3; Chemokine CCL4; Cytokines; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Inhibitors; Humans; Interleukin-6; Leukemia Inhibitory Factor; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphokines; Lymphoma, Non-Hodgkin; Macrophage Inflammatory Proteins; Male; Middle Aged; Stem Cell Factor; Stem Cells; Stromal Cells; Transforming Growth Factor beta; Tumor Cells, Cultured

Topics: Child; Cytokines; Fatal Outcome; Female; Humans; Infant, Newborn; Lymph Nodes; Lymphatic Diseases; Lymphoma, Non-Hodgkin; Pulmonary Fibrosis; Respiratory Distress Syndrome, Newborn; Transforming Growth Factor beta

The study was carried out on 22 patients with non-Hodgkin's lymphoma (NHL) who had received sequential infusions of two thymidine analogues iododeoxyuridine (IUdR) and bromodeoxyuridine (BrdU). Cell cycle kinetic studies seemed to differentiate distinctly between low grade lymphoma (n = 8, LI = 2.6%) compared to that of intermediate grade (n = 9, LI = 13%, p = 0.0001) and high grade NHL (n = 5, LI = 16.3%, p = 0.0062). While the majority of 14 intermediate and high grade lymphomas had a high labeling index there were 3/14 patients with a LI of 5.5%, 5.5% and 4.1% respectively. A decrease in the rate of programmed cell death (PCD) or apoptosis due to the overexpression of bcl-2 has been implicated as the possible pathogenesis for follicular lymphoma. We determined the presence of bcl-2 protein immunohistochemically and apoptosis by in situ end labeling of DNA which detects cells in early stages of PCD not recognized morphologically. Nine NHL patients demonstrated PCD ranging from 1%-40%, while it was undetectable in 13/22 patients. Of these 13 cases, 6 showed the presence of bcl-2 expression. To understand the relationship of the microenvironment to the lymphoma cells, the presence of transforming growth factor beta (TGF-beta) was determined immunohistochemically. TGF-beta was present in all the cases where bcl-2 was present, except one. This study highlights some of the key biological features of NHL cells and their microenvironment.

Topics: Apoptosis; Bromodeoxyuridine; Cell Cycle; Cell Division; Humans; Idoxuridine; Immunohistochemistry; Lymphoma, Non-Hodgkin; Macrophages; Multivariate Analysis; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Transforming Growth Factor beta

Topics: Animals; Blotting, Northern; Gene Expression; Humans; Leukocytes, Mononuclear; Lymphoma, Non-Hodgkin; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Neoplasm Transplantation; Nucleic Acid Hybridization; RNA, Neoplasm; Thymidine; Transforming Growth Factor beta