Anti-cytokine Treatment Research Articles

12 Effect of Anticytokine Treatment in A Mouse Model for Perinatal White Matter Lesions

Background: White matter lesions in neonates can result in motor handicaps such as cerebral palsy. Ischemia/ reperfusion and excitotoxic injuries have been considered probable aetiologies, but epidemiological data implicate that maternal-fetal infection and associated increase in circulating cytokines most likely also contributes to cerebral palsy. Tumor necrosis factorá (TNFá) is a cytokine that has a central position in the inflammatory cascade in many tissues and controls the release of other pro-inflammatory cytokines such as interleukin-1â (IL-1â). Numerous studies of systemic inflammatory diseases show that neutralization of TNFá with antibodies or soluble receptors inhibits the production of proinflammatory cytokines. Less is known about the effect of TNFá blocking agents in neonatal brain injury. In a study using lipopolysaccharide-induced brain injury, TNFá antibody had no effect whereas IL-1 receptor antagonist attenuated brain damage. Here, we have investigated the role of TNFá and in model of excitotoxic white matter lesion.Methods: The glutamate analog ibotenate was injected into the periventricular white matter of 5-day-old mice. At postnatal day 10, brains were sectioned in the coronal plane and the number of sections with brain damage was evaluated using cresyl-violet staining. The following groups of pups (n=8–10) were exposed to ibotenate: pretreatment (P1–5, i.p.) with IL-1â (10ng/kgx2), TNFá soluble receptor (etanercept, 100 μg/kgx1), IL-1 receptor antagonist (anakinra 0.3 g/kgx1) or PBS. Posttreatment (P5–7) with etanercept (1–500μg/kgx1), anakinra (0.3–1,0 g/kgx1) or PBS. In addition, TNFá knockouts (Jackson lab) and corresponding wild type mice were subjected to ibotenate intracerebral injection and pretreatment with IL-1â (10ng/kgx2).Results: TNFá soluble receptor or IL-1 receptor antagonist did not affect white matter lesions induced by ibotenate alone. Likewise, excitotoxic lesion did not differ between TNFá knockouts and wildtypes. However, if the excitotoxic lesion was enhanced by pretreatment with IL-1â, TNFá soluble receptor entirely attenuated this exacerbation (p<0.05).Conclusion: White matter damage induced by a combination of excitotoxicity and inflammation is reduced by a TNFá neutralizing agent. This indicates that TNFá is a key cytokine also in the brain and suggests a role for TNFá blocking drugs in preventing neonatal white matter lesions.

Therapy with biologic agents in SLE

AbstractThe revolution of biologic targeted therapy for autoimmune disease is underway. While anticytokine treatment (anti‐TNF‐α and anti‐IL‐1Ra) are proving beneficial in such diseases as rheumatoid arthritis and spondyloarthropathies, the road to successful treatment in systemic lupus erythematosus (SLE) is more complex, and perhaps because the mechanisms of disease remain unelucidated. The aims of novel therapies in SLE are to target the autoimmune disease at different points: B‐cell depletion (Lymphostat‐B, Rituximab), inhibition of T–B interaction (IDEC‐131), blockade of cytokines (anti‐IL‐10 antibodies), manipulation of idiotypes (IVIG), tolerance induction to DNA and to Ig‐peptides and peptide therapy (Riquent). We review the current knowledge on biologic agents in SLE patients. We utililized MEDLINE for relevant information from 2000 to 2003. Since biologic agents in this disease are at preliminary stages, we include information from abstracts, open trials, as well as phase I, II, and III studies. Anecdotal reports are not included. B‐cell depletion therapy is promising.

Absence of tumour necrosis factor facilitates primary and recurrent herpes simplex virus-1 infections.

Tumour necrosis factor (TNF) is an important cytokine in the innate immune response against various infections, including herpes simplex virus (HSV) infection. It has recently become a molecular target of anti-cytokine treatment in certain inflammatory diseases. TNF depletion resulted in a more rapid emergence of infectious HSV-1 in the explant cultures of latently infected trigeminal ganglia (TG), compared with controls. To further evaluate the importance of TNF in the host's defence responses against HSV-1, TNF-knockout mice were challenged via scarified cornea. These mice were more susceptible to primary acute corneal HSV-1 infection than controls, as manifested by an increased mortality rate and higher infectious virus titres in the eyes and TG, indicating that TNF is critical for defence during acute HSV infection. These results imply that the administration of anti-inflammatory TNF antagonists might facilitate the propagation of infectious HSV, resulting in an exacerbation of primary and recurrent acute lesions.

Interleukin 6 receptor as a target for the treatment of rheumatoid arthritis

Chronic synovial inflammation and joint damage are cardinal features of rheumatoid arthritis (RA). Although the precise cause remains unknown, cytokines have a major pathogenic role. The therapeutic benefit of antagonists...

Therapeutischer Einsatz der Tumor‐Nekrose‐Faktor‐α‐Hemmer Infliximab und Etanercept bei entzündlichen Hauterkrankungen

Hintergrund: Die Behandlung entzündlicher Hauterkrankungen ist häufig empirisch, da kausale Therapiemaßnahmen aufgrund unvollständiger Kenntnisse der Immunpathogenese meist nicht vorliegen. Die derzeit durchgeführten Therapien können zwar zur Remission der Erkrankung führen, allerdings müssen unter Umständen unerwünschte Nebenwirkungen in Kauf genommen werden. Aufbauend auf den Erfahrungen einer zytokinmodulierenden Therapie bei chronisch entzündlichen Erkrankungen wie der rheumatoiden Arthritis, könnte der Einsatz von TNF‐α‐Inhibitoren eine weitere, spezifischere und effektivere Behandlungsmöglichkeit einzelner entzündlicher Hauterkrankungen darstellen. Patienten und Methodik: Anhand eigener Erfahrungen und aktueller Literaturberichte stellen wir den derzeitigen Stand des neuen Behandlungsregimes von entzündlichen Hauterkrankungen mit TNF‐α‐Blockern dar. Neben pathogenetischen Wirkmechanismen wird auf die Erfahrungen bei der Anwendung der TNF‐α‐Inhibitoren eingegangen. Außerdem wird auf unerwünschte Begleitwirkungen und mögliche Kontraindikationen dieser Therapie hingewiesen. Ergebnisse und Schlußfolgerungen: Die bisherigen Erfolge zeigen, daß TNF‐α‐blockierende Substanzen bei entzündlichen Hauterkrankungen, insbesondere im Sinne der akuten Interventionstherapie, eine Bereicherung im Therapiespektrum darstellen können. Einheitliche Richtlinien über Indikationen und Kontraindikationen einer anti‐TNF‐α‐Therapie (Infliximab und Etanercept) bei entzündlichen Hauterkrankungen müssen erst erarbeitet werden, um die Therapie zu optimieren und die unerwünschten Begleitwirkungen gering zu halten.

In situ cytokine immune responses in acute disseminated encephalomyelitis: Insights into pathophysiologic mechanisms

Acute disseminated encephalomyelitis (ADEM) is thought to be an autoimmune disorder of the central nervous system in which myelin is targeted. Pathological studies on closely related human diseases (eg, multiple sclerosis) and on animal models for these demyelinating disorders have suggested the involvement of cytokines. Studies on peripheral immunocytes and on cerebrospinal fluid revealed the presence of cytokine-mediated responses in ADEM. We carried out this neuroimmunopathologic exploration and report for the first time the in situ expression of “inflammatory” cytokines in ADEM. Moreover, we note a particular spatial and molecular pattern whereby tumor necrosis factor-α and interleukin (IL)-1β are intensely expressed, whereas IL-6 is absent. Differential expression at different levels of the neuraxis was also noticed. Our findings suggest that these cytokines, reported to be toxic to myelin, are implicated in the molecular cascade, resulting in the neural damage. These observations might provide insights into molecular pathways involved in the immunopathogenesis of ADEM and might open new horizons in neuroimmunomodulation and anticytokine treatment. Hum Pathol 34:293-297. Copyright 2003, Elsevier Inc. All rights reserved.

Sarcoidosis.

Sarcoidosis commonly involves the eye, causing uveitis, the lacrimal gland, and the cranial nerves, including the optic nerve itself. Several microorganism types have recently been located in sarcoid granulomas, suggesting an infective cause in predisposed individuals. The approach to diagnosis has been refined, including the use of high-resolution computed tomography of the chest. New ophthalmic manifestations have been described, suggesting a wider role for sarcoidosis in intraocular inflammation, and indocyanine green angiography has clarified choroidal involvement. Immunosuppressive and anticytokine treatments can be effective in severe systemic sarcoidosis and should be considered in sight-threatening disease.

Anticytokine treatment prevents the increase in the activity of ATP-ubiquitin- and Ca(2+)-dependent proteolytic systems in the muscle of tumour-bearing rats.

The ascites hepatoma Yoshida AH-130 induces loss of body weight and tissue waste. Tumour necrosis factor alpha (TNF-alpha) plays a pivotal role in the pathogenesis of muscle wasting in this model system, but other cytokines, such as interleukin-6, may be involved. In order to verify whether a combined anticytokine treatment may synergistically counteract muscle protein degradation, tumour bearing rats were treated with pentoxyfilline (PTX, an inhibitor of TNF-alpha synthesis), or with suramin (SUR, an antiprotozoal drug blocking the peripheral action of several cytokines including IL-6 and TNF-alpha), or both the drugs, and the effects on muscle proteolytic systems were assessed. Muscle protein loss in the AH-130-bearing rats was associated with increased activity of both the ATP-ubiquitin- and the calpain- dependent proteolytic pathways (246% and 230% of controls, respectively). Both PTX and SUR, either alone or in combination, prevented the depletion of muscle mass and significantly reduced the activity of muscle proteolytic systems. In particular, treatment with SUR, either alone or with PTX, induced a decrease in enzymatic activities to values similar to those of controls. The results obtained in the present paper demonstrate that: (i) muscle depletion in this model is indeed associated with increased proteasome- and calpain-dependent proteolysis, as previously suggested by increased mRNA expression of molecules pertaining to both pathways; (ii) anticytokine treatments effectively reduce muscle protein loss by down-regulating the activity of at least two major proteolitic systems; (iii) SUR is more effective than PTX in reducing the activity of proteolytic systems, possibly because of its multiple anticytokine action.

Interferon-gamma (IFN-gamma)- and tumour necrosis factor (TNF)-induced nitric oxide as toxic effector molecule in chronic dextran sulphate sodium (DSS)-induced colitis in mice.

Excess nitric oxide formation caused by the activity of the inducible nitric oxide synthase has been implicated as a toxic effector molecule in the pathogenesis of experimental colitis and inflammatory bowel disease. It was therefore investigated whether inhibition of this synthase or the cytokines TNF and IFN-gamma, inducers of nitric oxide synthase, had effects on chronic colitis in mice. Chronic colitis was induced in mice by repeated feeding of DSS. Cytokines were neutralized by treatment with MoAbs and nitric oxide synthase was inhibited by aminoguanidine. The degree of colonic inflammation was assessed by a histological score and colon length. Aminoguanidine treatment reduced nitric oxide activity by 60% (P = 0. 0004), the histological score by 31% (P = 0.005) and increased colon length by 1.4 cm (P = 0.002). Neutralization of TNF and IFN-gamma resulted in increased colon length (0.7 cm, P = 0.07 and 0.8 cm, P = 0.03), improved histological score (19%, P = 0.045 and 25%, P = 0. 013), and reduced nitric oxide activity (31%, P = 0.07 and 54%, P = 0.004) compared with controls. The combination of anti-cytokine treatments had additive effects. TNF and IFN-gamma are involved in perpetuation of chronic DSS-induced colitis, and induction of excessive nitric oxide activity could be their common effector mechanism.

Localisation of transforming growth factor β1 and β3 mRNA transcripts in normal and fibrotic human lung

BACKGROUNDTransforming growth factor β1 is implicated in the pathogenesis of lung fibrosis. It promotes extracellular matrix accumulation by increasing procollagen synthesis and reducing degradation. TGFβ1 gene and protein expression increase...

Localisation of transforming growth factor β1 and β3 mRNA transcripts in normal and fibrotic human lung

BACKGROUNDTransforming growth factor β1 is implicated in the pathogenesis of lung fibrosis. It promotes extracellular matrix accumulation by increasing procollagen synthesis and reducing degradation. TGFβ1 gene and protein expression increase in experimental lung fibrosis, and TGFβ1 antibodies attenuate fibrosis in mice. The role of other TGFβ isoforms is unclear. This study aimed to localise TGFβ1 and TGFβ3 gene expression in fibrotic human lung and compare it with that in normal human lung.METHODSLung tissue from patients with cryptogenic fibrosing alveolitis and fibrosis associated with systemic sclerosis was examined by in situ hybridisation. Macroscopically normal lung from carcinoma resections was used as control tissue. Digoxigenin labelled riboprobes were synthesised from TGFβ isoform specific cDNA templates.RESULTSThe digoxigenin labelled riboprobes were sensitive and permitted precise cellular localisation of mRNA transcripts. TGFβ1 and TGFβ3 mRNA transcripts were widespread in normal lung and localised to alveolar macrophages and bronchiolar epithelium. TGFβ1 but not TGFβ3 mRNA was detected in mesenchymal and endothelial cells. In fibrotic lung tissue mRNA transcripts for both isoforms were also detected in metaplastic type II cells. TGFβ1 gene expression was enhanced in some patients. TGFβ3 was expressed in fibrotic lung but was not consistently altered compared with controls.CONCLUSIONTGFβ1mRNA transcripts were localised in normal and fibrotic human lung and TGFβ3 gene expression in human lung fibrosis was shown for the first time. The results suggest that TGFβ1 may play the predominant role in pathogenesis. It is suggested that TGFβ1 should be the primary target of anticytokine treatments for pulmonary fibrosis.

Treatment of rheumatoid arthritis: new therapeutic approaches with biological agents.

Rheumatoid arthritis is a chronic polyarthritis leading to joint destruction and remarkable disability. Current therapies have various degrees of efficacy, but toxicity frequently limits their long-term use. Furthermore, treatment of refractory rheumatoid arthritis includes increasing disease-modifying antirheumatic drugs dosage, using combination therapy, and adding or increasing the posology of corticosteroids. Although the etiology of the disease remains unknown, our increasing knowledge of the mechanisms underlying pathogenic events in rheumatoid synovitis, has provided opportunities to specifically target cell surface markers or cytokines involved in the inflammatory response. The objective of this review is to describe the different therapeutic approaches with biological agents that are either being utilized or are under development. Some of these products reflect the evolving capacity for the biotechnology industry to synthesize and humanize therapeutic agents: anti-tumor necrosis factor (TNF) alpha monoclonal antibodies (MoAb) and recombinant TNF-receptor construct appear to be validated tools. These treatments alone, or in combination with methotrexate are very effective in rheumatoid patients. Data from clinical trials and issues related to mechanisms of action, potential toxicity, and future perspectives for these novel therapeutic options are considered in this review. Anti-cytokine treatment include other interesting approaches to interfere with on-going inflammatory processes, such as the use of recombinant human interleukin (IL)1 receptor antagonist, or recombinant human IL10. T cell constimulatory blockade, induction of apoptosis in the synovial tissue, and gene therapy could represent future strategies in rheumatoid disease.

Future prospects for anti-cytokine treatment

The era of anti-cytokine treatment in rheumatology has just begun. The first generation therapeutic agents, biological agents that block tumour necrosis factor α such as monoclonal antibodies or receptor Ig...

Anti-interleukin-1 and anti-tumor necrosis factor-alpha synergistically inhibit adjuvant arthritis in Lewis rats.

Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) play dominant roles in mediating the progression of many inflammatory joint diseases, including rheumatoid arthritis in humans, collagen-induced arthritis in mice and rats, and adjuvant arthritis in rats. Blockade of either cytokine partially controls these diseases. The present study investigated the value of combination anti-cytokine therapy in arthritis: the efficacy of IL-1 receptor antagonist (IL-1ra) and 30 kDa polyethylene glycol (PEG)-conjugated soluble TNF receptor type I (PEG sTNF-RI) given together was assessed in Lewis rats with adjuvant arthritis. Administration of either IL-1ra or PEG sTNF-RI partially alleviated joint inflammation, loss of bone mineral density, and loss of body weight. In contrast, combination of these anti-cytokine treatments exhibited a synergistic capacity to inhibit these changes, even when combining doses of IL-1ra and PEG sTNF-RI that did not affect lesion severity when used alone. Statistical analysis of these adjuvant arthritis data using the isobologram method proved that IL-1ra and PEG sTNF-RI were clearly synergistic in inhibiting inflammation, loss of bone mineral density, loss of body weight, and histopathologic parameters of inflammation and joint destruction. These results suggest that treating autoimmune arthritic diseases with combinations of anti-IL-1 and anti-TNF molecules will achieve superior efficacy compared to the use of a single class of anti-cytokine agent and may allow for dose reductions that could prove useful in minimizing potential side effects.

Growth failure occurs through a decrease in insulin-like growth factor 1 which is independent of undernutrition in a rat model of colitis

BACKGROUNDLinear growth retardation is a frequent complication of inflammatory bowel disease in children. The precise mechanisms causing growth failure are not known.AIMSTo determine the relative contribution of reduced calorie intake...

Cancer cachexia: from experimental models to patient management.

Cachexia is frequently associated with advanced or terminal cancer states, but it can also develop early during the course of neoplastic disease. This syndrome, which is characterized by body weight loss and negative nitrogen balance, significantly affects patient survival and quality of life. Studies on experimental models have shown that a complex interplay of different factors, such as anorexia, classical hormones, cytokines and other less well defined factors, concur in causing tissue wasting. On the basis of these results, it has been possible to prevent the onset of experimental cachexia by targeting therapeutic interventions at the underlying metabolic perturbations. Anticytokine treatments, either acting centrally or peripherally, have received particular attention, and are currently reaching the stage of clinical trials.

Interleukin-6 Release by Cultured Peripheral Blood Mononuclear Cells Inversely Correlates with Height Velocity, Bone Age, Insulin-like Growth Factor-I, and Insulin-like Growth Factor Binding Protein-3 Serum Levels in Children with Perinatal HIV-1 Infection

Spontaneous and phytohemagglutinin (PHA)-stimulated interleukin (IL)-6 release by cultured peripheral blood mononuclear cells was related to height velocity, bone age, insulin-like growth factor-I (IGF-I), and IGF binding protein-3 (IGFBP-3) serum level standard deviation scores (SDS) of 32 children [aged 91 (median; range 13–151) months] with human immunodeficiency virus-type 1 (HIV-1) perinatal infection and severe disease. Spontaneous and PHA-stimulated IL-6 release inversely correlated with height velocity, bone age, IGF-I, and IGFBP-3 SDS. Ten children with height velocity SDS ≤ −2, compared to 22 children with height velocity SDS > −2, showed higher spontaneous and PHA-stimulated IL-6 release and lower IGF-I and IGFBP-3 SDS (irrespective of CD4-positive T-lymphocyte counts, viral load, liver disease, or nutrition status). IL-6 overproduction may be a mechanism of IGF-I and IGFBP-3 down-regulation and impaired linear growth in children with perinatal HIV-1 infection. Growth-promoting strategies, including targeted anticytokine treatments, could be devised for such children.

Insights from mouse models of colitis.

Emerging studies using mouse models of experimental colitis are defining the nature of the immunological disturbances that initiate inflammation and destruction of the intestine. A better understanding of disease-promoting and -suppressing CD4+ T cells is providing insight into the mechanisms controlling immune responses within the intestinal compartment. Moreover, a role for distinct T cell populations, including intraepithelial gammadelta T cells, in maintaining the physical integrity of the intestine was suggested by recent studies. Cytokine gene-knockout mice and anti-cytokine treatments remain important tools to define the pro- and anti-inflammatory functions of cytokines. These advances are fostering the design and evaluation of new therapeutic approaches that may eventually be applied to treat human inflammatory bowel disease.

Immune responses to Aspergillus antigen in IL-4-/-mice and the effect of eosinophil ablation.

Exposure to Aspergillus fumigatus allergens results in enhanced total serum IgE and peripheral blood eosinophils in mice. The associated pulmonary inflammation and immunologic responses are comparable to those detected in human allergic bronchopulmonary aspergillosis. Allergen-induced cytokines are thought to regulate the inflammatory and immune responses in these animals. In the present study, we exposed C57BL/6 and BALB/c mice to A. fumigatus antigen. Both wild-type and IL-4 knockout phenotypes of animals of both strains were used. Some animals were also treated with anti-IL-5 or anti-IFN-gamma. Total serum IgE, Aspergillus species IgG subclass, peripheral blood eosinophils, and lung histology were studied. The results demonstrate similar lung inflammation in all wild-type and IL-4-/- animals exposed to A. fumigatus antigen. Similarly, in spite of the diverse immune response produced by the anticytokine treatment, no major differences were detected among any of the animal groups studied. It can be concluded that A. fumigatus exposure in an immunologically unaltered host is predominantly of a Th2 type, and that depletion of the Th2 cytokine leads to a similar lung inflammation but with a characteristic Th1 response, suggesting that the pathogenesis of allergic aspergillosis is the result of multiple induction pathways.

Serum interleukin-1 β, interleukin-6, nitric oxide and α1-antitrypsin in scorpion envenomed children

During the present study, thirty-eight children in Upper Egypt (less than 12 years old) were admitted to Pediatric Intensive Care Unit for scorpion envenomation. They were compared with thirteen apparently healthy children of matching age as controls. The victims and controls were subjected to complete clinical examination and full blood count. The evaluations of the serum levels of interleukin-1 β (IL-1 β), interleukin-6 (IL-6), nitric oxide (NO) and α 1-antitrypsin ( α 1-AT) were performed once for the controls and twice for the victims, the first sample on admission and the 2nd sample after 24 h. All victims showed significantly higher mean values of IL-1 β, IL-6, NO, α 1-AT and leucocytic count both on admission and on follow up when compared with controls. Manifestations of mild envenomation were detected among 28.9% of the victims, while 71.1% of the victims manifested severe scorpion envenomation. The severely envenomated children showed significantly higher mean values of IL-1 β, IL-6, NO, α 1-AT and leucocytic count both on admission and on follow up when compared with mild cases. The case fatality rate in the current study was 7.8%. The non-surviving victims showed significantly higher mean values of IL-1 β, IL-6 and leucocytic count both on admission and on follow up in comparison to the survivors. Furthermore, those fatal cases showed a non-significant decline in the studied biochemical indices on follow up after 24 h, while the survivors showed a significant decline in the serum levels of IL-6, IL-1 β, NO and α 1-AT after 24 h of post arrival to the hospital. In conclusion, these data revealed that cytokines are involved in the pathogenesis of scorpion envenomation and correlated with the severity of envenomation. This may provide a rationale for anticytokine treatment.