Abstract
An autoimmune disorder is a condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue. Autoimmune diseases include a heterogenous group of disorders with variable presentation and severity. What causes the immune system to no longer distinguish between healthy body tissues and antigens is unknown. One theory holds that various microorganisms and drugs may trigger some of these changes, particularly in persons who are genetically prone to autoimmune disorders. Inflammation is one of the first responses of the immune system to antigen like infection or debris.
The goals of treatment are to reduce symptoms and control the autoimmune process while maintaining the body’s ability to fight disease. Immunosuppressive and immunomodulatory therapies are often used for treatment with considerable success in some cases. These diseases may also be severe and refractory to conventional treatment. Thus more aggressive intervention might be indicated in a subset of patients. This review attempts to summarise some current concepts and future perspectives on the new therapy in treatment of severe autoimmune diseases.
Key word : immune system, autoimmune disease, inflammation, conventional treatment, new therapy
An autoimmune disorder is a condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue. There are more than 80 different types of autoimmune disorders. Normally the immune system’s helps protect the body from harmful substances, called antigens. Examples of antigens include bacteria, viruses, toxins, cancer cells, and foreign blood or tissues from another person or species. The immune system produces antibodies that destroy these harmful substances. But in patients with an autoimmune disorder, the immune system can’t tell the difference between healthy body tissue and antigens. The result is an immune response that destroys normal body tissues. The response is a hypersensitivity reaction similar to allergies, where the immune system reacts to a substance that it normally would ignore. In allergies, the immune system reacts to an external substance that would normally be harmless. With autoimmune disorders, the immune system reacts to normal body tissues.
What causes the immune system to no longer distinguish between healthy body tissues and antigens is unknown. One theory holds that various microorganisms and drugs may trigger some of these changes, particularly in persons who are genetically prone to autoimmune disorders. An autoimmune disorder may result in the destruction of one or more types of body tissue, abnormal growth of an organ and changes in organ function.
Immune system
The immune system is a network of organs, cells and molecules that work together to defend the body against attacks by foreign (not of the body) invaders such as germs, bacteria, viruses, parasites and fungi. When one of these invaders (antigens) tries to break into the body, the body’s first line of defense is the skin and mucous membranes. The skin and mucous membranes house macrophages (white cells of the tissues) and antibodies. The macrophages job is to digest the antigens while the antibodies trap the antigens that got away. If the antigens break through these barriers, the body reacts by producing lymphocytes (B and T cells) programmed to attack and kill the antigen.
The immune system protects organisms from infection with layered defenses of increasing specificity. Most simply, physical barriers prevent pathogens such as bacteria and viruses from entering the body. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals. However, if pathogens successfully evade the innate response, vertebrates possess a third layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system adapts its response during an nfection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.
Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are those components of an organism’s body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigen (short for antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response.
Inflamation and complement system is humoral and chemical barriers in immune system. Inflammation is one of the first responses of the immune system to antigen like infection or debris. The symptoms of inflammation are redness and swelling, which are caused by increased blood flow into a tissue. Inflammation is produced by eicosanoids and cytokin, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain leukocytes. Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell. Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote healing of any damaged tissue following the removal of pathogens.
The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to “complement” the killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response. Many species have complement systems, including non-mammals like plants, fish, and some invertebrates. In humans, this response is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a rapid killing response. The speed of the response is a result of signal amplification that occurs following sequential proteolytic activation of complement molecules, which are also proteae. After complement proteins initially bind to the microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback. The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their plasma membrane.
The autoimmune process can have varied consequences. For example, slow destruction of a particular type of cell or tissue, stimulation of an organ into excessive growth or interference in its functions. Organs and tissues frequently affected include the thyroid, pancreas, adrenal glands as well as red blood cells and connective tissues (skin, muscle and joints). Autoimmune disorders are classified into two types, organ-specific (directed mainly at one organ) and non-organ-specific (widely spread throughout the body). Examples of organ-specific autoimmune disorders are insulin-dependent diabetes (Type I) which affects the pancreas, Hashimoto’s thyroiditis and Graves’ disease which affects the thyroid gland, pernicious anemia which affects the stomach, Addison’s disease which affects the adrenal glands, celiac disease in intestine and chronic active hepatitis which affects the liver. Examples of non-organ-specific autoimmune disorders are rheumatoid arthritis, multiple sclerosis, lupus erythematosus, sjogren syndrome,reactive arthritis and myasthenia gravis.
Treatment of Autoimmune Diseases
An immunomodulator is a drug used for its effect on the immune system. There are two types of such drugs based on their effects: immunostimulators and immunosuppressant.
Immunostimulators are substances (drugs and nutrients) that stimulate the immune system by inducing activation or increasing activity of any of its components. One notable example include granulocyte macrophage colony-stimulating factor. There are two main categories of immunostimulators:
1. Specific immunostimulators are those which provide antigenic specificity in immune response, such as vaccines or any antigen.
2. Non-specific immunostimulators are those which act irrespective of antigenic specificity to augment immune response of other antigen or stimulate components of the immune system without antigenic specificity, such as adjuvants and non-specific immunostimulators.
Immunosuppressive drugs, immunosuppressive agents, or immunosuppressants are drugs used to control autoimmune disorders or inflamation when excessive tissue damage occurs. The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy and to stimulate protective responses against pathogens that largely elude the immune system.
Immunosupressants inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to:
1. Prevent the rejection of transplanted organs and tissues (e.g., bone marrow, heart, kidney, liver)
2. Treat autoimmune diseases or diseases that are most likely of autoimmune origin (e.g., rheumatoid arthritis, myasthenia gravis, systemic lupus erythematosus, Crohn’n disease, and ulcerative colitis).
3. Treat some other non-autoimmune inflammatory diseases (e.g., long term Allergic Asthma. control).
These drugs are not without side-effects and risks. Because the majority of them act non-selectively, the immune system is less able to resist infection and the spread of malignant cells. There are also other side-effects, such as hypertension, dyslipidemia, hyperglicemia, peptic ulcers, liver, and kidney injury. The immunosuppressive drugs also interact with other medicines and affect their metabolism and action. Actual or suspected immunosuppressive agents can be evaluated in terms of their effects on lympocyte subpopulations in tissues using immunohistochemistry.
Immunosuppressive drugs can be classified into five groups: Glucocorticoids, Cytostatics, Antibodies, Drugs acting on immunophilins and other drugs. Anti-inflamatory drugs are often used to control the effects of inflammation. NSAID and glucocorticoids are the most powerful of these drugs; however, glucocorticoids can have many undesirable side effects (e.g., central obesity, hyperglycemia, osteoporosis) and their use must be tightly controlled. Glucocorticoids suppress the cell-mediated. They act by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-γ, the most important of which is the IL-2. Smaller cytokine production reduces the T- cell proliferation. Glucocorticoids also suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and IL-2 receptors. This diminishes both B cell clone expansion and antibody synthesis. Glucocorticoids influence all types of inflammatory events, no matter what their cause. They induce the lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospolipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect.
Therefore, lower doses of anti-inflammatory drugs are often used in conjunction with cytotoxic or immunosuppressive drugs such as folic acid analogues, such as methotrexate. It binds dihydrofolate reductase and prevents synthesis of tetrahydrofolate. It is used in the treatment of autoimmune diseases (for example rheumatoid arthritis) and in transplantations.; purine analogues such as azathioprine and mercaptopurine that acts as a purine analogue and an inhibitor of DNA synthesis. By preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and the humoral immunity. It is also efficient in the treatment of autoimmune diseases.
Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. However, the killing is indiscriminate and other organs and cell types are affected, which causes toxic side effects. Immunosuppressive drugs such as cyclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways. Due to their highest effectiveness, purine analogs are most frequently administered.
Cyclosporin is used in the treatment of acute rejection reactions, but has been increasingly substituted with newer immunosuppressants, as it is nephrotoxic. The drug is used particularly in the liver and kidney transplantations, although in some clinics it is used in heart, lung and heart/lung transplants. It binds to an immunophilin, followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the passage of G0 into G1 phase. Tacrolimus is more potent than cyclosporin and has less-pronounced side-effects. Contrary to cyclosporine and tacrolimus that affect the first phase of the T lymphocyte activation, sirolimus affects the second one, namely the signal transduction and their clonal proliferation. It binds to the same receptor (immunophilin) as tacrolimus, however the produced complex does not inhibit calcineurin, but another protein. Therefore, sirolimus acts synergistically with cyclosporine and, in combination with other immunosuppressants, has few side-effects. Also, it indirectly inhibits several T lymphocyte kinases and phosphatases, preventing the transmission of signal into their activity and the transition of the cell cycle from G1 to S phase. In a similar manner, it prevents the B cell differentiation to the plasma cells, which lowers the quantity of IgM, IgG, and IgA antibodies produced. It acts as an immunoregulatory agent, and is also active against tumors that involve the PI3K/AKT/mTOR pathway.
The goals of treatment are to reduce symptoms and control the autoimmune process while maintaining the body’s ability to fight disease. Some patients may need supplements to replenish a hormone or vitamin that the body is lacking. Examples include thyroid supplements, vitamins, or insulin injections. If the autoimmune disorder affects the blood, the person may need blood transfusions. Measures to help with movement or other functions may be needed for autoimmune disorders that affect the bones, joints, or muscles. Radiation of the lymph nodes and plasmapheresis (a procedure that removes the diseased cells and harmful molecules from the blood circulation) are other ways of treating an autoimmune disease.
Current therapy of autoimmune diasease
Interferon (IFN-β) suppresses the production of Th1 cytokines and the activation of monocytes. It is used to slow down the progression of multiple sclerosis. IFN-γ is able to trigger lymphocytic apoptosis.
A TNF-α- (tumor necrosis factor-alpha-) binding protein is a monoclonal antibody or a circulating receptor such as infliximab, etanercept, or adalimumab that binds to TNF-α, preventing it from inducing the synthesis of IL-1 and IL-6 and the adhesion of lymphocyte-activating molecules. They are used in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis. TNF or the effects of TNF are also suppressed by various natural compounds, including curcumin (an ingredient in turmeric) and catechins (in green tea). These drugs may raise the risk of contracting tuberculosis or inducing a latent infection to become active. Infliximab and adalimumab have label warnings stating that patients should be evaluated for latent TB infection and treatment should be initiated prior to starting therapy with them.
Mycophenolate (mycophenolic acid) acts as a non-competitive, selective, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), which is a key enzyme in the de novo guanosine nucleotide synthesis. In contrast to other human cell types, lymphocytes B and T are very dependent on this process. Small biological agents like FTY720 is a new synthetic immunosuppressant, currently in phase 3 of clinical trials. It increases the expression or changes the function of certain adhesion molecules (α4/β7 integrin) in lymphocytes, so they accumulate in the lymphatic tissue (lymphatic nodes) and their number in the circulation is diminished. In this respect, it differs from all other known immunosuppressants. Myriocin has been reported being 10 to 100 times more potent than cyclosporine.
Currently, MMF is used in patients who have contraindications for azathioprine (such as the need for allopurinol) or as the primary choice of an antimetabolite. Based on the experience in clinical trials, the recommended initial dose is 2 g/d divided in two doses.
In a preliminary retrospective case-control study in kidney allograft recipients with established chronic rejection, adding MMF to maintenance immunosuppression provided no clear benefit. The primary toxic side effects are anemia in rats and leukopenia, diarrhea, and anorexia in dogs and monkeys, and these side effects can be reduced by lowering the dose. The most common side effects of MMF in humans are diarrhea, vomiting, opportunistic infections, and leukopenia. The mechanism of myelotoxicity is not well understood. Because of selective inhibition of the de novo pathway of purine synthesis, MPA should affect only proliferating lymphocytes. In contrast to transplant recipients, patients treated with MMF for psoriasis rarely develop leukopenia.
Leflunomide and Malononitriloamides, Leflunomide and the malononitriloamides (MNA) are a new class of immunomodulating drugs that are currently under investigation for use in transplantation. In 1985, the anti-inflammatory and immunomodulating properties of leflunomide were recognized, which differ from classical anti-inflammatory and immunosuppressive drugs. The immunosuppressive effects of leflunomide have been investigated extensively in animal models of transplantation. Because of its long half-life (11 to 16 d) in humans, the clinical development of leflunomide has been restricted to use in patients with autoimmune diseases such as rheumatoid arthritis. A large preclinical program has been started to evaluate the potential use of the leflunomide analogues HMR 715 and HMR 279. These analogues, malononitriloamides, are very similar in structure to the active metabolite of leflunomide, A77 1726, and may have a more favorable pharmacokinetic profile. Available data from human trials with leflunomide are entirely from Phase I and II trials in rheumatoid arthritis. Oral doses between 10 and 25 mg/patient per d were effective compared with placebo. A total of 402 patients was enrolled in the Phase II prospective randomized trial to access the safety and effectiveness of leflunomide. A dose-dependent improvement in the primary and secondary outcome measures was observed. For the MNA, clinical data are not available. The most important side effect in cynomolgus monkeys was anemia. In the Phase II leflunomide study, adverse effects included gastrointestinal symptoms, rash and allergic reactions, weight loss, and reversible alopecia. The incidence of infections in the leflunomide group was not increased; decreases in hematocrit and hemoglobin were observed in all groups.
Copolymer-1 (Cop-1). Current study results from the report, ‘T cell independent mechanism for copolymer-1-induced neuroprotection,’ have been published. “Despite active investigation of copolymer-1 (Cop-1) for nearly 40 years the mechanisms underlying its neuroprotective properties remain contentious. Nonetheless, current dogma for Cop-1 neuroprotective activities in autoimmune and neurodegenerative diseases include by stander suppression of autoimmune T cells and attenuation of microglial responses,” researchers in the United States report. “In this report, we demonstrate that Cop-1 interacts directly with primary human neurons and decreases neuronal cell death induced by staurosporine or oxidative stress.
Table 2. Biological therapies in development for systemic lupus erythematosus
|
Therapy
|
Mechanism of action
|
Trials
|
|
(1) Recombinant IL-1 receptor antagonist (Anakinra)
|
IL-1: potential role in development and maintenance of inflammation in SLE
IL-1RA; physiological antagonist to IL-1.
Elevated IL-1RA in some patients [99] reduced ILRA
production by monocytes, granulocytes;
lower levels in renal versus non-renal disease. Aim with IL-1RA is to address
imbalance with IL-1
|
Well tolerated. Principally effective (transient) for arthritic symptoms Reduction in C3 and C4; need to monitor serological markers
|
|
(2) Anti-IL-10 monoclonal antibody
|
IL-10; pleiotropic cytokine, induces B cell
differentiation
|
Use in NZB/WF1 mice delayed disease
onset and autoantibody production. Clinical trial with 20 mg/day murine
monoclonal antibody improved joint
and cutaneous symptoms, reduced
SLEDAI. Well tolerated,all patients
developed anti-chimeric antibodies
|
|
(3) B cell toleragens (LJP 394)
|
Synthetic molecule composed of multiple
B cell dsDNA epitopes attached to non
immunogenic carrier. Bind to anti-dsDNA
receptors; modulates B cell responses,
Serological improvement but minimal
reduction in renal flares [107]
precipitates cell death and anergy and thus
cessation of autoantibody production
|
Randomized, DBPC
|
|
(4) Monoclonal anti-B lymphocyte stimulator
|
BLys is member of TNF protein family; anti-BLys modulates B cell immune responses by (BLyS) reduction of apoptosis, interference in B cell development and differentiation
|
Phase I study : reduction in immunoglobulin and
anti-dsDNA titres
Phase II trial under way
|
DBPC: double-blind placebo-controlled; IL-1: interleukin 1; IL-1RA: interleukin I receptor antagonist; C3: complement 3; C4: complement 4; IL-10: interleukin 10.
This neuroprotection is mediated through protein kinase Calpha and brain-derived neurotrophic factor. Dendritic cells (DC) uptake Cop-1, deliver it to the injury site, and release it in an active form. Interactions between Cop-1 and DC enhance DC blood brain barrier migration. In a rat model with optic nerve crush injury, Cop-1-primed DC induce T cell independent neuroprotection,” wrote J. Liu and colleagues, University of Nebraska. The researchers concluded: “These findings may facilitate the development of neuroprotective approaches using DC-mediated Cop-1 delivery to diseased nervous tissue.”
Stem cell transplantation. The purpose of SCT in the treatment of ADs is to allow delivery of intensive chemotherapy or chemoradiotherapy in order to cause severe immunosuppression or even total immunoablation. Infused stem cells then repopulate the patient and give rise to new haematopoiesis and a complete immune system. In allogeneic SCT, the immune system is provided by the donor cells. In ASCT, autologous progenitor cells give rise to differentiated cells, including those involved in various immune functions.
Several anecdotal case reports suggest that allogeneic SCT performed for another indication have led to objective responses or even cures in patients with AD including rheumatoid arthritis, multiple sclerosis, psoriasis and ulcerative colitis. Experience is less impressive in patients who have received ASCT for treatment of malignant disease and who have had a concomitant AD. Remissions or responses have been reported in patients with Crohn’s disease, ulcerative colitis, rheumatoid arthritis, nonerosive polyarthritis, psoriasis and systemic lupus erythematosus. On the other hand, early relapses of ADs after ASCT have also been reported. During the last few years more than 100 ASCTs for ADs have been reported to the EULAR/EBMT database. Experience is still very preliminary and it will take several years before any firm conclusions can be drawn on the possible role of ASCT in the treatment of severe forms of diseases with putative autoimmune etiology.
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