Current Drug Targets - Inflammation & Allergy - Volume 4, Issue 1, 2005

Antiangiogenesis in Chronic Inflammation This issue of “Current Drug Targets - Inflammation & Allergy” is dedicated to the topic of “Antiangiogenesis in chronic inflammation”. Interest in angiogenesis research remains strong in recent years: many laboratories worldwide are actively involved in the study of several aspects of this field and the literature on angiogenesis increases exponentially. The growth of new microvessels from resting vessels is the outcome of a fine balance between molecules that are either positive or negative regulators of angiogenesis (the so called “angiogenic switch”). The explosion of clinical research in angiogenesis is a result of the realization that in many diseases characterized by persistent, unregulated angiogenesis, as cancer, atherosclerosis, rheumatoid arthritis and diabetic neuropathy, a common underlying pathogenetic aspect is a derangement in angiogenesis. Suppressors of angiogenesis have potential clinical applications in conditions where abnormal proliferation of blood vessels is related to the disease progression. In this issue several leading investigators report new findings about antiangiogenesis in chronic inflammation. The role of angiogenesis in chronic inflammation is analyzed and the effect of inflammatory mediators on angiogenesis is reviewed, where possible we have tried to indicate the areas of each process that are poorly understood in order to prvide directions for future research. Dr. Naldini and Carraro present an overview on the relevance of both physiological and pathological inflammatory processes in angiogenesis, with particular regards to microenvironment. Dr. Crivellato and myself summarize the most recent acquisition concerning mast cells involvement in angiogenic processes and chronic inflammatory processes. Dr. Ranieri and co-workers review recent studies on the vasculature targeting strategies for the treatment of chronic inflammatory diseases. Dr. Strieter and co-workers discuss the biology of the angiogenic and angiostatic CXC chemokines and their disparate angiogenic activity in the context of a variety of chronic fibroproliferative disorders. Dr. Roccaro and co-workers present recent data about the use of antiangiogenesis as a therapeutic tool in the treatment of rheumatoid arthritis. Finally, Dr. Monnier and co-workers review the most recent advances in understanding the mechanisms by which non-steroidal anti-inflammatory drugs and inhibitors of cyclooxygenase suppress angiogenesis and discuss their potential clinical use as antiangiogenic drugs.

The angiogenic process involves several cell types and mediators, which interact to establish a specific microenvironment suitable for the formation of new capillaries from pre-existing vessels. Angiogenesis occurs in several physiological and pathological conditions, such as embryo development and wound healing, diabetic retinopathy and tumours. Inflammatory cells, namely monocytes/macrophages, T lymphocytes and neutrophils, fully participate in the angiogenic process by secreting cytokines that may affect endothelial cell (EC) functions, including EC proliferation, migration and activation. Angiogenesis is the result of a net balance between the activities exerted by positive and negative regulators. With regards to inflammatory cells and endothelium cross-talk, such balance is conceptually very similar to that of proinflammatory and anti-inflammatory mediators that modulate an appropriate inflammatory response. In this review we will mainly discuss the relevance of both physiological and pathological inflammatory processes in angiogenesis, with particular regards to microenvironmental contribution. We will also describe some of the most relevant pro-inflammatory cytokines in the modulation of the angiogenic process. Furthermore, we will concentrate on what has been recently reported about the mechanism by which some of these cytokines are induced during inflammation to promote a suitable microenvironment for angiogenesis and tumour progression. Pro-angiogenic cytokines, such as IL-1 and TNF, and anti-angiogenic cytokines such as IFN-α and IL-12, will be briefly described. We will try to provide a rationale for the use of both cytokines and cytokine blockades as novel potential pharmaceutical targets to modulate angiogenesis in chronic inflammation as well as in cancer.

Mast cells (MC) are granulated secretory cells that have long been recognized as a rich source of biologically highly active mediators such as biogenic amines, prostaglandins, leukotrienes, proteases, cytokines and chemokines. Most of their biological functions however has been rather elusive. There are now emerging data assigning these cells a relevant role in orchestrating angiogenesis, both in normal and pathological conditions. MC indeed synthesize and release a large array of proangiogenic factors upon different stimulation pathways. In addition, MC have been recognized as key cells in mediating host innate and adaptive immune responses. This review summarizes the most recent acquisitions concerning MC involvement in angiogenic processes and chronic inflammatory reactions.

The pathogenesis of a number of chronic inflammatory processes can be attributed to prolonged neovascularization. This article reviews recent studies on the vasculature targeting strategies for the treatment of chronic inflammatory diseases. Targeting of the vasculature of inflamed organs could underlie a new pharmacological approach in the treatment of inflammatory diseases by taking advantage of formulations that deliver drugs to blood vessels specifically located at disease sites and to inflammatory cells.

The CXC chemokines are an unique family of cytokines known for their ability to behave in a disparate manner in the regulation of angiogenesis. The mechanisms for the different activity in regulating angiogenesis by members of this chemokine family is related to the following: 1) the presence or absence of the structural / functional motif (Glutamic acid-Leucine-Arginine; ‘ELR’ motif) that immediately precedes the first cysteine amino acid residue in the primary structure of these cytokines; 2) interferon-inducible gene expression; and 3) receptors that these chemokines use to mediate their biological activity. Members that contain the ‘ELR’ motif (ELR+) are potent promoters of angiogenesis, and mediate their angiogenic activity via binding and activating CXCR2 on endothelium. In contrast, members that are inducible by interferons and lack the ELR motif (ELR-) are potent inhibitors of angiogenesis, and bind to the alternatively splice variant of CXCR3, CXCR3B on endothelium. This review will discuss the biology of these angiogenic and angiostatic CXC chemokines, and discuss their disparate angiogenic activity in the context of a variety of chronic fibroproliferative disorders.

Angiogenesis, i.e., the induction of new blood vessels from existing vasculature, is a crucial event in the formation and maintenance of the pannus in rheumatoid arthritis (RA). The arthritis is characterized by destruction of peripheral joints in which the cartilage and bone are destroyed by proliferative synovitis. This is characterized by infiltration of inflammatory cells and formation of new blood vessels. Angiogenesis occurs since the early stage of the disease, and supports progression of the arthritis. It has been demonstrated in animal models of arthritis that inhibition of angiogenesis reduces of the arthritis. This suggests that pharmacological inhibition of angiogenesis may play an important role in the treatment of RA. In particular, disruption of new blood vessels can not only prevent delivery of nutrients to the inflammatory site, but can also lead to vessel regression, hence reversal of disease. To sum up, since angiogenesis is central in maintaining of synovitis in RA, antiangiogenesis probably represents a therapeutic tool. This view is supported by recent studies in animal models of arthritis where antiangiogenic drugs deliver a therapeutic benefit.

The formation of new blood vessels, a process globally referred to as angiogenesis, occurs in a number of pathological conditions, such as cancer and chronic inflammation. Recent findings indicate that cyclooxygenase-2 (COX-2), the inducible form of the cyclooxygenase (COX) isoenzymes, acts as a potent inducer of angiogenesis. Non-steroidal anti-inflammatory drugs (NSAIDs) are classical inhibitors of COX enzymes, which are widely prescribed for the treatment of inflammation, pain and fever. Selective COX-2 inhibitors (COXIBs) have been subsequently developed with the purpose to improve the safety profile of this class of therapeutics. More recently, substantial preclinical evidence demonstrated that NSAIDS and COXIBs have anti-angiogenic properties. This newly recognized activity opens the possibility of using these drugs for the treatment of angiogenesis-dependent diseases. In this article we review the most recent advances in understanding the mechanisms by which NSAIDs and COXIBs suppress angiogenesis, and we discuss their potential clinical use as anti-angiogenic drugs.

Molecular Biology-Pathophysiology of Inflammation and Autoinflammation It is a great pleasure and an honor as well for me to present to the readers of this Journal a Special Issue dedicated to a set of topics in the area of molecular biology-pathophysiology of inflammation and autoinflammation. Inflammation, a rather cardinal concept in biology and not only in medicine, representing the most common reaction to a variety of stimuli has recently been widened as to cover conditions related to immune mechanisms without any evidence of involvement of antibodies or antigen specific cells (auto-inflammation) as well. Although seemingly rare, genetically controlled and encompassing a variety of diverse entities, it turns to be an ideal model of tissue reaction with a lot of secrets hiding behind very primitive concepts. Understanding the pathogenesis of entities, (=EA=FC=EC=EC=E1) such as Familial Mediterranean Fever, is essential not only for reliable diagnosis, counseling and treatment but also as a first step in understanding better the concept of inflammation and the other so-called auto-inflammatory conditions. The pathophysiology of inflammation and autoinflammation is thoroughly covered in several chapters of this issue. Distinguished co-authors from several centers around the world have contributed to detailing these concepts from the clinical, pharmacological, molecular and developmental view. Boumpas and Kourbeti (Greece) discuss the concept of biological treatment strategies in autoimmunity. Dourakis and Alexopoulou (Greece) unfold the secrets of clinical implications of the genetic heterogeneity of hepatitis, a very special infection with a wide impact on public health. Grateau (France) presents the serious and fascinating problem of amyloidoses that are currently becoming more and more difficult to understand. Gumucio (Michigan-US) deals with the emerging molecular details of inflammatory processes occurring at least in part via the interaction of several intracellular mediators and pyrin, the protein involved in pathogenesis of Familial Mediterranean Fever. Tunca and Ozdogan (Turkey) review the concept of molecular and genetic characteristics of hereditary autoinflammatory diseases. Gul (Turkey) reviews the similarities between the hereditary autoinflammatory diseases and an acquired entity of auto-inflammatory type, namely Bechet's disease. Karageuzyan (Armenia) proposes his model on oxidative stress in the pathogenesis of several disease states, hereditary or acquired. Samarkos and Vaiopoulos (Greece) discuss the literature data on the causative role and induction of autoimmunity. Cattan (France) reviews the relations between vasculitides and Familial Mediterranean Fever, an as-yet unsolved question; he also deals with the putative selection advantages, if any, of Mediterranean Fever gene. Sarkisian (Armenia) is reporting on the genotype-phenotype correlation(s) of pyrin mutations in Armenia, a hot area for Mediterranean Fever. Manna (Italy) reviews the pharmacology of the most popular (and most efficient) agent for treating Mediterranean Fever, colchicin. Germenis and his group (Greece) comment on the versatility of complement framework, a strategic function in innate immunity. I am much obliged to all authors and their collaborators for the time and efforts they devoted for this production. I wish to thank Bentham Publishers for honouring me with their decision and invitation to act as a Guest Editor in this Special Issue. I wish to thank people in my Department for allowing me enough time for the editing duties. I am sure that this volume will prove valuable contribution to a better understanding of the complex and diverse field of the pathophysiology of inflammation and auto-inflammation.

The advances in the understanding of the pathogenesis of the autoimmune diseases have led to new treatment targets. Biological agents enhance or replace conventional immunosuppressive therapies in the treatment of autoimmune diseases. TNF-α has been validated as a good treatment target but the potential modalities also include the inhibition of the interaction between LFA-3 (lymphocyte function-associated antigen 3) and CD2, the blockade of the IL-1 receptors, the antibodies against the α4 integrins, the antibodies against B-cell CD20 and the inhibition of the activation of T-cells. The new treatments have had a major impact on inflammatory symptoms, the radiological damage and the anemia of chronic disease in rheumatoid arthritis and have substantially controlled the signs and symptoms in the spondylarthropathies group and plaque-type psoriasis. The efficacy of the biologic agents in systemic lupus erythematosus warrants further investigation but there have been some promising results in proliferative lupus nephritis. Several small studies have explored their use in the treatment of Sjogren's syndrome, adult onset Still's disease and several vasculitides but the results are still preliminary and warrant confirmation. The efficacy of the biological agents has been impressive. Susceptibility to infections has always been a major concern; a high level of suspicion is necessary and strategies should be implemented for the prevention, the rapid identification and pre-emptive therapy of such infections.

The genetic heterogeneity of hepatitis B virus (HBV) (8 genotypes A-H) has been applied for tracing the route of HBV transmission and the geographical migration of HBV carriers but it also appeared to have clinical implications. The secondary structure of e encapsidation signal could explain why the precore mutant virus prevails in Mediterranean countries, where genotype D is most prevalent, while the wild type virus is frequent in Western countries, where genotype A is most prevalent. There is increasing evidence that patients infected with genotype C have more severe outcome of chronic liver disease than those infected with genotype B. Genotype B was associated with fulminant hepatitis and more severe episodes of acute exacerbation of chronic HBV infection. Patients infected with genotype B appeared to seroconvert earlier than those infected with genotype C. The hepatitis delta virus (HDV) has 3 genotypes (I, II, III) which are associated with different disease patterns. Genotype III is the most distantly related HDV genotype and is associated with the most severe outcome while genotype II with relatively mild liver disease. The most geographically widespread genotype is I and is associated with a broad spectrum of chronic liver disease. The hepatitis C virus (HCV) displays high genetic heterogeneity with six genotypes (1-6), multiple subtypes and quasispecies. This viral diversity has epidemiological and clinical implications and has been associated with the severity of liver disease, prognosis, response to treatment and failure to generate an effective protective vaccine. HCV genotype 1 is the predominant genotype in Western countries and has been associated with a low response rate to interferon-alpha (IFN-α) or to the combination of ribavirin and IFN-α. Consequently the duration of treatment has been tailored according to HCV genotype.

Amyloidosis remains currently a severe potential complication of many chronic inflammatory disorders. It is not exactly know why some patients develop a progressive amyloidosis, whereas others do not although latent deposits may be present. A permanent acute phase response, ideally evaluated with serial measurement of serum protein SAA, the precursor of the AA protein deposited in tissues, seems to be a prerequisite to the development of inflammatory (AA) amyloidosis. Genetic factors have however been recently emphasized. Among persistent or emerging causes of AA amyloidosis, hereditary periodic fever syndromes also known as auto-inflammatory syndromes are a group of diseases characterised by intermittent bouts of clinical inflammation with focal organ involvement mainly: abdomen, musculoskeletal system and skin. The most frequent is familial Mediterranean fever which affects patients of Mediterranean descent all over the world. Three other types have been recently clinically as well as genetically characterised. A thorough diagnosis is warranted, as clinical and therapeutic management is specific for each of these diseases.

Familial Mediterranean fever (FMF, MIM24900), described as a clinical entity only slightly over a half-century ago, has ancient roots among populations surrounding the Mediterranean basin. It is the most prevalent of the hereditary periodic fever syndromes, a group of disorders characterized by episodic attacks of fever and inflammation. Seven years ago, it was discovered that FMF is caused by mutations in MEFV, a gene that encodes a protein variously called pyrin or marenostrin. As exciting as that discovery was, physicians and patients alike were disappointed that the protein sequence of pyrin/marenostrin did not immediately suggest clues as to the molecular etiology of FMF. Though we are still far from a complete understanding of the function of pyrin/marenostrin at the cellular level, continued study of this intriguing protein is revealing new molecular details about inflammatory processes; the emerging information is relevant not only to FMF, but to innate immunity in general. Data from several laboratories demonstrate that pyrin/marenostrin is intimately connected to three important cellular pathways: apoptosis, cytoskeletal signaling and cytokine secretion. These connections occur, at least in part, through the direct interaction of the pyrin/marenostrin protein with two cytosolic protein adaptors: ASC (also called PyCARD or Tms1) and PSTPIP (also called CD2BP1). Here, we review the more recent literature regarding the molecular and cellular biology of pyrin/marenostrin and pinpoint open questions for future study.

Autoinflammatory diseases are defined as recurrent “unprovoked” inflammatory events which do not produce high-titer autoantibodies or antigen-specific T cells. There are currently eight hereditary forms of these diseases: Familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), chronic infantile neurologic cutaneous articular (CINCA) syndrome or neonatal-onset multisystem inflammatory disease (NOMID), pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) and Blau syndrome. Apart from FMF (which has a prevalence of about 0.1 percent among non-Ashkenazi Jews, Armenians, Turks and Arabs), they are very rare disorders. FMF and HIDS are autosomal recessive diseases, all the other members of the family are autosomal and dominantly transmitted. Their common clinical features are recurrent and usually short attacks of synovitis and various skin eruptions; abdominal pain and fever are also frequently observed. The genes of all of these diseases have been discovered and, with the exception of HIDS, it was found that the proteins they encode share certain domains taking part in innate immunity and apoptosis. Thus it was evident that hereditary autoinflammatory diseases may help us understand better a number of important and prevalent pathologic events. We have reviewed the recent and rapidly accumulating knowledge on the molecular aspects of these disorders.

Autoinflammatory diseases are a group of heritable disorders that are characterized by seemingly unprovoked episodes of inflammation at certain locations and and relative lack of high-titer autoantibodies or antigen-specific T cells. Behçet's disease is an inflammatory disorder of unknown aetiology, and many of its characteristic recurrent manifestations overlap with those of autoinflammatory diseases. Behçet's disease has a complex genetic aetiology, and it is more prevalent in certain geographic regions and/or in particular ethnic groups. Enhanced inflammatory response and over-expression of proinflammatory cytokines are the prominent features of Behçet's disease, and they are compatible with the findings in other autoinflammatory disorders. There are also evidences of antigen-driven immune response in Behçet's disease, but it possibly develops on the background of enhanced innate immune reactivity. Delineation of the similarities of Behçet's disease to other hereditary autoinflammatory diseases may help to clarify its pathogenesis and also to identify the missing links in the shared inflammatory pathways.

According to modern images and results of our observations the oxidative stress (OS) is a non-specific though certain component of pathogenesis at numerous diseased states of organism having in the basis the thoroughness of pathogenic disturbances of phospholipids (PL) metabolism and processes of their free radical oxidation (FRO), which takes place in the membrane formations of as the whole cell, as well as the mitochondrial and microsomal fractions (MCF and MSF) of the white rat brain, liver mitochondria, lung shadows, at the same time erythrocyte and lymphocyte shadows at brain acute edema, ischemia, reperfusion and desympathization, infarction of myocardium, tuberculosis of lungs, diabetes, Familial Mediterranean Fever (FMF), intoxications under halothane anaesthesia (HA) and with micotoxin zearalenon. The regularities observed promote to understand from the point of view of modern approaches the molecular mechanisms of initiation, development and generalization of factors for OS formation under pathologic conditions. It is more obvious at zearalenon intoxication with intensification of lipids FRO processes and failures in PL-PL ratio phenomena. The lymphocytes membranes of the white rats spleen subjected OS induced by zearalenon intoxication permit us conclude that the general immune status of the organism decreases. It is generally peculiar to the states under conditions of generalized intoxication. The observed increase of phospholipase A2 activity induces the release of high concentrations of lysophosphatidylcholines (LPC) and non-etherified fatty acids (NEFA) of polyenic range with prevail of arachidonic acid as a pathogenic factor, namely, at modelling brain acute edema by tetraethylolovo to white rats. Formation of the above mentioned disturbances to some extent depends on hydrophobic properties of toxins, particularly, zearalenon. The latter gives certain tropism to dopamine-β-monooxygenase (DBM), and ability to stimulate functional activity of the enzyme. Striking haemolytic properties of phospholipase A2 induced by existence of LPC and NEFA high concentrations, and products of their peroxidation, promote elimination of separate protein fractions of erythrocyte membranes (EM) responsible for OS formation and decrease of erythrocytes resistance to peroxide hemolysis. Increase of DBM activity under the effect of relatively moderate doses of zearalenon (1-15 μg/ml) is accompanied with extra intensification of catecholamine synthesizing function of the organism with lethal result. Data of publications represented testify exceptional efficiency of sodium thiosulfate (STS) as a powerful synergist for endogenous factors of antioxidant effect, particularly α-tocopherol (α-T), which is the main component for the system of cell antiradical defence. Detoxicating effect of STS can be demonstrated indeed on the example of zearalenon intoxication during the first two hours with the reduction of metabolism disturbances of PL and products of its peroxidation [1, 2]. Comparative evaluation of molecular mechanisms of STS normalizing effect as a supplier for hydrogen and sulphur ions, as well as an effective synergist for α-T on the level of various formations of the live cell in compare with the effects of α-T and ubiquinone [3-11], allowed to make a special accent on the role of STS in interaction with energy-dependent enzymatic systems of cell antiradical defence, as well as accumulation and transformation of energy on the level of mitochondrial membranes [12, 13]. The results obtained by us confirm a number of clinical experimental observations, which demonstrate treatment and prophylactic role of STS at different pathologic states of the organism [14-25]. STS protectory role at toxic injuries of the organism is higher at its preliminary introduction to the organism before modelling of the studied diseased states, especially at zearalenon and halothane (H) intoxication (in the last case before HA). These data serve a sound affirmation for protectory function of STS, detailed revelation of molecular properties of pathogenesis of the studied intoxication to which a part of our clinical and experimental studies at present is devoted.

The autoimmune diseases result from inappropriate responses of the immune system to self antigens. The etiology of autoimmune diseases remains largely unknown but candidate etiologic factors include genetic abnormalities and infections. Although there are considerable data supporting the role of infections in a variety of autoimmune diseases, this role has been unequivocally established in only a few autoimmune diseases. The difficulty in establishing the infectious etiology of autoimmune diseases stems from several factors such as the heterogeneity of clinical manifestations in individual autoimmune diseases and the time interval between infection and autoimmune disease. The data on this association derive from clinical observations, epidemiological studies and research using laboratory techniques, protein sequence database screening and animal models. Infectious agents can cause autoimmune diseases by different mechanisms, which fall into two categories: antigen specific in which pathogen products or elements have a central role e.g. superantigens or epitope (molecular) mimicry, and antigen non-specific in which the pathogen provides the appropriate inflammatory setting for “bystander activation”. The most important mechanisms are molecular mimicry and superantigens. As far as molecular mimicry is concerned the recent data on the degeneracy of T cell recognition shifted the focus from searching for linear sequence homology to looking for similarity of antigenic surfaces. Special mention has to be made to retroviruses as they have some unique means of inducing autoimmunity.

Vasculitis is definitely associated with familial Mediterranean fever. This familial Mediterranean fever-associated vasculitis takes one of three forms: polyarteritis nodosa, with or without microscopic polyangiitis, and Henoch-Schonlein purpura. Behcet disease and inflammatory bowel diseases may also be associated with familial Mediterranean fever, though this is yet to be formally proven. The selective biological advantage, if any, for carriers of simple heterozygotic mutations in the gene responsible for familial Mediterranean fever, MEFV, is not known. Indirect arguments are given for a better defense against certain groups of bacterial pathogens and amongst intra-cellular bacteria, Mycobacterium tuberculosis.

Familial Mediterranean Fever (FMF, MIM 249100), or Periodic disease, is a recessively transmitted and ethnically restricted condition prevalent in population from the Mediterranean decent. FMF notoriously has been hard to diagnose until mutations in the MEFV gene have been identified and as a tremendous help are used for the diagnosis of difficult cases. Since FMF can be controlled by medication, it is extremely desirable to have a firm diagnosis. The aim of this study was to establish the frequency of the most common mutations and genotypes in Armenian population. Molecular analysis of MEFV gene mutations in 3000 Armenian patients has demonstrated direct correlation between the clinical severity and the molecular diagnostic criteria of the disease, including the development of renal amyloidosis with MEFV genotypes. MEFV genotyping performed in the framework of a genetic counseling may reveal and identify affected individuals in presymptomatic phase, providing the possibility of a precocious start of the therapy.

Familial Mediterranean Fever (FMF), an autosomal recessive disorder, is characterised by recurrent attacks of fever and serositis, lasting 24-72 hours. Since 1972 colchicine has become the drug of choice for prophylaxis against FMF attacks and amyloidosis FMF-associated. Colchicine, an alkaloid neutral, is absorbed in the jejunum and ileum. It metabolised by liver and only small amounts are recovered unchanged in the urine. Really plasma half-life is prolonged in patients with liver or renal failure. Colchicine is able to prevent activation of neutrophils, binding β-tubulin and making β-tubulin-colchicine complexes; this way inhibits assembly of microtubules and mitotic spindle formation; moreover its mode of action includes modulation of chemokines, prostanoids production, inhibition of neutrophil and endothelial cell adhesion molecules. The minimal daily dose in adults is 1.0 mg / die, but in children there is not a definite dose. Since in vitro high dosages of colchicine stop mitosis, this drug might interfere with male and female fertility and with children growth, but, according to current guidelines and because of rare side effects of the drug, FMF patients are recommended to take colchicine. Since colchicine treatment is often complicated by frequent gastrointestinal side effects, by our experience, in order to improve colchicine tolerance we recommend: lactose-free diet and treatment of intestinal bacterial overgrowth and / or Hp-infection, assessed by breath tests. Since our data showed that 10-15% of FMF patients seem are non-responders or intolerant to colchicine, today we are working in the design of colchicine analogues which may have lesser toxicities and a larger therapeutic window.

Complement has been long perceived as an innate immune system that plays a pivotal role in the maintenance of host defense against infectious agents and the propagation of pro-inflammatory responses in the context of human disease. Complement activation has been associated with the onset of acute inflammatory reactions leading to complications such as acute graft rejection, local tissue injury and multiorgan failure. However, recent studies have indicated that various complement activation products may exert a beneficial effect by contributing to critical developmental and regenerative processes. Appreciating this extraordinary ‘versatility’' of complement proteins provides a framework for revisiting the design of effective complement therapeutics. A balanced strategy will have to consider limiting the detrimental proinflammatory effects of complement while preserving those activities that promote tissue repair and regeneration, cell survival and early development.