Current Drug Targets - Inflammation & Allergy - Volume 1, Issue 4, 2002

Prednisone alone or a lower dose of prednisone in combination with azathioprine induces remission and enhances survival in autoimmune hepatitis. Treatment failure, incomplete response, drug-induced side effects, and relapse after drug withdrawal are unsatisfactory outcomes that justify the search for new therapies. Potent new drugs promise greater blanket immunosuppression than current regimens, and insights into the pathogenic mechanisms of the disease make site-specific interventions possible. Cyclosporine and tacrolimus are calcineurin inhibitors that impair the transcription of interleukin 2, reduce the expression of cytokines, and diminish T lymphocyte proliferation. Mycophenolate mofetil antagonizes the synthesis of purines and depletes stores of guanine nucleotides necessary for DNA synthesis and expansion of T cell clones. Controlled clinical trials are warranted to establish the role of these new drugs in the treatment of autoimmune hepatitis. Promising site-specific therapies include peptides that competitively block autoantigen presentation, agents such as cytotoxic T lymphocyte antigen 4 that inhibit the second co-stimulatory signal of immunocyte activation, T cell vaccination, oral tolerance therapy, and cytokine manipulation with monoclonal antibodies and recombinant supplements. Confident animal models of experimental autoimmune hepatitis are necessary to mature these interventions. In conclusion, promising immunosuppressive agents that alter cytokine expression and T lymphocyte proliferation may be of value in the treatment of autoimmune hepatitis. Critical mechanisms of immunocyte activation, cytotoxic T cell expansion, and cytokine modulation are the targets of site-specific interventions.

Almost two decades ago, tumor necrosis factor (TNF) was identified as a protein produced by the immune system that played a major role in suppression of tumor cell proliferation. Extensive research since then has revealed that TNF is a major mediator of inflammation, viral replication, tumor metastasis, transplant rejection, rheumatoid arthritis, and septic shock. As of today, 18 different members of the TNF superfamily have been identified, and most of them have been found to mediate a wide variety of diseases including cancer, arthritis, bone resorption, allergy, diabetes, atherosclerosis, myocardial infarction, graft versus host disease, and acquired immune deficiency disease. All the cytokines of the TNF superfamily mediate their effects through the activation of the transcription factor NF-κB, c-Jun N-terminal kinase, apoptosis, and proliferation. Thus, agents that can either suppress the production of these cytokines or block their action have therapeutic value for a wide variety of diseases. In this review, we have elucidated the signal transduction pathways used by the members of the TNF family and the effects of deletion of genes that mediate the pathways. Our current understanding of the signaling pathways for TNF and other family members could serve as a target for the development of therapeutics.

Acute pancreatitis is a common clinical condition. The exact mechanisms by which diverse etiological factors induce an attack are unclear but once the disease process is initiated, common inflammatory and repair pathways are invoked. Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction, if marked, this leads to a systemic inflammatory response syndrome (SIRS). An excessive SIRS leads to distant organ damage and multiple organ dysfunction syndrome (MODS). MODS associated with acute pancreatitis is the primary cause of morbidity and mortality in this condition. The systemic effects of acute pancreatitis have many similarities to those of other conditions such as septicemia, severe burns and trauma. Potentially, there is a therapeutic window between symptom onset and the development of distant organ damage in acute pancreatitis, when anti-inflammatory therapy may be of use. Recent studies conducted by us and other investigators have established the critical role played by inflammatory mediators such as TNF-α, IL-1β, IL-6, IL-8, CINC / GRO-α, MCP-1, PAF, IL-10, CD40L, C5a, ICAM-1, and Substance P in acute pancreatitis and the resultant MODS. It is reasonable to speculate that elucidation of the key mediators in acute pancreatitis coupled with the discovery of specific inhibitors will make it possible to develop a clinically effective anti-inflammatory therapy.

The efficacy of conventional allergen-specific immunotherapy (SIT) for allergic conditions and venom hypersensitivity is well documented. However it's use is limited due allergic side effects including anaphylaxis and the difficulty of standardising proteins in complex allergenic mixtures. The aim of new therapeutic strategies is to circumvent these limitations and approaches include allergen non-specific therapy, such as anti-IgE and anti-cytokine therapy and other allergen specific techniques including the peptide based vaccines (PBV), modified allergens (allergoids) and DNA vaccines.PBV are small linear peptide fragments containing T cell epitopes which are designed to reduce the ability to cross link antigen-specific IgE. Studies in animal models have confirmed proof of principle demonstrating the induction of hyporesponsiveness using high doses of peptides. However, the principle limitation to clinical use of PBV is the polymorphism of HLA class II molecules. There are ongoing clinical studies using peptidebased vaccines for cat, bee and grass allergies - looking at both immunological mechanisms and clinical outcome measures.The mechanisms underlying the efficacy of PBV appear to be similar to those described for classical immunological tolerance. Thus, the peptides may induce anergy due to absence of co-stimulation, activationinduced cell death, a switch from a Th2 to a Th1 cytokine profile, the induction of regulatory T cells or combinations of these mechanisms. Successful immunotherapy, in bee sensitive individuals, is associated with the elaboration of IL-10. Clonal deletion is unlikely as an overall mechanism as there is evidence that the subsequent in vitro response to associated, non-injected, peptides can be suppressed.Mechanistic studies continue to provide insight into the mode of action of whole allergen and peptide-based immunotherapy. Clinical studies designed on the basis of these observations hold the promise of safer vaccines with improved efficacy. Whether this strategy can be used for allergy to complex allergen mixtures such as dust mites will need further evaluation.

Searches for chemical mediators of inflammation underlying classical signs of inflammation i.e. heat, redness, swelling, and pain have been performed and various experimental models for evaluation of new agents to manage these inflammatory signs have been developed extensively during the last century. Now, at the beginning of the 21st-century, after great progress in gene technology, the necessity of in vivo animal study is being reconsiderered. Therefore, this review introduces and describes findings obtained by the use of various experimental animal models. We have compared the inflammatory characteristics among species using reported animal models such as dye exudation in the skin, paw edema, pleurisy, and writhing reaction, then we have precisely examined mediators involved in these inflammatory reactions. In the process of plasma exudation and pain perception in the earlier phases of acute inflammation, involvement of the kallikrein-kinin system and prostanoids was demonstrated. Precisely, bradykinin, and PGI2 among the prostanoids, are major mediators for exudation and pain perception of the initial acute phase of inflammation, both mediators collaborate to enhance these effects. PGE2, perhaps produced by cyclooxygenase-2, was involved in induction of plasma exudation and pain perception in a later phase than the timing of involvement of PGI2. Precise roles of various prostanoids will hopefully be clarified by the research projects in progress.

TNFα is a crucial cytokine in the establishment and maintenance of inflammation in multiple autoimmune diseases. With the introduction of infliximab and etanercept, two injectable biologic TNFα blocking drugs are now available. Both are effective in the treatment of rheumatoid arthritis, reducing clinical inflammation and damage to bones. In addition, infliximab is FDA-approved for the treatment of Crohn's disease. More recent controlled trials have shown effectiveness for TNFα blockers in psoriasis, psoriatic arthritis, and ankylosing spondylitis. Further trials are underway in diverse inflammatory conditions including including uveitis, sarcoidosis, Behcet's syndrome, and graft versus host disease. Although the safety profile has been generally excellent, the rare development of reactivation tuberculosis, anti double-stranded DNA antibodies, or a demyelination syndrome point out the need for further close follow-up of treated patients. New formulations of recombinant anti-TNFαbiologics undergoing clinical trials use modifications to reduce antigenicity, increase the half-life, and maintain or extend the efficacy of these agents. Future development of TNFα antagonists is turning to small molecule inhibitors. The inhibition of the TNFα signaling cascade is under study using blockers of the p38, JNK, and ERK kinases, and by antagonists of transcription factor NF-κB activation. The goal of this approach is to develop compounds that are orally available, have increased selectivity compared to generalized blockade of TNFα, yet are therapeutically useful for a range of chronic inflammatory diseases.

Severe acute pancreatitis causes a high incidence of mortality due to the systemic inflammatory response syndrome leading to multiple organ failure. At present, there is no treatment against severe acute pancreatitis, other than supportive critical care.The relationship between pancreatic injury and the uncontrolled systemic response is not completely understood. Nevertheless, experimental and clinical evidences have shown that pro-inflammatory cytokines and oxidative stress are critically involved in the development of local and systemic complications associated with severe acute pancreatitis.Serum levels of pro-inflammatory cytokines, such as TNF-α and IL-1ß, increase during the course of acute pancreatitis and they appear to be the driving force for the initiation and propagation of the systemic reponse. Accordingly, pretreatment with an antibody against TNF-α or blockade of TNF-α production with pentoxifylline ameliorates experimental acute pancreatitis. In addition, serum IL-6 and IL-8 levels appear to be correlated with severity of pancreatic inflammation.The role of oxidative stress in acute pancreatitis has been evidenced indirectly by beneficial effects of antioxidants as well as directly by pancreatic glutathione depletion and increased lipid peroxidation. Furthermore, circulating xanthine oxidase released by the damaged pancreas acts as a source of systemic oxidative stress contributing to lung inflammation.In conclusion, pancreatic injury seems to trigger at least two different pathways, i.e. pro-inflammatory cytokines and oxidative stress, both involved in the systemic effects of acute pancreatitis. Elucidation of these mechanisms and their interactions is critical to develop a treatment based on the pathophysiology of acute pancreatitis.