Cytokines and molecular therapy最新文献

{"title":"The role of granulocyte colony-stimulating factor in mobilization and transplantation of peripheral blood progenitor and stem cells .","authors":"R Haas,&nbsp;S Murea","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The article provides a review of the role of granulocyte colony-stimulating factor (G-CSF) for mobilization and transplantation of peripheral blood progenitor and stem cells. Recombinant gene technology has permitted the production of highly purified material for therapeutic use in humans. Progenitor cells can be assessed using semisolid and liquid culture assays or direct immunofluorescence analysis of cells expressing CD34. This antigen is found on lineage-determined hematopoietic progenitor cells as well as on more primitive stem cells with extensive self-renewal capacity. Administration of G-CSF during steady-state hematopoiesis or following cytotoxic chemotherapy leads to an increase of hematopoietic progenitor cells in the peripheral blood. The level of circulating CD34+ cells post-chemotherapy is greater compared with G-CSF administration during steady state. On the other hand, CD34+ cells harvested post-chemotherapy contain a smaller proportion of more primitive progenitor cells (CD34+/HLA-DR- or CD34+/CD38-) compared with G-CSF treatment alone. Independent of the mobilization modality, the amount of previous cytotoxic chemo- and radiotherapy adversely affects the yield of hematopoietic progenitor cells. While continuous subcutaneous administration of G-CSF between 5 and 16 micrograms/kg bodyweight is preferred, additional dose-finding studies may be helpful to optimize current dose schedules. Adhesion molecules like L-selectin, VLA (very late antigen)-4 and LFA (leukocyte function antigen)-1 are likely to play a role in mobilization, since these antigens are expressed on CD34+ cells from bone marrow in different densities compared with blood-derived CD34+ cells collected following G-CSF-supported cytotoxic chemotherapy. It is also relevant for transplantation that during G-CSF-enhanced recovery post-chemotherapy, peripheral blood is enriched with a greater proportion of CD34+ cells expressing Thy-1 in comparison with CD34+ cells from bone marrow samples obtained on the same day or before the mobilization therapy was started. The early nature of the CD34+/Thy-1+ cells is very likely since this phenotype has been found on stem cells from human fetal liver and bone marrow and on cord blood cells. As a result, G-CSF-mobilized blood stem cells provide rapid and sustained engraftment following high-dose therapy, including myeloablative regimens. Positive selection of CD34+ cells as well as ex vivo expansion using different cytokines are currently being investigated for purging and improvement of short-term recovery post-transplantation. Future developments include the use of blood-derived hematopoietic stem cells for somatic gene therapy. The availability of growth factors has been an important prerequisite for the development of these new avenues for cell therapy.</p>","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 4","pages":"249-70"},"PeriodicalIF":0.0,"publicationDate":"1995-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multidrug resistance expression and proliferative studies in poor risk acute myeloid leukemia treated with the FLAG (G-CSF plus fludarabine and Ara-C) regimen.","authors":"A Tafuri,&nbsp;L De Felice,&nbsp;M T Petrucci,&nbsp;M G Mascolo,&nbsp;M R Ricciardi,&nbsp;C Ciliberti,&nbsp;M P Martelli,&nbsp;M C Petti","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Fourteen poor risk acute myeloid leukemia (AML) patients were treated with G-CSF prior (from day 0) and during chemotherapy with fludarabine and Ara-C from day 1 to day 5 (the FLAG regimen). Several biological parameters were monitored on the blast population: multidrug resistance (MDR) functional expression by rhodamine-123 efflux (Rhd-E), cell cycle changes, induction of apoptosis and leukemic clonogenic cell growth (CFU-L). The mean basal Rhd-E value was 14.4% (range 0-51.2), and 12/14 patients exhibited a dye efflux > 4%, efficiently blocked by the MDR-reversal agent cyclosporin A. After 24 h of G-CSF administration, cell cycle studies showed in bone marrow (BM) samples a significant mean increase in S phase (p = 0.04) and in RNA content of G1 cells (p = 0.01), coupled to a significant increase in apoptosis (p = 0.02). Clonogenic cell growth analysis showed a twofold increase in BM CFU-L in 6 of the 14 cases tested. When G-CSF activity was assessed without the addition of exogenous growth factors (autonomous proliferation), a significant increase (p = 0.02) in CFU-L was found only in patients who achieved a complete remission (CR); these patients were also characterized by lower S-phase values at diagnosis. Eight of the 14 patients treated achieved CR, but the median response duration was three months, and only two cases are still in CR. The FLAG regimen can thus induce remission in poor risk AML patients. The responses, however, are short, suggesting that resistant cells are not efficiently affected by either the use of agents not involved in the MDR-efflux mechanism or by the G-CSF priming strategy. Other post-induction therapies need to be considered in further approaches.</p>","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 4","pages":"301-7"},"PeriodicalIF":0.0,"publicationDate":"1995-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20312803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular approaches to cancer immunotherapy.","authors":"G Forni,&nbsp;F Cavallo,&nbsp;M Consalvo,&nbsp;A Allione,&nbsp;P Dellabona,&nbsp;G Casorati,&nbsp;M Giovarelli","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The use of cytokines and costimulatory molecule gene-engineered tumor cells to enhance tumor immunogenicity and elicit curative responses against established tumors and tumor recurrences has become an attractive prospect. The immunotherapy data obtained in many experimental tumor systems using these engineered cells are reviewed here to provide a realistic assessment of the potential and limits of this technique.</p>","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 4","pages":"225-48"},"PeriodicalIF":0.0,"publicationDate":"1995-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor suppressor activity of the human consensus type I interferon gene.","authors":"Y Geng,&nbsp;D Yu,&nbsp;L M Blatt,&nbsp;M W Taylor","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Type I interferons have potent antiproliferative activity both in vitro and in vivo, and their tumor suppressor activity has been suggested. A series of eukaryotic vectors containing a synthetic human consensus type I interferon gene (IFN-con1) under the control of different promoters (cytomegalovirus early promoter, murine metallothionein promoter and the Rous sarcoma virus LTR) were constructed and stably transfected into type I IFN-deficient myelogenous leukemic K562 cells. Constitutive expression of IFNcon1 reverted the malignant phenotype, as indicated by loss of tumorgenicity in nude mice. When stably transformed cells were mixed with parental tumor cells, there was retardation of tumor growth. Constitutive expression of IFNcon1 reverted the malignant phenotype in vitro, as indicated by growth inhibition in culture, and reduction in colony formation on soft agar. Furthermore, IFNcon1 gene expression resulted in elevated erythroid differentiation, growth arrest in S phase and induced apoptosis. Thus the presence of an active IFNcon1 gene overcomes the oncogenic potential of K562 by coordinated modulation of cell proliferation, differentiation and programmed cell death, and it acts as a tumor suppressor in vivo.</p>","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 4","pages":"289-300"},"PeriodicalIF":0.0,"publicationDate":"1995-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20312802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Submitogenic concentrations of anti-CD3 monoclonal antibody exert antiapoptotic effects in preactivated CD4+ but not CD8+ human T cells.","authors":"L Karawajew,&nbsp;A N Veselkov,&nbsp;F Herrmann","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Immunological memory has been ascribed to the presence of long-lived memory cells. The mechanisms underlying their generation are not completely understood, but dependence on antigen persistence has been discussed in this regard. However, in spite of in vivo evidence favoring this model, studies on TCR/CD3 stimulation of T cell lines or unseparated peripheral blood T cell in vitro have failed to demonstrate prolonged survival of preactivated cells. We have examined the dose-dependent effect of TCR/CD3 engagement mimicked by immobilized anti-CD3 antibody. To this end, well-defined populations of CD4+ and CD8+ lymphoblasts isolated from bulk cultures of preactivated PBMCs by flow sorting were examined. These cells were restimulated with immobilized anti-CD3 in the presence or absence of various costimulatory factors, and were analyzed for their viability state, as well as their apoptotic and proliferative behavior. We have shown that inhibition of apoptosis following CD3 stimulation occurs at submitogenic concentrations, while activation-driven apoptosis requires high-density TCR/CD3 activation. Prevention of apoptosis by submitogenic CD3 stimulation was, however, observed only when CD4+ but not when CD8+ cells were investigated, and was not readily influenced by other costimulatory factors present in cultures. This observation points to the importance of antigen persistence in regulating survival of memory CD4+ but not CD8+ cells.</p>","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 4","pages":"271-9"},"PeriodicalIF":0.0,"publicationDate":"1995-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular biology of glucocerebrosidase and the treatment of Gaucher disease.","authors":"J A Barranger,&nbsp;J Tomich,&nbsp;S Weiler,&nbsp;S Sakallah,&nbsp;C Sansieri,&nbsp;T Mifflin,&nbsp;A Bahnson,&nbsp;F S Wei,&nbsp;J F Wei,&nbsp;M Vallor","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The inherited deficiency of glucocerebrosidase results in a group of sphingolipid storage disorders referred to collectively as Gaucher disease. Study of the biochemistry and cell biology of glucocerebrosidase has made possible an effective enzyme replacement therapy for the disease. Definition of the molecular genetics of glucocerebrosidase has improved diagnostic capabilities and presents the exciting possibility of a cure through gene therapy.</p>","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 3","pages":"149-63"},"PeriodicalIF":0.0,"publicationDate":"1995-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-1 and its inhibitors: a biologic and therapeutic model for the role of growth regulatory factors in leukemias.","authors":"R Kurzrock,&nbsp;M Wetzler,&nbsp;Z Estrov,&nbsp;M Talpaz","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Production of growth factors may provide a mechanism for disease evolution in some leukemias. Interleukin-1 is a plelotropic cytokine with the ability to synergize with other growth factors as well as to stimulate their production and release. Autocrine and/or paracrine secretion of interleukin-1 has been implicated in the pathogenesis of both chronic and acute myelogenous leukemia. Recently, a series of both specific and nonspecific IL-1 inhibitory molecules have been identified. These include IL-1 receptor antagonist, soluble IL-1 receptors, IL-1-converting enzyme inhibitor, IL-4, IL-10 and IL-1-antisense. Early experiments demonstrating the ability of some of these molecules to inhibit acute and chronic myelogenous leukemia growth suggest that clinical trials of these compounds may provide a novel management approach in these malignancies. Here we review the potential biologic and therapeutic role of IL-1 and its inhibitors in the myeloid leukemias.</p>","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 3","pages":"177-84"},"PeriodicalIF":0.0,"publicationDate":"1995-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and immune responses of tuberculosis patients treated with low-dose IL-2 and multidrug therapy.","authors":"B J Johnson,&nbsp;S R Ress,&nbsp;P Willcox,&nbsp;B P Pati,&nbsp;F Lorgat,&nbsp;P Stead,&nbsp;R Saha,&nbsp;P Lukey,&nbsp;P Laochumroonvorapong,&nbsp;L Corral","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The immune response to infection with M. tuberculosis depends on cytokine activation of effector cells. We therefore conducted a pilot study of recombinant human interleukin-2 (rhuIL-2) as an adjunct to multidrug therapy (MDT) to evaluate the safety of this approach and to determine whether IL-2 can enhance the cellular immune response in patients with pulmonary tuberculosis (TB). Patients included in this study presented with a wide range of extent and duration of infection, and were grouped into three categories for data analysis: (1) patients with newly diagnosed, acute-stage TB who were just beginning MDT; (2) patients who had received a minimum of 45 days MDT before the start of the study and who had responded to treatment; and (3) patients with multidrug-resistant (MDR) TB who had been on MDT for at least seven months without apparent beneficial clinical response. Twenty patients received 30 days of twice-daily intradermal injections of 12.5 micrograms of IL-2. Patients from all three groups showed improvement of clinical symptoms over the 30-day period of treatment with IL-2 and MDT. Results of direct smear for acid fast bacilli (AFB) demonstrated conversion to sputum-negative following IL-2 and MDT treatment in all newly diagnosed patients and in 5/7 MDR TB patients. (The size of the skin test response to purified protein derivative (PPD) of tuberculin increased during the 30-day IL-2 adjunctive therapy in newly diagnosed patients, but decreased or disappeared in the other two groups of treated patients.) Assays in vitro for phenotype distribution, natural killer (NK) cell activity, frequency of cells proliferating in response to exogenous IL-2, and antigen-induced blastogenesis demonstrated systemic responses to intradermally administered rhuIL-2. Levels of interferon-gamma (IFN-gamma) in plasma, peripheral blood mononuclear cell (PBMC) IFN-gamma mRNA and IFN-gamma mRNA in biopsy of site of skin test response to purified protein derivative (PPD) were highest in those patients with the most acute symptoms at the beginning of the study, and decreased during rhuIL-2 and MDT. IL-2 immunotherapy did not modify levels of mRNA expression for other cytokines. Patients receiving IL-2 did not experience clinical deterioration or significant side effects. These results suggest that IL-2 administration in combination with conventional MDT is safe and may potentiate the antimicrobial cellular immune response to TB.</p>","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 3","pages":"185-96"},"PeriodicalIF":0.0,"publicationDate":"1995-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of cytokines in modulating neonatal myelopoiesis and host defense.","authors":"J Rosenthal,&nbsp;M S Cairo","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Neonatal sepsis is a major cause of morbidity and mortality in newborn infants. Hematopoiesis and host defense in the neonate is developmentally immature compared with the adult. Defects in both the quantitative and qualitative aspects of the phagocytic system contribute significantly to a relative state of immunodeficiency in the neonate. Dysregulation of neonatal hematopoiesis and the immune response is a significant contributing factor to the increased susceptibility of the neonate to infection. A relatively small set of pluripotent stem cells gives rise to large numbers of functionally diverse mature effector cells. Cell proliferation and differentiation are regulated and controlled by highly specific protein factors, affecting single and multiple lineage hematopoiesis. Reduced neonatal rat myeloid progenitor pools, accelerated myeloid progenitor proliferative rates and decreased total body neutrophil storage pools predispose the newborn rat to depletion of mature effector neutrophils and a tendency to develop neutropenia during states of increased demand such as overwhelming bacterial infection. We review here the multifactorial complex biological process involved in the regulation of hematopoietic growth factors. We also review the biological effects of various non-lineage-committed and lineage-committed growth factors as reported in in vitro investigations and in vivo neonatal animal experiments. We also review our results of phase I/II clinical studies utilizing rhuG-CSF in neonates with presumed sepsis, and of rhuGM-CSF in very low birth weight neonates.</p>","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 3","pages":"165-76"},"PeriodicalIF":0.0,"publicationDate":"1995-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD80-transfected human breast and ovarian tumor cell lines: improved immunogenicity and induction of cytolytic CD8+ T lymphocytes.","authors":"B Gückel,&nbsp;M Lindauer,&nbsp;W Rudy,&nbsp;A Habicht,&nbsp;M Siebels,&nbsp;S Kaul,&nbsp;G Bastert,&nbsp;S C Meuer,&nbsp;U Moebius","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Human tumor cell lines derived from breast and ovarian carcinomas have been found to be ineffective in stimulating the induction phase of an immune response such as T cell proliferation in allogeneic mixed tumor cell lymphocyte cultures. Since representative tumor cell lines are effectively lysed by activated T lymphocytes, the induction of an effector phase is not impaired. In order to reconstitute the potential to induce primary T cell activation, we transfected CD80 into a breast (KS) and an ovarian carcinoma (GG) cell line. CD80 expression in KS cells resulted in improved primary T cell activation, whereas it was ineffective in the case of GG cells. However, treatment of CD80-transfected GG cells with INF-gamma rendered them immunogenic, and resulted in T cell proliferation. Likewise, TNF-alpha and/or INF-gamma augmented T cell proliferation induced by CD80-transfected KS cells. Furthermore, T lymphocytes stimulated with cytokine-treated CD80+ KS cells gave rise to a long term proliferating CD8+ CTL line with class I MHC restricted cytolytic antitumor activity. These studies emphasize the requirement for costimulation in generating tumor-specific immunity, and demonstrate the efficacy of CD80 in generating CD8+ cytolytic T lymphocytes.</p>","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 3","pages":"211-21"},"PeriodicalIF":0.0,"publicationDate":"1995-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}