Emerging Treatments for Autoimmune Hepatitis Pp-317-326
A.J. Czaja
The Role of TNF and Its Family Members in Inflammation
and Cancer: Lessons from Gene Deletion Pp-327-341
B.B. Aggarwal, S.
Shishodia, K. Ashikawa and A.C. Bharti
Novel Therapeutic Targets for Acute Pancreatitis and
Associated Multiple Organ Dysfunction Syndrome Pp-343-351
M. Bhatia
Peptide-based Vaccines in the Treatment of Specific
Allergy Pp-353-361
C. Alexander, A.B. Kay
and M. Larché
Critical Roles for Bradykinin and Prostanoids in Acute
Inflammatory Reactions: A Search Using Experimental Animal Models Pp-363-376
A. Ueno and S. Oh-ishi
TNFa as Therapeutic Target: New Drugs, More Applications Pp-377-392
A.M. Reimold
Role of Cytokines and Oxidative Stress in the
Pathophysiology of Acute Pancreatitis: Therapeutical Implications Pp-393-403
L.G. Gómez-Cambronero,
L. Sabater, J. Pereda, N. Cassinello, B. Camps, J. Viña and J. Sastre
Abstracts
[Back to top] Emerging
Treatments for Autoimmune Hepatitis
A.J. Czaja
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.
[Back to top] The
Role of TNF and Its Family Members in Inflammation and Cancer: Lessons from
Gene Deletion
B.B. Aggarwal, S.
Shishodia, K. Ashikawa and A.C. Bharti
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.
[Back to top] Novel Therapeutic Targets for Acute Pancreatitis and
Associated Multiple Organ Dysfunction Syndrome
M. Bhatia
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.
[Back
to top] Peptide-based Vaccines in the Treatment of Specific Allergy
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.
[Back to top] Critical Roles for Bradykinin and Prostanoids in Acute
Inflammatory Reactions: A Search Using Experimental Animal Models
A. Ueno and S. Oh-ishi
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.
[Back to top] TNFa as
Therapeutic Target: New Drugs, More Applications
A.M. Reimold
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-TNFα biologics
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.
[Back to top]
Role of Cytokines and Oxidative Stress in the
Pathophysiology of Acute Pancreatitis: Therapeutical Implications
L.G. Gómez-Cambronero,
L. Sabater, J. Pereda, N. Cassinello, B. Camps, J. Viña and J. Sastre
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.