Cytokine Receptor Antagonists Research Articles

Therapy of radiation injury.

It is apparent from preclinical and clinical research to date that continued evaluation of new and alternative treatment strategies is required to eliminate the obligate periods of neutropenia and thrombocytopenia after acute high-dose irradiation. Future treatment strategies may involve new combinations of cytokines to affect hematopoietic stem cell proliferation and "engineered" cellular grafts to provide short-term in vivo expansion of neutrophils and platelets in an effort to bridge the cytopenic gap until endogenous or transplanted stem cells regenerate the hematopoietic and immune systems. Cytokine-mobilized peripheral blood and cord blood will provide alternative sources of allogeneic stem and progenitor cells in support of primary engraftment, delayed engraftment or secondary failure of the initial graft, as well as starting populations for various ex vivo expansion protocols. Further insights into the relative quality of stem cell populations and the factors that regulate their survival and self renewal, and the identification and roles of adhesion molecules in stem cell mobilization, engraftment, and interaction with the adult marrow microenvironment will provide the basis for future treatment strategies for the radiation-induced hematopoietic syndrome. As our ability to treat the hematopoietic syndrome improves, damage to other organ systems such as the skin, lung, and/or gastrointestinal tissue will emerge as dose-limiting. At the same time, the characterization of receptors for inflammatory cytokines, cytokine receptor antagonists, and anti-endotoxin antibodies has allowed significant insights into the mechanisms and pathogenesis of sepsis. However, translation of this knowledge into a treatment modality for septic patients is precluded by the lack of any clear-cut beneficial effect from the many clinical trials. The research and clinical results presented in this volume and recent conferences reflect the body of knowledge that will lead to further developments in assessment, prophylaxis, and treatment of radiation injuries in the areas of infectious disease and the hematopoietic, gastrointestinal, and cutaneous syndromes.

Fatigue in chronically ill patients

Fatigue is the most common symptom among palliative patients, often considered more distressing than pain, nausea or vomiting. This article reviews the current literature and puts forward up to date treatment recommendations. Methylphenidate showed a small but significant improvement versus placebo in a recently published systematic review. Donepezil did not show a significant benefit versus placebo in a double blind, placebo-controlled study. Hypogonadism is a frequent condition that can cause fatigue in patients with advanced cancer and other chronic illnesses and androgen replacement therapy warrants further investigation. Among antidepressants, bupropion has shown encouraging results. The role of hematopoietic agents for advanced cancer patients receiving palliative care is minimal as anemia is less of a contributing factor in this setting. Cytokine receptor antagonists play an important theoretical role but further studies are needed before they could be recommended. L-Carnitine has shown encouraging results. Methylphenidate is still considered the first choice of treatment among pharmacological therapies. Modafinil shows promise, but insufficient studies have been conducted in this setting. Bupropion may have benefits in treating depression and fatigue. Among complementary therapies, L-carnitine has the most potential. Further studies are needed before cytokine receptor antagonists and androgen replacement therapy can be recommended.

Curcumin and pancreatic cancer: Phase II clinical trial experience

4599 Background: Pancreatic cancer is virtually always lethal, and the only FDA-approved therapies–gemcitabine and erlotinib–produce objective responses in less than 10% of patients. Curcumin (diferuloyl methane) is a plant-derived dietary ingredient that suppresses NF-κB and numerous other pathways relevant to pancreatic cancer and has potent preclinical anti-tumor activity. Herein, we evaluated the safety and potential antitumor activity of curcumin against advanced pancreatic cancer, and its impact on biologic correlates. Methods: Patients received 8 grams of curcumin by mouth daily for two months and were then restaged. Maintenance therapy was continued at the same dose and schedule until disease progression. Results: Twenty-five patients were enrolled as of the date of analysis, with 21 evaluable for response. Circulating curcumin was detectable, albeit at low steady-state levels (about 31 ng/ml), suggesting poor oral bioavailability. To date, two patients have had prolonged stable disease (8 and 12+ months). Interestingly, one patient had a brief, but marked tumor regression (73%) (accompanied by significant increases (4–35-fold) in serum cytokine (interleukin-6 (IL-6), IL-8, IL-10, and IL-1 receptor antagonist (IL-1RA) levels). No toxicities have been observed. Curcumin down-regulated expression of NF-κB, COX-2 and phosphorylated STAT3 in peripheral blood mononuclear cells (PBMC) from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers)although the decrease did not reach statistical significance for p65. Curcumin was determined in patient plasma samples after enzymatic digestion with glucuronidase enzyme. While there was considerable variation in plasma curcumin levels from patient to patient, drug levels peaked at 22–41 ng/ml and remained relatively constant over the entire 4 week experimental period. Conclusions: We conclude that oral curcumin is well tolerated and, despite its limited absorption, has biologic activity in patients with pancreatic cancer. [Table: see text] No significant financial relationships to disclose.

Adenovirus expressing interleukin-1 receptor antagonist alleviates allergic airway inflammation in a murine model of asthma

Interleukin-1 (IL-1) is a proinflammatory cytokine and IL-1 receptor antagonist (IL-1ra) is a natural inhibitor that binds to IL-1 receptor type I without inducing signal transduction. It is suggested that IL-1 is required for allergen-specific T helper type 2 cell activation and the development of airway hyper-responsiveness (AHR), but the immunologic effect of exogenous IL-1ra in allergic asthma remains unclear. To examine the effect of IL-1ra on airway inflammation and immunoeffector cells in allergic asthma, recombinant adenovirus expressing human IL-1ra (Ad-hIL-1ra) was delivered intranasally into ovalbumin (OVA)-immunized mice. Single intranasal administration of Ad-hIL-1ra before airway antigen challenge in OVA-immunized mice significantly decreased the severity of AHR and reduced pulmonary infiltration of eosinophils and neutrophils. Suppression of IL-5 and eotaxin with concomitant enhancement of interferon gamma in bronchoalveolar lavage fluid was also noted in OVA-immunized mice by administration of Ad-hIL-1ra. In addition, histological studies showed that Ad-hIL-1ra was able to decrease OVA-induced peribronchial inflammation. Taken together, our results indicated that administration of Ad-hIL-1ra may have therapeutic potential for the immunomodulatory treatment of allergic asthma.

Molecular therapeutic targets in inflammation: cyclooxygenase and NF-kappaB.

Inflammation is the host response to infection and injury. Inflammatory cells respond to foreign substances and inflammatory stimulus by producing bioactive mediators such as prostanoids, cytokines and chemokines. These mediators have complex, pleiotropic effects and interact with many cell types to amplify the inflammatory response. Dysregulation of these processes can lead to acute and chronic inflammatory diseases and pharmacological intervention is necessary to attenuate cellular inflammation pathways. Cyclooxygenase-2, the key inducible enzyme responsible for producing prostanoids, and the nuclear factor-kappa B (NF-kappaB) activation pathway, which regulates the transcription of inflammatory genes, represent attractive targets for developing anti-inflammatory therapeutics, as both pathways are activated by diverse inflammatory stimuli. This article reviews recent advances in anti-inflammatory drug development in both of these areas. Selective inhibitors of inflammation including cyclooxygenase inhibitors, antibodies against inflammatory cytokines, cytokine receptor antagonist, antibodies against adhesion molecules and therapeutics directed against the NF-kappaB activation pathway will be discussed.

Altered Levels of the Soluble IL-1, IL-4 and TNF Receptors, as well as the IL-1 Receptor Antagonist, in Intermittent Allergic Rhinitis

Background: The effects of cytokines are modulated by soluble cytokine receptors (SCR) and receptor antagonists. Therefore, allergic disease may depend on altered proportions between cytokines, their SCR and receptor antagonists, rather than absolute changes in cytokine levels. Little is known about SCR in intermittent allergic rhinitis (IAR). Objective: To examine the concentrations of SCR, i.e. sIL-1R2, sIL-4R, sIL-6R and sTNFR1, as well as the interleukin-1 receptor antagonist (IL-1Ra) in nasal fluids from allergen-challenged patients with IAR and healthy controls. Methods: 30 patients with birch- or grass-pollen-induced IAR and 30 healthy controls were studied. In the patients nasal fluids were obtained before as well as 1 and 6 h after allergen provocation. Results: Both symptom scores and rhinoscopic signs of rhinitis increased in the patients after allergen challenge. Comparisons between patients and controls showed that sIL-4R was lower in patients before and 1 and 6 h after provocation. IL-1Ra was lower before and 1 h after provocation. In addition, lower concentrations of sTNFR1 were found in patients after 1 h, while sIL-1R2 concentrations were higher after 1 h. Comparisons of patients before and after challenge showed that IL-1Ra and sTNFR1 decreased after 1 h, while sIL-1R2 increased. No significant differences were found compared to 6 h. sIL-6R did not significantly differ between the study groups. Conclusions: After allergen challenge, significant changes in the nasal fluid levels of IL-1Ra, sIL-1R2 and sTNFR1 were found. By contrast, sIL-4R remained at lower levels than in controls both before and after challenge. Since sIL-4R modulates IgE synthesis, this may play a role in the pathogenesis of IAR.

Effects of Perioperative Human Granulocyte Colony-stimulating Factor on Immune Function and Perioperative Infections in Patients Undergoing Abdominal Surgery.

The authors concluded that perioperative rhG-CSF alleviated the acute-phase inflammatory response normally induced by the process of major surgery. rhG-CSF also increased circulating levels of cytokine receptor antagonists and preserved several markers of normal monocyte and lymphocyte responsiveness. These results indicate that perioperative rhG-CSF can decrease some of the adverse effects of the immunoinflammatory reaction normally seen in the host response to the trauma and stress induced by major surgical procedures. The authors cited evidence from other studies that indicated the utility of exogenous rhG-CSF administration to reduce the incidence and significance of sepsis and serious bacterial infections in neutropenic patients. Although the clinical outcomes data from this study were apparently insufficient to allow for statistical analyses, there was a trend toward decreased incidence of serious infection and fatal sepsis in the rhG-CSF group. They proposed to expand these results to a larger study of even higher-risk surgical populations in an effort to determine the broader clinical relevance of their current results.

New perspectives in treatment of glomerulonephritis.

In chronic glomerulonephritis (GN) the development of the tissue damage and progression to fibrosis is related to the individual immune response which brings about excessive inflammation, failure to activate regression and glomerular repair and excessive fibrogenic activity. Therefore, the present standard treatment of GN has two aims, to fight the acute inflammation and to inhibit the progressive renal fibrosis. New avenues in the anti-inflammatory and immunosuppressive treatment of the active phase of glomerular diseases include the use of drugs proven to be of value in organ transplantation (mycophenolate mofetil, rapamycin or anti-immune adhesion and anti-co-stimulatory molecules). Interest has recently focused on anti-inflammatory cytokines (monoclonal antibodies, peptidic antagonists or anti-sense oligonucleotides against TNF-alpha, anti-PDGF-beta, anti-TGF-beta and cytokine receptor antagonists) and anti-inflammatory natural cytokines (such as IL4, IL10, IL13 or low doses of TGFbeta). Other drugs may act by depleting B cells (such as anti-CD20 monoclonal antibody) or on several immune pathways, such as thalidomide or anti-cyclooxygenase 2. Several anti-sclerogenic drugs are already used for treatment of the chronic phase of glomerular diseases, such as antagonists of angiotensin II, statins and antioxidants. Other drugs are still experimental, including endothelin receptor antagonists and neutral endopeptidase or vasopeptidase inhibitors and other drugs operating on extracellular matrix accumulation/degradation mechanisms, e.g., pirfenidone. There are extremely interesting developments concerning activators of endogenous anti-inflammatory mechanisms, such as those regulated by peroxisome proliferator activated receptors. There is a need for successful treatment of chronic GN in childhood. This short review of the most promising new drugs shows there is reason to believe that the next decade will provide exciting new tools for the treatment of these diseases in children.

Rationale for the use of structure-modifying drugs and agents in the treatment of osteoarthritis

This paper summarizes our current stand on potential pathophysiological targets for osteoarthritis (OA) therapies. Although OA is a complicated disease, involving the cartilage, synovial membrane, and subchondral bone, a number of interactive pathways have been found to explain the structural changes in the disease process. Study of these three tissues has yielded a list of targets to examine for their potential to affect disease progression. At the cartilage level, therapeutic agents, such as growth factors, could be targeted to increase chondrocyte anabolism. At the synovial level, cytokines and cytokine receptor antagonists are potential targets for therapy. In the subchondral bone, cytokines, growth factors and eicosanoids, and locally synthesized factors affecting bone metabolism are also potential targets of therapy. Recent progress in the understanding of the pathophysiology of OA has led to exploration of several interesting new approaches toward the treatment of this disease. New classes of molecules that inhibit one or more OA disease processes are under evaluation for their potential to alter the degenerative process. The prospect of finding a cure for OA is more promising than ever. Based on the discovery of major pathophysiological pathways leading to the structural changes observed in OA, novel ways to treat the progression of OA lesions are emerging.

Overview of Cutaneous T-Cell Lymphoma: Prognostic Factors and Novel Therapeutic Approaches

The cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of entities. The WHO classification distinguishes indolent low-risk entities, including mycosis fungoides/Sézary syndrome (MF/SS), from aggressive entities, including peripheral T-cell lymphoma and its variants and HTLV-1 associated acute T-cell leukemia/lymphoma. Mycosis fungoides represents the most benign of the cutaneous T-cell lymphomas, with 10-year relative survival ranging from 100% to 41%, depending on the degree of skin involvement. Probability of progression to extracutaneous disease within 20 years of diagnosis can be up to 40%, depending on stage. Treatment strategies for early stage CTCL include topical therapies with or without interferon-α or oral agents, while advanced stage patients often progress and are treated with chemotherapy and novel agents. Multiagent cytotoxic regimens are palliative with no demonstrated survival benefit. Among the novel therapies for CTCL is bexarotene, a retinoid X-receptor (RXR)-selective agonist, which has demonstrated efficacy in advanced refractory CTCL. Other novel agents include the interleukin (IL)-2 fusion toxin (ONTAK), pentostatin (a potent adenosine deaminase inhibitor), histone deacetylase inhibitors such as depsipeptide, NF-κB inhibitors, cytokine receptor antagonists, immunomodulatory therapies and allogeneic stem cell therapy. The value of new therapeutic approaches to CTCL urgently needs to be assessed.

Current and emerging therapies for the management of chronic inflammation in asthma

The pathophysiology of asthma, current treatment guidelines, and emerging immunomodulating treatments are reviewed. Asthma is a chronic disease of inflammation, which left untreated, may result in irreversible lung damage. Inhaled antigens elicit a T-helper cell type-2 response, leading to the production of immunoglobulin E (IgE) and eosinophil sensitization. Eosinophil infiltration into the airway is thought to play an important role in chronic inflammation and increases several weeks before an acute exacerbation in moderate to severe asthma. The updated guidelines from the National Asthma Education and Prevention Program and the National Institutes of Health focus on the use of daily antiinflammatory treatment in patients with persistent asthma. Inhaled corticosteroid (ICS) therapy remains the cornerstone for controlling mild and moderate asthma, but when used in higher doses for moderate-to-severe asthma it may cause long-term adverse effects, including osteoporosis and glaucoma. Step-up therapy should be the combination of a long-acting beta-agonist (LABA) and an ICS. Leukotriene modifiers may provide additional symptom control in patients with moderate to severe asthma but have not been shown to be as cost-effective as monotherapy. Newer entities focus on direct immune modulation and include monoclonal antibodies targeting various inflammatory-response receptors (IgE, interleukin [IL]-2, IL-4, and IL-5). Phosphodiesterase-4 (PDE-4) inhibitors may be effective for chronic obstructive pulmonary disease, but have not delivered consistent results for controlling asthma. Cytokine-receptor antagonists and leukocyte-suppressing antiinflammatory drugs (LSAIDs) are currently under investigation and have yielded promising preliminary results as alternatives for the treatment of asthma. Current and emerging therapies for the management of chronic inflammation in asthma include ICSs, LABAs, leukotriene modifiers, monoclonal antibodies, PDE-4 inhibitors, cytokine-receptor antagonists, and LSAIDs.

Differential early posttransplant cytokine responses in living and cadaver donor renal allografts.

Differences in early posttransplant immunologic responses between living donor (LDT) and cadaver donor transplant (CDT) recipients have not been thoroughly studied. This is the first study comparing lymphocyte subpopulations and plasma levels of different cytokines, soluble cytokine receptors, cytokine receptor antagonists, and neopterin during the first 2 posttransplant weeks. Lymphocyte subpopulations (CD3, CD4, CD8, CD16, CD19, and CD25) and plasma levels of soluble (s) interleukin(IL)-1 receptor antagonist (RA), IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-8, IL-10, transforming growth factor-beta(2), tumor necrosis factor-alpha, interferon-gamma, and neopterin were studied in 52 CDT and 33 LDT recipients 1 to 2, 4 to 6, and 8 to 10 days after transplantation. The most impressive finding was a consistently higher neopterin plasma level in CDT than LDT recipients. Although plasma neopterin decreased during the second posttransplant week in both groups (CDT, P = 0.0001; LDT, P = 0.001), the difference in plasma neopterin levels 8-10 days after transplantation was highly significant (P = 0.005). In contrast, LDT had consistently higher sIL-1RA plasma levels during the first 2 posttransplant weeks. Whereas sIL-1RA plasma levels decreased in both groups during the first posttransplant week (CDT, P = 0.001; LDT, P = 0.005), they increased during the second posttransplant week in LDT (P = 0.02) but remained stable and low in CDT recipients. Eight to ten days after transplantation, the difference was highly significant (P = 0.002). These data suggest that transplantation of CDT is associated with strong monocyte-macrophage activation with consistently high neopterin plasma levels, whereas the effect of inflammatory cytokines seems to be down-regulated in LDT recipients by an increased release of antiinflammatory sIL-1RA.

P3259 Ex vivo gene transfer of cytokine and chemokine receptor antagonists prolongs cardiac allograft survival in a rat model of heart transplantation

P3259 Ex vivo gene transfer of cytokine and chemokine receptor antagonists prolongs cardiac allograft survival in a rat model of heart transplantation

Autoimmune perspective of insulin-dependent diabetes mellitus: cytokines as therapeutic targets

Insulin-dependent diabetes mellitus (IDDM) is believed to be an autoimmune disorder characterized by specific and progressive loss of pancreatic beta cells. Macrophages and dendritic cells are the first to invade the pancreas. These cells recognize beta cell autoantigens and then present to CD4 + T helper (Th) cells. CD4 + T cells are, in turn, documented to activate CD8 + cytotoxic T cells and macrophages. The activated CD8 + T cells and macrophages may serve as final effectors to destroy beta cells. Cytokines are important mediators secreted by these immune cells involved in beta cell destruction and thus may serve as attractive therapeutic target sites. Several cytokine-based therapies such as monoclonal antibodies directed against cytokines or their receptors, soluble cytokine receptors and cytokine receptor antagonists, which can block the production/action of proinflammatory cytokines (IL-1β, TNF-α, IFN-y) may be investigated. Immunostimulatory agents directed at specific augmentation of Th2 subset (IL-4, IL-10) or Th3 subset (TGF-β) of CD4 + Th cells may also offer an alternative approach.

The Systemic Inflammatory Response to Cardiac Surgery

The Systemic Inflammatory Response to Cardiac Surgery

A synthetic corticosteroid, dexamethasone regulates generation of soluble form of interleukin-6 receptor of human lymphocytes, in vitro

In contrast to most of the soluble cytokine receptor antagonists properties, the soluble IL-6 receptor (sIL-6R) occurring in various body fluids of healthy persons and patients with various diseases is an agonist. The enhancing effect is due to its ability to form complex with IL-6 and to bind to gp130 making constitutively IL-6 receptor negative cells responsive for IL-6. The generation as well as the functional role of soluble IL-6 receptor is poorly understood. Earlier, we found that the sIL-6R levels in sera of patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) were higher than those of the control group measured by ELISA sandwich technology. In the present study we detected different levels of sIL-6R in the supernatants of lymphocyte cultures of healthy persons and patients with RA as well as SLE. Moreover, we found, that in vitro dexamethasone treatment stimulated generation of sIL-6R in both healthy persons and in active SLE, while it strongly suppressed production of sIL-6R in both RA groups. At mRNA level, we found that in SLE both the IL-6R mRNA encoding the membrane spanning and alternatively spliced (soluble) variants increased. Surprisingly, the strong decrease of sIL6R protein in RA was not found at mRNA level.

The development of cytokine receptor antagonists as potential therapeutic agents for the myeloproliferative disorders.

The aetiology of the myeloproliferative disorders and, in particular, of the myeloid leukaemias is unknown. The transformation of cells is primarily due to molecular aberrations leading to excessive cellular signalling and proliferation. In addition cytokines and their receptors may play a role in leukaemogenesis by increasing the proliferative capacity of leukaemic cells and extending their life span. Chemotherapeutic agents are regularly used to treat patients with leukaemia but they are non-discriminatory treatments that kill both healthy and cancer cells. Consequently patients receiving chemotherapy suffer unwanted toxicities in both the haematological and other systems. Therapies that specifically target malignant cells sparing normal cells are being investigated in a number of contexts. Cytokine antagonists can target growth factor-dependent cells by obstructing the interaction between cytokine and receptor. In this review we will discuss the myeloproliferative disorders in particular the leukaemias, the cytokines involved in leukaemogenesis, and the therapeutic potential of new agents that block specific cytokines.

Cytokine therapeutics for asthma: an appraisal of current evidence and future prospects.

Although current pharmacopoeia is effective in alleviating asthma symptomatology, it is equally unable to modify the fundamental immunological basis of the allergic diathesis. The explosion in knowledge of the immunobiology of cytokines that has occurred in the last decade has remarkably clarified our understanding of the pathogenesis of allergic asthma, and has unleashed a plethora of compelling opportunities. In the first part of this review, we will summarize current knowledge on the pathogenesis of allergic asthma, with particular emphasis on relevant cytokine networks. This will position us to appraise critically initiatives in the search to modulate cytokine targets that are key to the expression of the allergic asthma phenotype. We will review the use of recombinant cytokines, soluble cytokine receptors, cytokine receptor antagonists and cytokine inhibitors, in pre-clinical and clinical development. Finally, we will assess the applicability of transgene-based modalities, including anti-sense oligonucleotide technology and gene therapy, as novel therapeutic strategies in the treatment of allergic asthma.

Physiology of cytokine pathways in rheumatoid arthritis.

This review has summarized the physiology of some cytokine pathways in RA, emphasizing the redundant and synergistic nature of this network. However, it is important to understand that this system is self-regulating through the action of anti-inflammatory cytokines, opposing cytokines, cytokine receptor antagonists, and possibly naturally occurring antibodies to cytokines (Figure 1). Disease results when an imbalance in the cytokine network develops, either from excess production of pro-inflammatory cytokines or from inadequate presence of natural anti-inflammatory mechanisms. The current therapeutic approaches to RA that are aimed at restoring this balance include the use of monoclonal antibodies to TNFalpha, soluble TNFalpha receptors, and IL-1Ra. Other therapeutic agents that interfere with the cytokine network are in various stages of preclinical and clinical evaluation.

1 p38 MAP Kinase: Molecular Target for the Inhibition of Pro-inflammatory Cytokines

Publisher Summary This chapter discusses that the network of immune and inflammatory responses is comprised of a variety of cell types. Coordination of this network occurs through both direct cell–cell contact and by way of intercellular signalling molecules. These signalling molecules regulate the growth, differentiation and function of a variety of target cells. Understanding the structure and function of these molecules has provided new and important insights into the fundamental biology of immunity and inflammation, and has led to the identification of new strategies for the development of more effective medicines for the treatment of a variety of autoimmune and inflammatory diseases. The chapter reviews that the pluripotent pro-inflammatory cytokines, interleukin-1 (IL-1), and tumor necrosis factor alpha (TNFα) appear to play particularly important roles in disease. Although, these proteins and their cellular receptors are structurally unrelated, they elicit a similar profile of pro-inflammatory responses. Because IL-1 and TNF are produced early in response to pro-inflammatory signals, and because of their central role in mediating this response, they have often been termed the master cytokines. While the success of these therapies has validated the importance of IL-1 and TNF in promoting disease, they also highlight the need for improved therapies that do not suffer from the disadvantages of proteinaceous macromolecules, which must be administered parenterally and are inherently more expensive to produce than small molecule drugs. To date, no orally active low molecular weight cytokine receptor antagonist has emerged from clinical trials. However, in the last decade several new strategies to interrupt the synthesis and signalling of these cytokines have emerged. One of the first of these targets to be elucidated is the stress-activated protein kinase, p38.