Current Pharmaceutical Design - Volume 17, Issue 29, 2011

Autoimmune diseases are a heterogeneous group of disorders and epidemiological studies demonstrate that their incidence is increasing worldwide. A complex interaction of genetic and environmental factors underlies their etiopathogenesis. It is certainly recognised that the pathogenesis of these disorders, their diagnosis and therapy is a ‘hot topic’ and one of the most intriguing subjects in medicine. Hopefully, the most recent findings may provide insights into future developments. In this issue, internationally recognised experts in the field have contributed providing an excellent overview of recent therapeutic strategies and of experimental approaches leading to future perspectives. I hope these papers may contribute a new view for treatment. I have first introduced the preliminary results of novel therapeutic approaches and novel experimental strategies including antagonists of cytokines and cytokine receptors, inhibitors of Toll like receptors, proteasome inhibitors, antisense oligonucleotides to common susceptibility genes vehicled by nanocarriers, inhibitors of leukocyte migration and kinase inhibitors. I have also presented the results of ongoing trials in humans that rely on these novel biologicals in reference to both organ and non-organ specific autoimmune disorders. Professor Delfino and collaborators (Department of Clinical and Experimental Medicine, University of Perugia, Italy) reviewed the role of the thymus in the pathogenesis of autoimmune diseases and envisages that future therapeutic strategies should exploit manipulations in the negative selection process and/or the differentiation of T regulatory cells. Professor Czaja (Mayo Clinic College of Medicine, Rochester, Minnesota) highlighted promising pharmacological, molecular and cellular interventions for autoimmune hepatitis. Feasible new drugs include calcineurin-inhibitors, next generation purine antagonists and glucocorticoids, inhibitors of the mammalian target of rapamycin. Possible molecular interventions utilize recombinant molecules that affect immunological regulatory pathways, monoclonal antibodies that halt activation pathways and synthetic peptides that affect antigen exposure or induce antigen tolerance. In reference to rheumatoid arthritis the review of Professor McDermott and collaborators (Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, UK) focused on the role of tumor necrosis factor (TNF) in the pathogenesis of the disease. Anti-TNF agents were the first therapeutic agents to be successfully employed in the treatment of rheumatoid arthritis. Their mechanism of action, adverse effects and safety were presented and the development of biosimilars was discussed. Dr Rosado and collaborators (Research Laboratories, Children's Hospital Bambino Gesu, Rome Italy) provided an extensive review of therapeutic strategies alternative to conventional immunosuppression for the treatment of systemic lupus erythematosus. These include the use of new drugs targeting the Toll like receptor/MyD88 pathway and immunomodulators interfering with B-cell specific pathogenetic pathways.....

Autoimmune diseases are a heterogeneous group of disorders and epidemiological studies demonstrate that their incidence is increasing worldwide. It is known that a complex interaction of genetic and environmental factors underlies their complex etiopathogenesis. In the light of the aforegoing the exact molecular key events were difficult to be explored; these represent the leading step to the prevention and treatment of autoimmune disorders. Novel therapeutic approaches are nowadays under investigation and specific treatments have been preferentially applied in experimental models of disease. New results were brought about and fascinating new pathways for treatment of autoimmunity were launched in the past years. Nevertheless novel targets for intervention, revealed to be successful in animal models, were not necessarily proven to be successful in humans, therefore were not necessarily introduced in clinical trials. In this review we present and discuss the results of novel therapeutic approaches and novel experimental strategies including antagonists of cytokines and cytokine receptors, Toll like receptors inhibitors, proteasome inhibitors, antisense oligonucleotides vehicled by nanocarriers, inhibitors of leukocyte migration, kinase inhibitors. We also present the results of ongoing trials in humans that rely on novel biologicals agents. These are presented as applied to organ and non-organ specific autoimmune disorders. In the future, novel therapeutic strategies will also combine different drugs that possibly intervene at different levels in which the immune system may be halted in its function.

In humans, T-cell development takes place in the thymus, which contains an external cortical region and an inner medulla. The skeleton of the thymus consists of stromal cells and is filled with thymocytes in different stages of differentiation. Thymocytes undergo to a development process before becoming mature T lymphocytes ready for export to the peripheral lymphoid organs. Classically, T-cell development has been reported to occur in four steps. First, bone marrow derived thymocytes that express neither CD4 nor CD8 surface antigens (double negative [DN] thymocytes) undergo an extensive phase of proliferation and differentiation and begin to express CD4 and CD8 (step 2: double positive [DP] thymocytes). During a subsequent negative selection process, approximately 5% of these DP cells undergo apoptosis. If these cells are not eliminated, they could differentiate into autoreactive lymphocytes, leading to the development of peripheral autoimmune diseases. In the thymus, a particular population of T regulatory (Treg) cells also develops. These Treg cells migrate to the periphery and are capable of suppressing autoreactive lymphocytes that may have escaped from the negative selection process. Autoimmune diseases are generally the result of insufficient negative selection of autoreactive cells in the thymus or a deficiency in Treg cell production or function. Future therapeutic strategies for autoimmune diseases should exploit manipulations in the negative selection process and/or the differentiation of Treg cells in the thymus.

Current corticosteroid regimens are effective in autoimmune hepatitis, but therapy can be complicated by side effects, disease progression, incomplete response, and relapse after drug withdrawal. The aims of this review are to describe the promising pharmacological, molecular and cellular interventions for autoimmune hepatitis and to stimulate further investigations that can refresh or replace current treatments. Murine models that introduce pertinent human disease-related antigens by vaccination or viral infection promise a resource by which to evaluate new treatments. Promising new drug therapies include the calcineurin-inhibitors (cyclosporine, tacrolimus), next generation purine antagonists (mycophenolate mofetil, 6-thioguanine nucleotides), next generation glucocorticoids (budesonide, deflazacort), and inhibitors of the mammalian target of rapamycin (rapamycin). Feasible molecular interventions are recombinant molecules that affect immune regulatory pathways (cytotoxic T lymphocyte antigen 4, recombinant interleukin 10), monoclonal antibodies that disrupt activation pathways (antibodies to CD3, CD28, CD 20, or tumor necrosis factor-α), and synthetic peptides that block antigen display or promote antigen desensitization (oral tolerance). New methods to stimulate or replenish regulatory T cell populations (adoptive transfer, mesenchymal stem cell or autologous bone marrow transplantation) are feasible as are genetic manipulations (gene silencing) and gene supplementations (gene replacement therapy). The emergence of new therapies for autoimmune hepatitis requires a standardized and universalized animal model of the human disease, consensus regarding the most promising modality to be tested, and formation of a cooperative international network of committed clinical investigators to evaluate new therapies in a pre-designed rigorous yet expeditious fashion.

Rheumatoid arthritis (RA), the most common autoimmune disease, is characterized by persistent synovitis and systemic inflammation. Genetic predisposition as well as autoantibodies and environmental factors, such as smoking, are associated with an increased risk of RA. Traditionally RA has been treated with disease modifying anti-rheumatic drugs (DMARDs) but in the last 15 years or so the introduction of biological response modifiers has revolutionized the treatment of RA. Among these anti-tumor necrosis factor (TNF) agents were the first to be successfully used in treating RA. The goal in treating RA is to induce remission or very low disease activity; remission is now accepted as the ultimate therapeutic goal by adoption of a “treat to target” strategy to achieve tight disease control. Therefore early diagnosis, as well as immediate intervention, are of the utmost importance. This review of the role of TNF in RA pathogenesis describes the mechanisms of action of currently used anti-TNF agents and the adverse events and safety of these drugs. Guidance on the use of anti-TNFs during pregnancy and prior to surgical procedures is also discussed. The intense efforts currently being made to identify biomarkers of response to anti-TNF therapy and recent progress in defining genetic predictors of response using genome- wide association studies (GWAS) are covered. However, so far, none of these studies have been translated into clinical application. The development of biosimilars or follow-on biologicals is also discussed and the first reported study of a biosimilar, involving a multicenter study of an etanercept biosimilar, Etanar, is described.

The paradigm that T cells are the prime effectors of autoimmune diseases has been recently challenged by growing evidence that B-lymphocytes play a role in the development, re-activation and persistence of autoimmune disorders. B-cells of different subsets may play different roles in autoimmune pathologies due to their ability to secrete antibodies, produce cytokines, present antigen and form ectopic germinal centers. Thus, a given therapeutic approach or drug may have distinct outcomes depending on which specific B cell subset is targeted. Immunosuppressive therapies such as azathioprine (AZA), cyclophosphamide (CyC) or methotrexate (MTX) are conventionally used in autoimmune diseases with the aim of reducing disease activity and improving the patient's general health conditions. These treatments do not target a specific cellular type or subset and have substantial side effects, such as impairment of liver function and fertility. Moreover, autoimmune patients may be refractory to immunosuppressive therapy. In these cases finding an effective treatment becomes a challenge. The fast evolution in antibody technology is leading to the production of a wide array of humanized monoclonal antibodies, targeting specific cell types or pathways, initiating a new era in the treatment of autoimmune disorders. In addition, the recent discovery that toll like receptors (TLRs) activation can fire up autoimmunity in humans and maintain disease gives the grounds for the development of new drugs targeting the TLR/MyD88 pathway. In contrast to conventional immune-suppression, the availability of drugs interfering with Bcell specific pathogenetic pathways gives the possibility to choose therapies tailored to each disease and, possibly, to each patient.

Intravenous Immunoglobulins (IVIg) are administered both as replacement therapy for certain immunodeficiencies and as immunomodulatory therapy for some autoimmune diseases. While the treatment with IVIg is approved in only a few autoimmune diseases, the number of off-label indications is increasing. The varied mechanisms by which IVIg attains its beneficial effect are diverse. There is much evidence for the beneficial and safety profile for IVIg in low as well as high-dose protocols. Patients prone to develop thrombotic events should be advised about the risk of IVIg therapy especially at high doses. This paper updates the mechanisms of action of IVIg as well as recent off-label indications.

Psoriasis is a chronic inflammatory disease with a complex pathophysiology and a multigenic background. Autoimmunity and genetic hallmarks couple to confer the disease, which is characterized by chronic plaques (85-90% of all cases) and/or psoriasis arthritis (PsA), and involve the peripheral and sacro-iliac joints, nails, and skeleton. Dissecting the ethiopathogenetic mechanisms of psoriasis and PsA is a major basic research challenge. One important question is whether a single inflammatory mediator can be responsible for the interactive network that forms between immune cells and cytokines in this disease. Despite much progress, no research has yet been able to define a single model to explain the multifaceted pathogenesis of psoriasis and PsA. It is known that both the innate and adaptive immune systems are involved, antigen presenting cells and T lymphocytes play a prominent role, and that the deregulation of the T helper (Th)- 1/Th-2/Th-17/Th-23 axis is directly implicated in disease pathogenesis. Pharmacological therapy for psoriasis has evolved with the development of human knowledge of the disease pathophysiology. Thus, the first “ethiopathogenetic” drugs (e.g., methotrexate, cyclosporin, and alefacept) inhibited T-cell activation directly or targeted coaccessory molecules implicated in T-cell activation. When the mechanism underlying psoriatic inflammation was accepted as a cytokine network disorder, more specific biologics were studied in murine models and were later used clinically. Tumor necrosis factor was the first successful target of cytokine inhibition therapy for psoriasis and PsA (e.g., infliximab, adalimumab, and etanercept). With the recently discovered role for Th-17 in autoimmunity, drugs targeting interleukin-23 (ustekinumab) have become accepted for the pharmacological treatment of psoriasis. The expansion of pharmacological treatment options for psoriasis is not complete. As the knowledge of pathogenetic mechanisms increases, it may be possible to design therapeutic approaches that selectively target the ethiopathogenetic cells or cytokines while sparing the others. In this way, using a more targeted drug therapy may preserve the integrity of the immune system. Thus, one great struggle in treating this complex disease is the challenge to synthesize the “perfect” drug.

Multiple Sclerosis (MS) is the most common autoimmune demyelinating disorder in Western countries and can lead to permanent disability. Over the past decades remarkable progress has been made in providing new therapeutic strategies to tackle the burden of the disease. Oral drugs and monoclonal antibodies are the main innovative approaches that have been tested in advanced stage clinical trials. Several new drugs have been shown to be superior to traditional disease modifying treatments (DMTs), in terms of both clinical and imaging outcome measures. Oral drugs have the advantage of offering a convenient route of administration. Recently fingolimod has received approval for the treatment of relapsing remitting (RR)-MS in several countries, becoming the first oral drug available to patients. Whilst the majority of the current studies focus on RR-MS, some trials investigate the primary or secondary progressive subtypes as well as the early forms of the disease aiming at delaying the conversion to clinically definite MS. Overall the future of the treatment options looks promising, although the occurrence of significant adverse events in some instances points to cautious evaluation of risks and benefits. Extension studies for most of the new drugs are under way and will provide evidence on the efficacy and long term effects of the new treatment strategies.

The recruitment, trafficking, and in situ maintenance of specific subsets of activated lymphocytes constitute crucial steps for the initiation and perpetuation of chronic autoimmune inflammation. The fact that, after IFN-γ stimulation, thyrocytes secrete CXCR3- binding chemokines, which in turn recruits Th1 lymphocytes expressing CXCR3 and secreting IFN-γ, strongly supports the concept that the interferon-γ inducible chemokines (CXCL9, CXCL10, and CXCL11) and their receptor CXCR3 play an important role in the initiation of autoimmune thyroid diseases (AITD). Thus, interfering with CXCR3 might result in the abrogation of the inflammatory process. The understanding of these pathogenetic mechanisms suggested novel therapeutic approaches, with a growing interest for finding a way to interrupt the interactions between chemokines and their receptors. In this review, we focus on the efforts performed in establishing new pharmacological compounds able to target the chemokine/chemokine receptors system as well as to prevent the secretion of CXCR3-binding chemokines, induced by pro-inflammatory cytokines. The crucial issue of selecting the relevant therapeutic targets in animal models of AITD was also discussed. Although some encouraging results have been reached, major hurdles were encountered on the way to success. As a result, we are still waiting for the first anti-chemokine anti-inflammatory drug. Given the importance of leukocytes recruitment to inflammatory sites, research will continue to address the issue of developing specific chemokinereceptor antagonists. We look forward to the development of these novel pharmacological compounds which will hopefully provide a more valid alternative to the currently used lifelong replacement therapies for AITD.

Type 1 Diabetes is an autoimmune disease most often associated with elevated and uncontrolled blood glucose levels. Therefore patient education and treatment compliance is often focused on disease maintenance through insulin treatment and blood glucose control. Unfortunately insulin therapy alone does not prevent the formation of diabetic complications. In order to find a real cure, the underlying pathology of the disease must be directly addressed. Diabetes is caused by the initial rapid destruction of the insulin producing beta cells of the pancreas by autoreactive T-cells. The autoimmune process is also maintained through dendritic cell auto-antigen presentation and the production of autoantibodies by B cells. Only through some forms of immunotherapy can the immune system be rebalanced to assure the survival of the remaining beta cell population. These techniques include cell ablation, competitive decoy auto-antigens, reduced cell activation, and auto-antigen introduction. Here we will review the current state of these different technologies and their progression through clinical trials for the treatment of type 1 diabetes.

In type 1 diabetes, beta cells are attacked and destroyed by auto reactive T cells causing major impairment of blood glucose metabolism and, ultimately, the development of life-threatening complications. Currently, the treatment of this chronic disease is based on the use of endogenous insulin and no curative therapies are available. Treatment approaches in this respect need to be directed toward the primary causes of the disease tackling beta cells' auto reactive T cells. The goal of any curative intervention in type 1 diabetes is the preservation of insulin-secreting cells. This may be achieved by the abrogation of the pathogenic reactivity to beta cell auto antigens while preserving full capacity to generate a normal immune response against foreign antigens. In this review, some of the most promising drugs for immune intervention in type 1 diabetes are presented and discussed including phase 3 clinical trials that involve: DiaPep277, Anti-CD3 Otelixizumab, Glutamic Acid Decarboxylase (GAD) and anti-IL1 receptor antagonist. These approaches are currently being tested in international multicenter trials and all of them have a very similar outcome in terms of a beneficial effect on beta cells.

Type 1 diabetes (T1D) is an autoimmune disease, leading to pancreatic β-cell destruction and loss of glycaemic control. Administration of exogenous insulin to diabetic patients prevents life-threatening metabolic derangement, but may fail to prevent other longterm complications, such as kidney failure or diabetic retinopathy. Islet transplantation is a low-risk surgical procedure, affording improved glucose homeostasis provided sufficient islets engraft in the liver. Here we review work on the use of stem cells to generate β- cells for islet transplantation, indicating the need for improved protocols for their derivation and full maturation. We also consider recent evidence indicating that adult stem/progenitor cells may affect islet transplantation by improving the viability of engrafted islets and controlling immune reactions to islet allo- and auto-antigens, extending stem-cell use in T1D beyond the regenerative approach.