Michael S. Edwards, PharmD, MBA
The human immune system, although described hundreds of years ago, is still being mapped out today, and medical knowledge in this area continues to expand because of its complexity. The human is made up of a complex network of cells and circulating factors that can respond to nearly all foreign invaders with which it comes into contact. The immune system mobilizes when invaded, producing an inflammatory response that identifies the invader for the other defenders that follow. The inflammatory response also activates many complex components of the system and leads the immune cells that are antigen specific to finish off and win the fight. Like most complex living entities, a learning process takes place, and specialized components of the system become specific to this invader and can mount an even faster defense the next time the body is exposed to this or similar antigens.
When the immune system is functioning correctly, as above, it causes few problems, but it does not always work in a way that is beneficial to the human body. Regulation that is imprecise can cause a multitude of autoimmune diseases that can cause detriment to the body. The most common examples of dysfunction of the immune system are seasonal allergies, asthma with an allergic component, and rheumatoid arthritis. Automimmune dysfunction is responsible for transplant rejection. The transplant is recognized as foreign, and the body's immune system attempts to remove the invader. Prevention of transplant rejection spurred many of the approved medications used in immunomodulation since the first kidney transplant in 1933. Recent discoveries have shown that the suppression of the immune response can potentially lead to certain types of cancer.
Inflammatory response is an innate immune response. Innate immunity is the built in factor to resist infection. It is present before birth and not antigen specific. The inflammatory response has no memory for previous exposure, and therefore is not enhanced by a second exposure. Although needed to fight off invaders, it is not very effective without antigen-specific cells. Adriana Zeevi, PhD, Professor of Pathology and Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, presented an overview of the immune system at the ASHP Midyear Clinical Meeting.
One of the more important components of innate immunity is phagocytosis. Phagocytes, which include neutrophils, eosinophils, macrophages, and monocytes, recognize invaders with many types of cell surface receptors that can identify pathogens. The monocytes and macrophages are less mobile, but are better phagocytes. The surface receptors are a group of proteins that can recognize patterns on the pathogens. Examples of the patterns that are recognized are: endotoxin or lipopolysaccharide, lipoteichoic acid, and peptidoglycans. Examples of phagocytic cell proteins are: C-type lectins (collectins), integrins, pentraxins, lipid transferases, and leucine-rich proteins. Phagocytes kill pathogens by engulfing the invader and then releasing stored scavengers and enzymes to finish the process. Two other components of innate immunity are complement, which is a group of 25 proteins that can cause cell lysis when activated, and natural killer (NK) cells, which can kill viral cells or malignant cells when active immunity is not present.
Antigen-specific immunity, also known as adaptive immunity, comes from 2 types of cells, the B lymphocytes and T lymphocytes. These 2 cells can respond to the inflammatory response that innate immunity originates, and will rapidly develop a specific immune response. The B cells then will develop into a specific antibody, or immunoglobulin, that will rapidly recognize the invasion of the same antigen. This cell can in some cases confer immunity for a lifetime. This adaptive immunity can react to protein, polysaccharide, nucleic acid, and lipid invaders.
Lymphocytes possess numerous cell surface proteins that have been identified by activity. The nomenclature is termed cluster of differentiation (CD). The system has identified more than 150 cell surface proteins with specific antibodies. This allows scientists to identify the cell types and their functional state of activity. A number of CD cells have been identified and used to describe function or produce treatments. The T cells are divided into 2 main subgroups, CD4 (helper T cells) and CD8 (cytotoxic T cells). The CD8 cells recognize viral peptides with the major histocompatibility complex (MHC) and kill the infecting cell. The CD4 cells use a different class of MHC (class II) to activate macrophages or B cells. CD3 is on all T cells but not on B cells. CD56 is located on NK cells. CD19 and CD20 are on B cells but not on T cells. Many clusters of differentiation have been identified, and new drugs will be developed to modulate these receptors. The CD20 identification on B cells was used to produce one of the more exciting cancer drugs.
One way that this complex system of immunity is being used is to prevent transplant rejection by developing an assay to guide dosing of immunosuppressants. This was explained by Gilbert J. Burckart, PharmD, Professor of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania. Currently, use of immunosuppressants depends solely on the measurement of the concentration of the drug in circulation and the clinical response. The Cybex Immune Cell Function Assay is being developed, which will quantify the effect of suppressant drugs on immune cell function. Nucleotide adenosine triphosphate (ATP) is increased in cells that are stimulated. Cells that are being immunosuppressed will have a lower level of ATP activity. The level of ATP activity will be 50% higher in healthy adults over immunosuppressed adults. The main problem is that about 20% of transplant recipients have high ATP activity, and the same number of healthy adults will have low activity. In this case, the test is not conclusive, but research is headed in the right direction and can lend additional data to drug levels in the transplant patient.
Other monitoring tests designed to determine immune competence are in the works. In many cases, such testing is superior to the measurement of drug levels for predicting rejection. Monitoring of the interleukin (IL)-10 gene polymorphism in a pediatric heart transplant population yields useful information. IL-10 has an anti-inflammatory action that can offer protection in some allografts, such as cardiac, liver, and lung. Patients with a low level of the IL-10 genotype have an increased rejection rate, and patients with an intermediate or high level of IL-10 genotype are at low risk for rejection. This information may be used to guide the level and duration of immunosuppressant therapy. A high level of IL-10 was a negative prognosticator in renal transplants and is associated with autoantibody production in lupus. Another polymorphism being studied is the tumor necrosis factor (TNF)-alpha gene. This gene is found with increasing frequency in rheumatoid arthritis and lupus. It also predicts rejection in most allografts.
Research in this area can lead to the development of many therapies that will improve outcomes in the transplant patient. These are the individualizing of immunosuppression based on the patient profile. Tailoring immunosuppressant therapy to patient-specific factors is the goal for reducing transplant rejection and decreasing unnecessary adverse events. For example, the early identification of patients that could have steroids discontinued or those patients at risk for developing infections would be of great benefit. By developing a test that will measure cytokine activity, the patient may be removed from immunosuppression earlier. The complete individualization of immunosuppressant therapy cannot be far behind.
It was the advent of corticosteroids in the 1950s that marked the beginning of a drug-based approach to manipulate the immune system. Over the next 30 years, the discovery proceeded slowly until the production of cyclosporine. During the subsequent 20 years, many more specific and useful agents have been developed. Over the next 10 years, as many as 15 new agents could be added to the FDA-approved armamentarium. The goal is to move toward the development of tolerance while still defeating any infection that might arise. The problem with this type of therapy is that the immune system is redundant and cannot be defeated as easily as one would think. The biopharmaceutical science of immunomodulating agents was discussed at the ASHP meeting by Raman Venkatarammanan, PhD, Professor, University of Pittsburgh.
Pharmacologic mechanisms to alter immune function have come a long way, with more then 80 agents identified. Many of the drugs that mediate immune function are not used for this purpose, including captopril, heparin, and nonsteroidal anti-inflammatory drugs (NSAIDs).
Many of the early drugs were of the type that moderate immunity by blocking the immune components of innate immunity. Recently, monoclonal antibodies such as eculizumab (Alexion Pharmaceuticals Inc, Cheshire, Connecticut) have been used in the treatment of lupus nephritis. Avant Immunotherapeutics Inc has had 2 soluble complement receptor type 1 agents in testing. These agents have been shown to have an effect on reperfusion edema and neutrophil migration after lung allotransplantation in experimental models. Other agents of the anticomplement type are a synthetic protease inhibitor and binding product with antifungal properties.
Anti-TNF agents have produced a number of highly marketable agents over the past few years. The best known are infliximab and etanercept, which bind with TNF-alpha and can inhibit its binding to the TNF receptors. Etanercept may also inhibit TNF-alpha production in the gut. These 2 agents have vastly improved quality of life in the rheumatoid arthritis population.
The regulation of chemokines has also spawned a number of new agents that are in investigational trials. FTY720 is one of these; it works through chemokine receptors. This is an exciting new agent with a unique mechanism of action; FTY720 works by regulating lymphocytes that are in circulation. The T and B lymphocytes are moved back into the lymph nodes. This helps remove the lymphocytes from the grafted organs and may still allow some activity when needed in other areas. Lab tests that show activity can be used to regulate effect that could allow the host and graft to live in harmony.
Another field of investigation in immunomodulation is the use of agents that decrease cell adhesion. By decreasing the number of cells that are identified as foreign, these agents can moderate the immune response. Many of these drugs have this property as 1 of 2 or 3 mechanisms of action. Some of the more exciting agents in this category are alefacept and efalizumab.
Agents that attack T-cell activation are also a major area of investigation. T-cell activation from the macrophage is completed by 3 pathways (signal 1, 2, and 3). Currently, drugs that inhibit signal 1 are the most commonly used in transplant patients. These are the previously mentioned cyclosporine and the newer and somewhat better tacrolimus. Signal 2 inhibitors are currently all investigational. CTLA4Ig is a recombinant protein of immunoglobulin and a cell surface protein that works like a false transmitter for T-cell activation. Examples of T-cell inhibitors that are signal 3 blockers are sirolimus and campath. Sirolimus seems to be an improvement on the earlier products.
Immunomodulators can be in the form of small molecules, large molecules, peptides, and many different types of proteins. Elements that must be taken into consideration are the same as in any drug that goes into the human body. Metabolic, absorptive, distribution, and excretion barriers must be taken into account when using these medications. The bioavailability of the FDA-approved drugs can run from 15% for sirolimus to as much as 95% for mycophenolate mofetil. Absorption peak can be as low as 1 hour for mycophenolate and as high as 6 hours for leflunomide. This information is useful when switching doses from intravenous (IV) route to oral route. The medications (leflunomide and mycophenolate) that have a high bioavailability can be dosed similarly when switching from IV to oral routes and produce a somewhat low variability in effect. By contrast, sirolimus and tacrolimus -- which have low bioavailability -- will require higher oral doses when a switch is made from parenteral to oral dosage. This can cause a greater variability in effect when a route change is made.
Most of the above-mentioned drugs can have some effect in all disease states that can be treated with immunomodulators. This shows the nonspecificity of most of these drugs and investigational entities. Because of this nonspecificity, patients must have their therapy individualized. There is a large intra- and inter-individual variation in pharmacokinetics with small and large molecules. Variation is reduced in protein-based medications. Another way of looking at pharmacokinetic variability is with the monoclonal antibodies. Murine-based products have a short half-life, but, as the product is switched to more chimeric or human-based, the half-life is extended.
Laboratory tests that measure activity at the cell level will greatly improve therapy, and the ability to use multimodality therapy will greatly improve immunomodulation in the near future.
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