Current Pharmaceutical Design - Volume 9, Issue 14, 2003

The treatment approach to rheumatoid arthritis has undergone a major evolutionary change in recent years in part as a consequence of growing appreciation of the severity of this condition and in part due to very considerable progress in understanding the important role of cytokines in the immunopathogenesis of this disease. The major focus of this review is on the rationale for targeting TNFα and IL-1 in rheumatoid arthritis and the results of clinical studies designed to assess the validity of this therapeutic approach. Recently published studies confirm that the long term use of a several biological agents targeting TNFα give rise to sustained improvements in symptoms and signs of rheumatoid disease and, furthermore, that TNFα blockade protects joints from structural damage. Although these drugs are well tolerated and have a good overall safety profile, pitfalls to the use of anti-TNFα agents apparent with increasing clinical experience include rare cases of tuberculosis. The mechanism of action of anti-TNFα therapy is discussed. Clinical trials of interleukin-1 receptor antagonist show relatively modest anti-inflammatory efficacy and an effect on X-ray indicative of retardation of joint damage. Other pro-inflammatory cytokines representing potential therapeutic targets include interferon-β, interferon-γ, IL-6, IL-15, IL-17 and IL-18. I will consider preliminary data, where available, arising from clinical trials designed to inhibit the activity of such molecules. In this review I will also discuss the rationale and preliminary data for other potential therapeutic strategies designed to augment the activity of anti-inflammatory cytokines such as IL-4, IL-10, and IL-11 in rheumatoid disease.

Although the pathogenesis of inflammatory bowel disease (IBD) remains elusive, it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals. Current disease management guidelines have therefore focused on the use of anti-inflammatory agents, aminosalicylates and corticosteroids. These conventional therapies continue to be a first choice in the management of IBD. Immunomodulators, such as azathioprine, 6-mercaptopurine, methotrexate or cyclosporin, are demonstrating increasing importance against steroid-resistant and steroid-dependent patients. However, some patients are still refractory to these therapies. Recent advances in the understanding of the pathophysiological conditions of IBD have provided new immune system modulators as therapeutic tools. Other immunosuppressive agents including FK506 and thalidomide have expanded the choice of medical therapies available for certain subgroups of patients. Furthermore, biological therapies have begun to assume a prominent role. Studies with chimeric monoclonal anti-TNF-α antibody treatment have been reported with dramatic successes. However, observations in larger numbers of treated patients are needed to explicate fully the safety of or risks posed by this agent such as developing lymphoma, or other malignancies. Another anti-inflammatory cytokinetherapy includes anti anti-IL-6R, anti-IL-12 or toxin-conjugated anti IL-7R, recombinant cytokines (IL-10 or IL-11). Given the diversity of proinflammatory products under its control, NF-κB may be viewed as a master switch in lymphocytes and macrophages, regulating inflammation and immunity. Although some of them still need more confirmatory studies, those immune therapies will provide new insights into cell-based and gene-based treatment against IBD in near future.

Granulocyte colony-stimulating factor is a potent stimulator for neutrophils in the circulation as well as those progenitors to be increased and be grown in the bone marrow. Recombinant forms of this colony-stimulating factor, therefore, are widely using in the various kinds of clinical fields such as for the treatment of bone marrow suppression after cancer chemotherapy and for the treatment of myelodysplastic disorders. One of the physiological function of granulocyte colony-stimulating factor is to activate neutrophils enough to fight against invaded microbes and others, thus it is hoped to be used for the treatment of various kinds of infectious diseases even while the host has a normal number of circulating neutrophils and normal bone marrow.The future possible clinical usage of granulocyte colony-stimulating factor as for the immunomodulation against various kinds of insults to the human is reviewed.

Many cytokines have been reported to be increased in human and animal models with cardiovascular diseases. Myocardial infarction (MI) is accompanied with an inflammatory reaction which induces cardiac dysfunction and remodeling. The inflammatory reaction has been investigated in animal models of MI or myocardial ischemia-reperfusion injury. The mechanisms by which cytokine cascade is activated in the infarcted myocardium have been recently elucidated. Several hematopoietic growth factors including interleukin-3 (IL-3), IL-6, granulocyte-macrophage colonystimulating factors (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and stem cell factor (SCF) have been reported to be positive regulators of granulopoiesis and act at different stages of myeloid cell development. G-CSF plays a critical role in regulation of proliferation, differentiation, and survival of myeloid progenitor cells. G-CSF also causes a marked increase in the release of hematopoietic stem cells (HSCs) into the peripheral blood circulation, a process termed mobilization. Although cardiac myocytes have been considered as terminally differentiated cells, it has been recently reported that there are many proliferating cardiac myocytes after MI in human heart. After it was demonstrated that bone marrow stem cells (BMSCs) can differentiate into cardiac myocytes, myocardial regeneration has been widely investigated. Recently, G-CSF has been reported to improve cardiac function and reduces mortality after acute MI. Although the mechanism by which G-CSF ameliorates cardiac dysfunction is not fully understood, there is the possibility that G-CSF may regenerate cardiac myocytes and blood vessels through mobilization of BMSCs. In the future, cytokinemediated regeneration therapy may become to be a novel therapeutic strategy for MI.

Since recombinant gene technology was established to provide rare important regulatory proteins as recombinant molecules, cytokine therapies have widely developed and enormously contributed to the treatment of various diseases, nevertheless, it has been revealed that recombinant therapeutic molecules are not always perfect because of sideeffects related to pharmacological functions of cytokines and / or potential antigenicity observed in some clinical cases. Although studies on the antigenicity of recombinant proteins have initiated, and observations in clinical studies have been accumulated over this decade, mechanisms of the autoantibody production are not clarified yet. Among various hematopoietic growth factors introduced into clinical trials, this report summarizes current issues of autoantibodies to primary regulators for terminal hematopoiesis.

Identification of CD8+ and CD4+ T-cell defined tumor antigens has opened the way for possible cancer immunotherapy. Peptide-based active immunization has begun mainly targeting melanoma. Surprisingly, some objective responses were obtained in the initial trials, leading to the accumulation of an explosive number of such antigens. Serological screening of cDNA expression libraries accelerated the identification of immunodominant antigens, resulting in the emergence of the concept of a “cancer-testis antigen.” On the other hand, an advance in basic immunology has been promptly adopted: dendritic cells, as potent professional antigen presenting cells have been preferentially used in combination with the antigen in clinical trials both in vivo and in vitro. Tetramer analysis provided a powerful tool to directly monitor antigen-specific T cells in vivo in these trials. Moreover, adoptive transfer of antigen-specific T cells has added a new perspective to recent cancer immunotherapy.

Clara cell 10-kDa protein (CC10) / uteroglobin (UG) is a nonglycoprotein with a molecular mass of 16 kilodaltons, which is produced by mucosal epithelial cells in the lung (Clara cells), uterus and prostate. Like other low molecular weigh proteins it is catabolized in renal proximal tubules. Structurally it is a homodimer of subunits of 70 amino acids covalently bound in an antiparallel manner. It belongs to secretogobin (SCGB) family and is assigned as subgroup 1A1. The function of the protein so far elucidated is immunoregulatory and anti-inflammatory in innate immunity. The knockout mouse of UG gene resulted in aggravation of inflammation by allergic and hyperoxic stimuli. It also showed very similar pathological features with human IgA nephropathy. The value is changed in the lung fluid and serum of various inflammatory and allergic lung diseases. Several kinds of single nucleotide polymorphisms (SNPs) in human CC10 / UG gene were recently discovered, Adenine allele accumulation in G38A SNP has possible association with asthma and IgA nephropathy, being paralleled with disease severity of IgA nephropathy. Its expression is enhanced by some transcriptional factors induced by cytokines such as interferon-γ. For cancer cells, the protein functions as an antagonist of neoplastic phenotype. CC10 / UG forms one of intra- and intercellular regulators involved in inflammation and malignant transformation in the respiratory and urogenital fields.