transforming-growth-factor-beta and Neutropenia

Normal ovarian tissue is rich in cytokines. Cytokines and chemokines are important in the physiology of ovarian function and of ovulation. Cytokines and chemokines may recruit cytokine-producing lymphocytes to the site of a developing follicle, and cytokines appear to play an important role in pre and post follicle development. Most of the same cytokines that are found in normal ovarian tissue are also found in association with malignancy in contrast to their functions in normal tissues. It is reasonable to assume that the functions of cytokines associated with malignancy may serve to promote the unregulated growth if tumor cells and metastasis. It is also likely that cytokines produced by tumors will modulate immune responses that favor tumor progression. In the following review, we have highlighted those functions of cytokines that have been identified as having the most significant impact on tumor growth and development. By examining activities of these cytokines in normal and in malignant ovarian tissues, it is hoped that future possible avenues for investigation may be opened up and that the results of these investigations will lead to strategies that can modulate the production or the activity of the cytokines leading to the growth of tumors or their metastases. Such strategies now fall under the general discipline of bioimmunotherapy. This is an expanding discipline as more is learned about growth regulation in cancer, and with the availability and rapid development of new molecules for therapeutic approaches.

Topics: Animals; Antigen Presentation; Apoptosis; Biomarkers, Tumor; Cell Transformation, Neoplastic; Cytokines; Disease Progression; Female; Humans; Immunotherapy; Interferon-gamma; Interleukin-12; Interleukin-6; Macrophage Colony-Stimulating Factor; Mice; Neutropenia; Ovarian Neoplasms; Ovary; Ovulation; Signal Transduction; T-Lymphocytes, Cytotoxic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To investigate the safety and efficacy of the combination of lenalidomide and prednisone in patients with myelofibrosis (MF).. Forty patients with MF were treated. Therapy consisted of lenalidomide 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) on days 1 through 21 of a 28-day cycle for six cycles, in combination with prednisone 30 mg/d orally during cycle 1, 15 mg/d during cycle 2, and 15 mg/d every other day during cycle 3. Lenalidomide therapy was continued indefinitely in patients exhibiting clinical benefit.. The median follow-up was 22 months (range, 6 to 27). Responses were recorded in 12 patients (30%) and are ongoing in 10 (25%). The median time to response was 12 weeks (range, 2 to 32). According to the International Working Group for Myelofibrosis Research and Treatment consensus criteria, three patients (7.5%) had partial response and nine patients (22.5%) had clinical improvement durable for a median of 18 months (range, 3.5 to 24+). Overall response rates were 30% for anemia and 42% for splenomegaly. Moreover, 10 of 11 assessable responders who started therapy with reticulin fibrosis grade 4 experienced reductions to at least a score of 2. All eight JAK2(V617F)-positive responders experienced a reduction of the baseline mutant allele burden, which was greater than 50% in four, including one of whom the mutation became undetectable. Grade 3 to 4 hematologic adverse events included neutropenia (58%), anemia (42%), and thrombocytopenia (13%).. The combination of lenalidomide and prednisone induces durable clinical, molecular, and pathologic responses in MF.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Fibroblast Growth Factor 2; Glucocorticoids; Humans; Janus Kinase 2; Lenalidomide; Male; Middle Aged; Mutation; Neutropenia; Platelet-Derived Growth Factor; Prednisone; Primary Myelofibrosis; Thalidomide; Thrombocytopenia; Transforming Growth Factor beta; Treatment Outcome

Activation of coagulation appears to play a role in tumor progression. This report describes the preliminary results of a phase II study using docetaxel plus enoxaparin in 15 patients with stage IV non-small cell lung cancer (NSCLC). Time to progression was the primary endpoint. Several surrogate markers of coagulation and angiogenesis were evaluated. Enoxaparin was administered at a daily dose of 1 mg/kg (subcutaneously). The initial dose of docetaxel was 100 mg/m2, given as a 60 min infusion every 21 days with prophylactic dexamethasone. Eight patients achieved an objective response (53%) and four had stable disease, with a median duration of 3.5 months. The median time to progression was 5 months (range, 2 to >15 months). The median survival was 11 months. The most frequent toxicities were neutropenia and asthenia. No significant bleeding or thrombotic events were observed. Eleven patients had elevated D-dimer plasma levels prior to therapy, and seven of these patients with a response or stable disease had a significant decline of the D-dimer during therapy. There were no consistent changes of the plasma levels of the angiogenic factors, except for transforming growth factor-beta-1 (TGF-beta1). The median baseline level of TGF-beta1 prior to therapy was 34,867 pg/ml. Twelve out of 13 patients who achieved a response or stable disease had a significant reduction of the TGF-beta1 levels during therapy. Enoxaparin in combination with chemotherapy was safe and well tolerated in patients with advanced NSCLC. This preliminary data suggests that enoxaparin may prolong the time to progression, and therefore justify the continuation of this trial.

Topics: Aged; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease Progression; Docetaxel; Enoxaparin; Female; Humans; Infusions, Intravenous; Injections, Subcutaneous; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Taxoids; Transforming Growth Factor beta; Transforming Growth Factor beta1

Coxsackievirus B3 (CVB3) is the primary cause of viral myocarditis. An early and abundant neutrophil accumulation in the myocardium is a hallmark of early CVB3 infection. Yet the relative contribution of neutrophils to host susceptibility to CVB3 myocarditis remains largely unknown. Herein, peripheral neutrophil depletion was implemented in a BALB/c mouse model of acute CVB3 myocarditis using the specific 1A-8 (anti-Ly6G) or a RB6-8C5 (anti-Gr-1) mAb covering a wide range. Anti-Ly6G treatment led to systemic neutropenia throughout the disease, but did not alter virus replication, disease susceptibility and histopathological changes in the heart and pancreas of mice. In contrast, depletion of both neutrophils and monocytes/macrophages by anti-Gr-1 mAb prior to and after infection significantly promoted susceptibility of mice to CVB3 infection which was associated with exacerbated cardiac and pancreatic viral load. However, depletion of Gr1+ cells significantly suppressed acute myocarditis and pancreatic acini destruction at day 7 post infection via reducing Ly6C

Topics: Animals; Antigens, Ly; Coxsackievirus Infections; Cytokines; Disease Models, Animal; Fibrosis; Heart; Inflammation; Leukocytes; Male; Mice; Mice, Inbred BALB C; Myocarditis; Neutropenia; Neutrophils; Pancreas; Receptors, Chemokine; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Viral Load; Virus Replication

Microfibril-associated glycoprotein (MAGP) 1 and 2 are evolutionarily related but structurally divergent proteins that are components of microfibrils of the extracellular matrix. Using mice with a targeted inactivation of Mfap5, the gene for MAGP2 protein, we demonstrate that MAGPs have shared as well as unique functions in vivo. Mfap5(-/-) mice appear grossly normal, are fertile, and have no reduction in life span. Cardiopulmonary development is typical. The animals are normotensive and have vascular compliance comparable with age-matched wild-type mice, which is indicative of normal, functional elastic fibers. Loss of MAGP2 alone does not significantly alter bone mass or architecture, and loss of MAGP2 in tandem with loss of MAGP1 does not exacerbate MAGP1-dependent osteopenia. MAGP2-deficient mice are neutropenic, which contrasts with monocytopenia described in MAGP1-deficient animals. This suggests that MAGP1 and MAGP2 have discrete functions in hematopoiesis. In the cardiovascular system, MAGP1;MAGP2 double knockout mice (Mfap2(-/-);Mfap5(-/-)) show age-dependent aortic dilation. These findings indicate that MAGPs have shared primary functions in maintaining large vessel integrity. In solid phase binding assays, MAGP2 binds active TGFβ1, TGFβ2, and BMP2. Together, these data demonstrate that loss of MAGP2 expression in vivo has pleiotropic effects potentially related to the ability of MAGP2 to regulate growth factors or participate in cell signaling.

Topics: Alleles; Alternative Splicing; Amino Acid Sequence; Animals; Bone and Bones; Bone Density; Bone Morphogenetic Proteins; Cell Movement; Contractile Proteins; Exons; Extracellular Matrix Proteins; Gene Targeting; Genetic Pleiotropy; Leukocyte Count; Male; Mice; Mice, Knockout; Molecular Sequence Data; Mutant Proteins; Neutropenia; Neutrophils; Organ Size; Protein Binding; RNA Splicing Factors; RNA Stability; RNA, Messenger; Transcription, Genetic; Transforming Growth Factor beta

Patients with chronic idiopathic neutropenia (CIN) display relatively low peripheral blood platelet counts and hypo-lobulated megakaryocytes in the bone marrow (BM). The underlying pathogenetic mechanismswere probed by studying the reserves and clonogenic potential of BM megakaryocytic progenitor cells using flow-cytometry and a collagen-based clonogenic assay for the identification of megakaryocyte colony-forming units (CFU-Meg). Thrombopoietin (TPO) and transforming growth factor-beta1 (TGFbeta1) levels were also evaluated in long-term BM culture supernatants using an enzyme-linked immunosorbent assay. CIN patients (n = 39) showed a low proportion of BM CD34(+)/CD61(+) megakaryocytic progenitor cells and low frequency of early and mixed CFU-Meg in the BM mononuclear, but not CD34(+), cell fraction, compared with healthy controls (n = 20). TPO and TGFbeta1 levels were significantly higher in patients compared with controls. TPO levels inversely correlated with platelet counts whereas TGFbeta1 values correlated inversely with CD34(+)/CD61(+) and CFU-Meg megakaryocytic progenitor cell numbers and positively with TPO levels. The addition of an anti-TGFbeta1 neutralising antibody significantly increased the numbers of CFU-Meg in CIN patients but not in controls, compared with baseline. These data suggest that increased local production of TGFbeta1 probably affects the BM megakaryocytic progenitor cell growth in CIN whereas the compensatory production of TPO finally balances the TGFbeta1-induced inhibitory effect.

Topics: Adult; Aged; Antibodies, Monoclonal; Bone Marrow; Cytokines; Female; Flow Cytometry; Humans; Male; Megakaryocytes; Middle Aged; Neutropenia; Thrombopoiesis; Transforming Growth Factor beta; Transforming Growth Factor beta1

To study the changes in serum immunoglobulins and some closely related pro-inflammatory cytokines in patients with nonimmune chronic idiopathic neutropenia of adults (NI-CINA).. Serum levels of gamma-globulins, IgG, IgA, IgM, IgG subclasses, interleukin-4 (IL-4), interferon-gamma (IFN-gamma) and transforming growth factor-beta1 (TGF-beta1) were evaluated in 83 NI-CINA patients and 65 normal controls using the respective conventional methods.. We found that serum gamma-globulin, IgG and IgG1 levels were all significantly increased in the entire group of patients studied, compared to controls (p<0.001, p<0.01 and p<0.01, respectively), while the levels of IgG3 were significantly reduced (p<0.001). Serum IgA were increased in patients with severe neutropenia (p<0.001). No significant changes were noted in serum IgM, IgG2 and IgG4 levels. The infrequent occurrence of detectable amounts of IL-4 and IFN-gamma in the serum was similar in both, patients and control subjects. Serum levels of TGF-beta1 were increased in all groups of patients studied and they correlated inversely with the levels of IgG3 (p<0.001) and positively with the levels of IgA (p<0.001), suggesting the possible involvement of the cytokine in immunoglobulin class switching.. Patients with NI-CINA have significant changes in serum immunoglobulins and some inflammation-related cytokines. These findings provide additional evidence for the existence of an unrecognized low-grade chronic inflammatory process in NI-CINA patients and coroborate our previously reported suggestion for the possible involvement of this inflammation in the pathogenesis of neutropenia in the affected subjects.

Topics: Adolescent; Adult; Aged; Chronic Disease; Female; gamma-Globulins; Humans; Immunoglobulin A; Immunoglobulin G; Inflammation; Interferon-gamma; Interleukin-4; Male; Middle Aged; Neutropenia; Regression Analysis; Transforming Growth Factor beta; Transforming Growth Factor beta1

Previous studies in our laboratory have shown that patients with chronic idiopathic neutropenia of adults (CINA) have increased serum levels of inflammatory cytokines including IL-1beta. Since IL-1beta may affect bone marrow stromal cell function, a study was designed to investigate the capacity of patients' stromal cells to produce adequate amounts of haemopoietic growth factors or excessive amounts of inhibitors of myelopoiesis in long-term bone marrow cultures (LTBMCs). The study was carried out on 52 CINA patients and 19 normal controls. We found that CINA patients had significantly low numbers of marrow lineage-specific CD34+ cells, including CFU-GM and CD34+/CD33+ cells. Stromal cells from patients' LTBMCs failed to stimulate CFU-GM colony formation by normal marrow cells in a manner comparable to that of stromal cells of controls. Patients' LTBMC supernatants had normal or increased amounts of G-CSF. Detectable amounts of supernatant GM-CSF were found in 35% of patients and 19% of controls. IL-3 and MIP-1alpha were not detected in any supernatant fluid. Moreover, supernatants from patients' LTBMCs had increased concentrations of IL-6 and TGF-beta1, which strongly correlated with serum IL-1beta. About 82% of our patients had TGF-beta1 values higher than the upper limit of values found in the controls. Individual TGF-beta1 values inversely correlated with the number of circulating neutrophils and the frequency of marrow CD34+/CD33+ cells. We suggest that increased levels of serum IL-1beta, resulting from an underlying low-grade chronic inflammatory process, may stimulate marrow stromal cells to produce both haemopoietic growth factors and inhibitors of myelopoiesis. Since steady-state myelopoiesis results from a balance between negative- and positive-acting cytokines, it seems very probable that the increased production of TGF-beta1 by bone marrow microenvironment in CINA patients may suppress myelopoiesis and contribute, to some extent, to the pathogenesis of neutropenia in affected subjects.

Topics: Adult; Aged; Antigens, CD34; Bone Marrow Cells; Cell Count; Cells, Cultured; Chronic Disease; Colony-Forming Units Assay; Culture Media, Conditioned; Cytokines; Female; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Immunophenotyping; Interleukin-1; Interleukin-3; Interleukin-6; Male; Middle Aged; Neutropenia; Stromal Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

We have developed a mouse model to utilize the specific regulatory effects of Transforming Growth Factor Beta-1 (TGF beta 1), the prototype for a family of growth inhibitory cytokines. A vital factor in the regulation of normal cellular growth for many cell types, TGF beta 1 prevents proliferation by reversibly arresting cells at the G1/S border of the cell cycle, thus delaying DNA synthesis and cell division. Since the dose of cytotoxic chemotherapy is limited by its adverse effects on bone marrow and gut cells, we proposed that a TGF beta 1-induced block at G1/S would diminish the S phase toxicity of high dose cytarabine (ara-C). The dosage of ara-C required to kill 90 per cent of 4-week old DBA/2 males was determined to be 3200 mg/kg every 12 hours x 2. Pretreatment with TGF beta 1 6-24 hours before the first dose of ara-C proved to be significantly protective; 8/9 TGF beta 1-pretreated mice survived versus 1/9 treated with TGF beta 1 for 3 hours or less or with ara-C alone (chi2 = 10.89 P = 0.001). A second experiment confirmed this effect; TGF beta 1 pretreatment for 6-24 hours protected 9/9 versus 0/9 survivors in the group treated with TGF beta 1 for 3 hours or less or with ara-C alone (chi2 = 18.0, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cytarabine; Digestive System; Drug Administration Schedule; Erythrocyte Count; Hematopoietic Stem Cells; Leukocyte Count; Leukopenia; Male; Mice; Mice, Inbred A; Mice, Inbred DBA; Mice, Inbred Strains; Neutropenia; Platelet Count; S Phase; Stem Cells; Survival Rate; Transforming Growth Factor beta

Several mechanisms have been proposed to explain the pathogenesis of severe congenital neutropenia (SCN); however, the mechanism(s) still remains unknown. In particular, clinical observations suggest that abnormal responsiveness of myeloid progenitors to hematopoietic growth factors (HGFs) is a possible mechanism. Therefore, to better define the status of hematopoietic progenitors in the bone marrow (BM) of patients with SCN, the responsiveness of myeloid progenitors to HGFs from two SCN patients was compared with the responsiveness of progenitors from healthy individuals. BM cells (BMCs) from the first SCN patient required higher (10- to 100-fold) concentrations of granulocyte colony-stimulating factor (G-CSF) to achieve maximal and half-maximal colony growth in vitro compared with BMCs from controls. In contrast, the dose-response of interleukin-3 (IL-3) and granulocyte-macrophage-CSF (GM-CSF) in colony formation was normal. Interestingly, IL-3, GM-CSF, and G-CSF at optimal doses showed reduced ability to induce neutrophil differentiation of BMCs from a SCN patient compared with BMCs from controls. Despite an abnormal responsiveness of mature myeloid progenitors to G-CSF in this SCN patient, myeloid progenitors responsive to the combination of stem cell factor (SCF) and G-CSF showed normal dose-response. In contrast to G-CSF alone, the combination of G-CSF and SCF induced the formation of neutrophils almost to the same extent compared with cultures of normal BMCs. Furthermore, also on BM progenitor cells obtained from the second patient with SCN, SCF highly synergized with G-CSF to promote neutrophil progenitor cell growth and differentiation in vitro. Thus, these results indicate that one mechanism of the pathogenesis in SCN patients is reduced responsiveness of neutrophil progenitor cells to G-CSF and that SCF can enhance the responsiveness of these cells to G-CSF.

Topics: Bone Marrow; Cell Differentiation; Cell Division; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Infant; Interleukin-3; Male; Neutropenia; Stem Cell Factor; Transforming Growth Factor beta

This study reports the characterization of a spontaneous lymphoblastoid cell line (LCL) raised from the peripheral blood of a patient with Kostmann's congenital neutropenia. The LCL was composed of EBV-infected polyclonal B cells and displayed surface markers and pattern of growth in vitro typical of normal LCLs. The supernatant of the LCL contained a colony inhibiting activity (CIA) that decreased the cloning efficiency of normal committed haemopoietic progenitors and was identified as immunoreactive transforming growth factor beta 1 (TGF-beta 1) by neutralization experiments with a specific antiserum. Control studies with a panel of LCLs spontaneously derived from the peripheral blood of patients seropositive for Epstein-Barr virus (EBV) infections showed that 5/30 LCLs produced a CIA. This CIA was not identifiable as TGF-beta 1 but rather was due to the combined effects of tumour necrosis factor alpha (TNF alpha), tumour necrosis factor beta (TNF beta) and interferon alpha (IFN alpha), that were present in the LCL supernatants. The hypothesis that the B cells latently infected by EBV in vivo and possibly expanded as a consequence of the infection may have contributed to the inhibition of the patient granulopoiesis by releasing TGF-beta 1 will be discussed.

Topics: B-Lymphocytes; Cell Line; Female; Hematopoietic Stem Cells; Herpesvirus 4, Human; Humans; Infant; Neutropenia; Transforming Growth Factor beta