Use of colony-stimulating factors in combination with high-dose chemotherapy

Recent clinical trials of two hematopoietic cytokines, granulocyte- and granulocyte-macrophage colony stimulating factors, in combination with chemotherapy, have shown that they allow substantially higher doses of chemotherapeutic agents to be used. Administering cytokines decreased the length of time for granulocyte recovery, the incidence of infection, the need for antibiotics, as well as shortening the duration of hospitalizations. Current work is focusing on the use of cytokines to stimulate circulating progenitor cells for pheresis and replacement. There are still striking gaps, however, in our knowledge of the interactions of the various cytokines with each other and with chemotherapeutic agents.     

Interleukin-1, characterization of the molecule, functional activity, and clinical implications.

Hematopoiesis is regulated by a number of growth factors, of which colony-stimulating factors (CSF) have been exclusively defined according to the cell type they grow in vitro in colony assays. A number of cytokines, including interleukin-1 (IL-1), which have been characterized to exhibit multiple activities, are also involved in the control of growth and differentiation of hematopoietic cells. Some CSFs and related cytokines have already been introduced into clinical evaluation. This review summarizes the current knowledge of the IL-1 molecules, their moleculargenetic, and protein features as well as their in vitro and in vivo actions which justify their development as therapeutic agents.     

Clinical applications of interleukin-2

Interleukin-2 (IL-2) is a cytokine with potent immunomodulating properties which has shown considerable antitumour activity in preclinical models. In clinical trials, the effects of IL-2 given by various routes and schedules have been investigated. IL-2 has been administered either as single drug or in combination with other cytokines and immunomodulating agents, chemo therapeutic agents, or reinfusions of ex vivo activated autologous cytotoxic effector cells. The results of published clinical studies with IL-2 based immunotherapy are reviewed in this paper.     

Cytokine disturbances in systemic lupus erythematosus

The pathogenesis of systemic lupus erythematosus (SLE) is complex, and the resulting disease manifestations are heterogeneous. Cytokine dysregulation is pervasive, and their protein and gene expression profiles may serve as markers of disease activity and severity. Importantly, biologic agents that target specific cytokines may represent novel therapies for SLE. Four cytokines (IL-6, TNFα, IFNα, and BLyS) are being evaluated as therapeutic targets in SLE. The present review will examine the roles of each of these cytokines in murine and human SLE, and will summarize results from clinical trials of agents that target these cytokines.     

Genetic Engineering and Nitrogen Fixation

Molecular cloning is based on isolation of a DNA sequence of interest to obtain multiple copies of it in vitro. Application of this technique has become an increasingly important tool in clinical microbiology due to its simplicity, cost effectiveness, rapidity, and reliability. This review entails the recent advances in molecular cloning and its application in the clinical microbiology in the context of polymicrobial infections, recombinant antigens, recombinant vaccines, diagnostic probes, antimicrobial peptides, and recombinant cytokines. Culture-based methods in polymicrobial infection have many limitation, which has been overcome by cloning techniques and provide gold standard technique. Recombinant antigens produced by cloning technique are now being used for screening of HIV, HCV, HBV, CMV, Treponema pallidum, and other clinical infectious agents. Recombinant vaccines for hepatitis B, cholera, influenza A, and other diseases also use recombinant antigens which have replaced the use of live vaccines and thus reduce the risk for adverse effects. Gene probes developed by gene cloning have many applications including in early diagnosis of hereditary diseases, forensic investigations, and routine diagnosis. Industrial application of this technology produces new antibiotics in the form of antimicrobial peptides and recombinant cytokines that can be used as therapeutic agents.     

Growth factors and cytokines in hair follicle development and cycling: recent insights from animal models and the potentials for clinical therapy

Hair growth disorders, particularly those that lead to hair loss (alopecia), are common and frequently cause significant mental anguish in affected individuals. The mechanisms underlying the majority of these disorders are unknown. However, insights into the specific molecular mechanisms of hair follicle development and cycling have recently been made using animal models, particularly mice that over- or underexpress a specific gene for a growth factor or cytokine. Other animal models have demonstrated that certain growth factors and cytokines can prevent much of the alopecia caused by cancer chemotherapeutic agents. These animal models have confirmed the importance of growth factors and cytokines in hair follicle development and cycling, and have formed the foundation for potential clinical therapy of hair growth disorders, particularly alopecia. Nevertheless, important questions concerning their efficacy, safety and delivery will need to be answered before successful clinical therapy of any hair growth disorder becomes a reality.     

The IL-2 cytokine family in cancer immunotherapy

The use of cytokines from the IL-2 family (also called the common γ chain cytokine family) such as interleukin (IL)-2, IL-7, IL-15, and IL-21 to activate the immune system of cancer patients is one of the most important areas of current cancer immunotherapy research. The infusion of IL-2 at low or high doses for multiple cycles in patients with metastatic melanoma and renal cell carcinoma was the first successful immunotherapy for cancer proving that the immune system could completely eradicate tumor cells under certain conditions. The initial clinical success observed in some IL-2-treated patients encouraged further efforts focused on developing and improving the application of other IL-2 family cytokines (IL-4, IL-7, IL-9, IL-15, and IL-21) that have unique biological effects playing important roles in the development, proliferation, and function of specific subsets of lymphocytes at different stages of differentiation with some overlapping effects with IL-2. IL-7, IL-15, and IL-21, as well as mutant forms or variants of IL-2, are now also being actively pursued in the clinic with some measured early successes. In this review, we summarize the current knowledge on the biology of the IL-2 cytokine family focusing on IL-2, IL-15 and IL-21. We discuss the similarities and differences between the signaling pathways mediated by these cytokines and their immunomodulatory effects on different subsets of immune cells. Current clinical application of IL-2, IL-15 and IL-21 either as single agents or in combination with other biological agents and the limitation and potential drawbacks of these cytokines for cancer immunotherapy are also described. Lastly, we discuss the future direction of research on these cytokines, such as the development of new cytokine mutants and variants for improving cytokine-based immunotherapy through differential binding to specific receptor subunits.     

Pulmonary artery hypertension: pertinent vasomotorial cytokines

Pulmonary artery hypertension is a syndrome that shows similar clinical and pathophysiological features characterized by elevated pulmonary arterial pressure and resistance. There have been a series of hypotheses trying to describe the development of pulmonary artery hypertension; however, none of them perfectly explains its pathogenesis. To highlight the pathogenesis, novel vasomotorial cytokines including hypoxia-inducible factor-1α, endothelin-1, urotensin II, Krüppel-like factor 4, calcitonin gene-related peptide, angiopoietins and serotonin closely related to pulmonary artery hypertension are discussed. The development of the new agents relating to these cytokines may improve the relevant treatment strategies.     

Cytokines as potential combination agents with PD-1/PD-L1 blockade for cancer treatment

Immunotherapy has caused a paradigm shift in the treatment of several malignancies, particularly the blockade of programmed death-1 (PD-1) and its specific receptor/ligand PD-L1 that have revolutionized the treatment of a variety of malignancies, but significant durable responses only occur in a small percentage of patients, and other patients failed to respond to the treatment. Even those who initially respond can ultimately relapse despite maintenance treatment, there is considerable potential for synergistic combinations of immunotherapy and chemotherapy agents with immune checkpoint inhibitors into conventional cancer treatments. The clinical experience in the use of cytokines in the clinical setting indicated the efficiency of cytokine therapy in cancer immunotherapy. Combinational approaches to enhancing PD-L1/PD-1 pathways blockade efficacy with several cytokines such as interleukin (IL)-2, IL-15, IL-21, IL-12, IL-10, and interferon-α (IFN-α) may result in additional benefits. In this review, the current state of knowledge about PD-1/PD-L1 inhibitors, the date in the literature to ascertain the combination of anti-PD-1/PD-L1 antibodies with cytokines is discussed. Finally, it is noteworthy that novel therapeutic approaches based on the efficient combination of recombinant cytokines with the PD-L1/PD-1 blockade therapy can enhance antitumor immune responses against various malignancies.     

Cytokines as suppressors of apoptosis

Many cytokines have been isolated by their ability to induce growth and have been called growth factors. But these cytokines are also essential to induce cell viability, and cell viability and growth can be separately regulated. Using as examples myeloid hematopoietic cells, lymphocytes and neuronal cells, in vitro and in vivo studies have shown the role of cytokines in inducing viability of different cell types during development to mature cells. Some cytokines can act on more than one cell type. Cytokines induce viability of normal and cancer cells by suppressing the apoptotic machinery activated by wild-type p53, or by cytotoxic agents including irradiation and compounds used in cancer chemotherapy. Cytokines can be used to decrease apoptosis in normal cells and inhibition of cytokine activity may improve cancer therapy by enhancing apoptosis in cancer cells. The apoptosis suppressing function of cytokines is mediated by changing the balance in the activity of apoptosis inducing and suppressing genes. Apoptosis suppression is upstream of caspase activation in the apoptotic process. Cytokines can suppress multiple pathways leading to apoptosis, only some of which were suppressed by other agents such as some antioxidants, Ca²⁺-mobilizing compounds and protease inhibitors.     

The role of cytokines in the establishment, persistence and eradication of the HIV reservoir

HIV persists in cellular and anatomical reservoirs during Highly Active Antiretroviral Therapy (HAART). In vitro studies as well as in vivo observations have identified cytokines as important factors regulating the immunological and virological mechanisms involved in HIV persistence. Immunosuppressive cytokines might contribute to the establishment of viral latency by dampening T cell activation and HIV production, thereby creating the necessary immuno-virological condition for the establishment of a pool of latently infected cells. Other cytokines that are involved in the maintenance of memory CD4(+) T cells promote the persistence of these cells during HAART. Conversely, proinflammatory cytokines may favor HIV persistence by exacerbating low levels of ongoing viral replication in lymphoid tissues even after prolonged therapy. The ability of several cytokines to interfere with the molecular mechanisms responsible for HIV latency makes them attractive candidates for therapeutic strategies aimed at reducing the pool of latently infected cells. In this article, we review the role of cytokines in HIV persistence during HAART and discuss their role as potential eradicating agents.     

Inhaled Janus Kinase (JAK) inhibitors for the treatment of asthma

Multiple asthma-relevant cytokines including IL-4, IL-5, IL-13, and TSLP depend upon JAKs for signaling. JAK inhibition may, therefore, offer a novel intervention strategy for patients with disease refractory to current standards of care. Multiple systemically delivered JAK inhibitors have been approved for human use or are under clinical evaluation in autoimmune diseases such as rheumatoid arthritis. However, the on-target side effect profiles of these agents are likely not tolerable for many asthmatic patients. Limiting JAK inhibition to the lung is expected to improve therapeutic index relative to systemic inhibition. Thus, inhaled JAK inhibitors with lung-restricted exposure are of high interest as potential treatments for asthma.     

Cytokines in rheumatoid arthritis: trials and tribulations

Biological agents that inhibit the activity of proinflammatory cytokines are being investigated for use in the treatment of rheumatoid arthritis. Thus far, two of these agents, both of which neutralize tumor necrosis factor alpha (TNF-alpha), have received US Food and Drug Administration approval for the treatment of the disease. Etanercept is a bioengineered fusion protein of the p75 soluble TNF receptor, and infliximab is a chimeric monoclonal antibody to TNF-alpha. Other agents that target proinflammatory cytokines are also being developed. By allowing earlier treatment and better-tolerated long-term therapy, biologics might help slow or prevent disease progression and joint destruction.     

细胞因子在类风湿关节炎发病机制中的作用

机体的免疫细胞和非免疫细胞合成和分泌的小分子多肽类因子统称为细胞因子。随着对类风湿关节炎（RA）的病因及发病机制的深入研究,发现细胞因子在RA发病过程中起重要作用。简要综述了细胞因子在RA发病中的促炎、抗炎作用,及细胞因子间的相互作用。     

Dendritic cells and cytokines in human inflammatory and autoimmune diseases

Dendritic cells (DCs) produce cytokines and are susceptible to cytokine-mediated activation. Thus, interaction of resting immature DCs with TLR ligands, for example nucleic acids, or with microbes leads to a cascade of pro-inflammatory cytokines and skewing of T cell responses. Conversely, several cytokines are able to trigger DC activation (maturation) via autocrine, for example TNF and plasmacytoid DCs, and paracrine, for example type I IFN and myeloid DCs, pathways. By controlling DC activation, cytokines regulate immune homeostasis and the balance between tolerance and immunity. The increased production and/or bioavailability of cytokines and associated alterations in DC homeostasis have been implicated in various human inflammatory and autoimmune diseases. Targeting these cytokines with biological agents as already is the case with TNF and IL-1 represents a success of immunology and the coming years will expand the range of cytokines as therapeutic targets in autoinflammatory and autoimmune pathology.     

The unique role of natural killer T cells in the response to microorganisms

Natural killer T (NKT) cells combine features of the innate and adaptive immune systems. Recently, it has become evident that these T cells have crucial roles in the response to infectious agents. The antigen receptor expressed by NKT cells directly recognizes unusual glycolipids that are part of the membrane of certain Gram-negative bacteria and spirochetes. Moreover, even in the absence of microbial glycolipid antigens, these T cells respond to innate cytokines produced by dendritic cells that have been activated by microbes. This indirect sensing of infection, by responding to cytokines from activated dendritic cells, allows NKT cells to react to a broad range of infectious agents.     

Dectin-1 expression and function are enhanced on alternatively activated and GM-CSF-treated macrophages and are negatively regulated by IL-10, dexamethasone, and lipopolysaccharide

Dectin-1 is the major macrophage receptor for beta-glucans and generates a proinflammatory response through the recognition of these carbohydrates on fungal pathogens. We have examined the effects of cytokines and other agents on the expression and functions of dectin-1 in both resident and elicited murine peritoneal macrophages (Mphi). Dectin-1 expression was found to be highly up-regulated by GM-CSF and by the cytokines that induce alternative macrophage activation, IL-4 and IL-13. In contrast, IL-10, LPS, and dexamethasone, but not IFN-gamma, down-regulated the expression of this receptor. Modulation of dectin-1 receptor levels correlated with the ability of these macrophages to bind zymosan and significantly affected the contribution of this receptor to the resultant proinflammatory response, as measured by the production of TNF-alpha, although some Mphi-specific differences were observed. These results correlate with the known effects of these cytokines and other agents on the ability of the immune system to recognize and respond to fungal pathogens.     

Chloroquine induces activation of nuclear factor-kappaB and subsequent expression of pro-inflammatory cytokines by human astroglial cells

Chloroquine, an antimalarial lysosomotropic base, is known for its anti-inflammatory effects and therefore used for treatment of autoimmune diseases. Given its anti-inflammatory effects, it has been under clinical trials to modify neurodegenerative processes. In this study, we examined whether chloroquine has an anti-inflammatory effect in the CNS by determining the in vitro effects of chloroquine on LPS-induced expression of cytokines by glial cells. We observed that (i) chloroquine augmented LPS-induced expression of pro-inflammatory cytokines such as lymphotoxin (LT)-beta, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, IL-1beta and IL-6 in human astroglial cells, while the same treatment suppressed LPS-induced expression of cytokines in monocytic and microglial cells; (ii) chloroquine alone induced expression of pro-inflammatory cytokines in a dose- and time-dependent manner in astroglial cells; (iii) other lysosomotropic agents such as ammonium chloride and bafilomycin A1 had minimal effects on cytokine expression; and (iv) chloroquine induced the activation of nuclear factor-kappa B in astroglial cells, which is a required component of chloroquine induction of cytokines. These results suggest that chloroquine may evoke either anti- or pro-inflammatory responses in the CNS depending on the cellular context.     

Molecular addresses in blood vessels as targets for therapy

We have isolated several organ- and tumor-homing peptides by using in vivo phage display. This technology involves the screening of peptide libraries in a living animal. The peptides that result from such a selection home to specific organs or tissues because they recognize molecular 'addresses', receptors that are differentially expressed in vascular beds. Targeted delivery of chemotherapeutics, pro-apoptotic peptides and cytokines to tumors using these peptides improved therapeutic efficacy in animal models. Translation of this technology into clinical applications will form the basis for targeting therapeutic and imaging agents in the context of cancer and other diseases.