Understanding Immune Support Products

Modern transplantation is a "gift of life" for patients in renal failure, but this "gift" comes with a price, the price of drug-induced toxicity and infectious complications that may lead to organ failure and death. Renal transplantation began as a life-saving treatment for patients with end-stage renal disease. As the field has evolved over the past four decades, it has become a highly successful form of treatment, with 1-year patient survival rates now exceeding 90%. Unfortunately, despite these successes, long-term allograft survival has not significantly improved over these years. According to the 2005 Annual Report of the US Organ Procurement and Transplantation Network, graft half-life is 10.3 years for deceased donor grafts and 13.5 years for living donor grafts. This has created significant demand for the development of new and improved immunosuppressive regimens that have low toxicity and increase the longevity of the transplant.

Before delving into contemporary immunosuppressive agents, it is pertinent to have a general understanding of how the immune system functions and how the current drugs act to suppress it. This aids in understanding the specific molecular targets of these agents and their relative toxicities. This knowledge comes from basic science research using animal models and in vitro studies. Basic science research is not only the basis for understanding current drugs but also for the development of new immunosuppressive agents that are currently being tested in clinical trials. This renewed interest in drug development is related to the recent discovery of costimulatory pathways and their critical role in T cell activation. Discovery of the specific molecules involved in these pathways has opened a new realm of highly specific immunosuppression with potentially less long-term toxicity.

Overview of the Immune System

Our bodies have two lines of defense against foreign substances such as microorganisms and viruses. The first line of defense is a barrier that is made up of the skin and mucous membranes, which are the body's first protection against invaders. If the bacteria get past the first line of defense and an infection occurs, the second line of defense swings into operation. This is a complex mixture of cells and molecules which make up the immune system. The immune system is spread throughout the body and involves many types of cells, organs, proteins, and tissues. Crucial to the immune system is the ability to distinguish between what is 'self' and what is 'non-self'. This means being able to identify and then attack specific pathogens, but at the same time not attacking the body's own cells and tissues. Failure to make the distinction results in autoimmune diseases (e.g. type I diabetes) or chronic inflammations. In some cases, the immune system identifies normal, healthy cells as invaders and will continuously attack them. This is the case in autoimmune diseases and it is similar to having an allergic reaction, in that the immune system triggers an attack against a harmless substance.

Importance of Understanding the Immune System

The immune system is often likened to a sophisticated defense force for the body, but its function is infinitely more intricate and finely balanced. A healthy immune system protects the body from disease and infection caused by bacteria, viruses, fungi, and parasites. When the immune system detects the presence of one of these infectious agents, it mounts an assault by releasing chemicals to alert the rest of the immune system, which causes various cells to move to the site of infection and prevent the infectious agent from causing further harm to the body. This process usually causes inflammation, which is familiar to us as the swelling, redness, and pain at the site of injury or infection. High doses of corticosteroids are frequently used to dampen an overactive immune system primarily because the medications used to control inflammation are not specific for the immune system and frequently they have an unacceptable level of toxicity. A good example is non-steroidal anti-inflammatory drugs (NSAIDs), which are a common treatment for inflammation but can lead to gastric ulceration and significant kidney damage. The immune system is an incredibly complex system. It has been estimated that a working knowledge of the immune system would take up to eight years of intense full-time study and research to gain an understanding! This highlights the complexity and subtlety of this system. Naturally, this chapter cannot hope to cover all of the information about the immune system, but it is important to have a basic understanding before we can hope to understand the role and function of immunosuppressive medications.

Introduction to Imuran and Rapacan

Imuran and Rapacan are medications used to suppress the immune system, and as a patient with chronic kidney disease, you may wish to ask your physician more about these options. Kidney transplantation is the treatment of choice for many people with ESRD, as quality of life and survival are better in people who receive transplants compared to those who remain on dialysis. However, the success of a transplant is often limited by the body's immune system, which is responsible for protecting against infection and disease, but also recognizes anything foreign or "non-self" and attacks it. This is a serious problem for transplant recipients because the immune system does not recognize a transplanted organ as belonging to the body and will try to get rid of it. Imuran and Rapacan play a vital role in attempting to prevent this from occurring. By understanding how these medications affect the immune system, it is hoped that patients will see the importance of protecting their new kidney from immune attack and be more likely to continue taking medications in the long term.

Functions of the Immune System

The immune system is a network of cells, tissues, and organs that work together to defend the body against attacks by "foreign" invaders. These are primarily microbes - tiny organisms such as bacteria, parasites, and fungi that can cause infections. The normal response of the immune system to foreign microbes is the generation of inflammation, as the immune system attempts to clear the microbe from the body. Immune responses can be mild, causing a little local inflammation to clear localized skin infections, for example, or they can be more severe, causing illnesses such as tuberculosis when the microbe is not easily cleared. If the microbe is not cleared with the initial inflammatory response, the immune system may recruit more cells and generate prolonged inflammation. While the inflammatory response is essential to clearing infections, it can also cause collateral damage to the body.

The immune system has evolved to deal with different microbes in ways that cause the least damage to the body. For example, immune responses to bacteria are often confined to local tissues, where the bacteria are cleared from the body by inflammatory damage to the surrounding tissue. It is unfortunate if this happens to be the skin! The response to bacteria in the bloodstream can cause systemic illness with fever and fatigue, but it is usually not severe and the immune system can clear the infection within a few days. In contrast, viruses are not affected by inflammation and do not cause much tissue damage where they replicate, but they can take over host cells and they can cause disease by eliciting harmful immune responses. The immune system has therefore evolved to eradicate many viruses without generating inflammation, through complex processes that are still not fully understood. If the microbe is too numerous or much damage has already been done, the immune system may resort to inflammation as a last resort to trying to eradicate the infection.

Recognition and Response to Pathogens

The immune system has a vast array of cells that are classified as antigen-presenting cells (APC). The role of APCs is to display an antigen on their surface to T cells, to which they will help coordinate an immune response to. One of the most important groups of APCs are macrophages, these cells have a large number of roles in the immune response. They are phagocytic, meaning that they are able to engulf and digest cellular debris and pathogens. This is an important and non-specific defense as mentioned before, but they are also able to recognize a wide range of pathogens and display their antigen on its surface so an adaptive immune response can be coordinated.

Hooks on to and destroys pathogens. The immune system is faced with the challenge of being able to identify those agents that cause disease, whilst not causing damage to its own body. The immune system recognizes and destroys or neutralizes pathogens through a series of steps referred to as the immune response. It has been described as a military-like defense, with the immune system having an arsenal of cells and chemicals that are always at the ready to seek and destroy any foreign substance in the body. This is done through both non-specific defenses such as skin and mucous membranes, and an array of cells and proteins that target specific microbial invaders. Failure to recognize or to effectively respond to pathogens can result in disease. The immune response can be separated into two recognition and effector.

Regulation of Immune Responses

The role of the macrophage is very varied and includes destroying pathogens, alerting the immune system to the presence of microbial invaders, and removing dead cells. Due to their diverse functions, macrophages are involved in many processes. For example, lung alveolar macrophages defend the lungs from airborne particles, whereas liver Kupffer cells are particularly effective at removing foreign particles from the bloodstream. After a pathogen has been engulfed and destroyed by a macrophage, part of it is displayed to the remaining immune system on the surface of the macrophage in a molecule called MHC. This acts rather like a wanted poster and enables other cells to identify the pathogen. Part of the acquired immune system (lymphocytes, to be discussed later) recognize pathogens and produce a specific immune response. Macrophages are important in the regulation of the immune response, and they secrete various molecules that influence this.

Circulating immune cells are called white blood cells. They are divided into three main types: granulocytes, monocytes, and lymphocytes. Each type of white blood cell has a different task. For example, granulocytes have enzymes that are effective at killing pathogens, and they are particularly attracted to sites of infection where they ingest and kill microorganisms. Monocytes in the bloodstream are able to leave the circulation and enter tissues, where they develop into macrophages.

Immune System and Autoimmune Diseases

Autoimmune diseases are usually associated with overactivity of the immune system. This might seem contradictory, as it is generally thought to be beneficial for one to have an overactive immune system. However, it has been widely recognized that the immune system has a tendency to attack self-antigens as well as foreign antigens. There are two theories which seek to explain the development of autoimmune diseases. The first is the sequestered antigen theory. This proposes that in some cases, antigens that are not usually found within the body become exposed to the immune system.

As the immune system would not have developed tolerance to such antigens, an immune response is mounted in an attempt to remove them. However, as the antigen is continuously produced, this leads to a chronic immune response, which may cause damage to healthy tissue. This can be seen in hepatitis, where immune complexes formed from viral antigens and antibodies can become deposited in liver tissue and cause damage. The second theory is the molecular mimicry theory. This proposes that in some cases, foreign antigens may share similarity to self-antigens. If an immune response is mounted against such antigens, T cells and antibodies may cross-react with self-antigens if they cannot distinguish between self and non-self antigens. This can lead to an attack on self-antigens and chronic damage to healthy tissue. This theory can be applied to the pathogenesis of rheumatic fever and its effects on heart tissue.

Imuran: An Immunosuppressant Drug

Azathioprine (Imuran) is an anti-inflammatory agent that is still used in the treatment of autoimmune liver diseases. It is a pro-drug, serving as a tissue-specific immuno-modulator. Azathioprine is a purine analogue that is converted in vivo to 6-mercaptopurine (6-MP). The key imidazole ring of a purine is the essential difference between azathioprine and 6-MP. This makes azathioprine a more stable compound. Azathioprine is non-selective, and so can affect normal as well as pathologic immune function. After being converted to 6-MP, azathioprine inhibits a number of enzymes involved in purine nucleotide synthesis. It is believed that the cytotoxic effects of 6-MP result in inhibition of the proliferation of cells, particularly T-lymphocytes which are relatively deficient in purine compared to other cells. It is likely that immune cells are more sensitive to this mechanism than other cell types, explaining in part why azathioprine has effects on immune function, and also why it can have toxic side effects. The metabolism of 6-MP is complex, and it is the subject of much investigation. The major enzymes involved are thiopurine methyltransferase (TPMT) and xanthine oxidase. Allopurinol, which inhibits xanthine oxidase, can increase 6-MP toxicity. High 6-MP dosage can saturate the TPMT reaction, so more 6-MP is metabolized by xanthine oxidase, with the production of cytotoxic 6-thiouric acid. This can be avoided by reducing 6-MP dosage if toxic effects occur, with the expectation that over time a degree of immunity can be induced without producing severe marrow depression.

Mechanism of Action of Imuran

On the other hand, the primary source of R comes from the hydrolase TPMT. Mycophenolate mofetil (MMF) is a competitive and non-selective inhibitor of IMPDH, the pivotal enzyme in the de novo synthesis pathway of guanosine nucleotides. IMPDH catalyzes oxidation of IMP to xanthosine monophosphate, a rate-limiting step in the guanosine nucleotide pathway, and MMF is converted to mycophenolic acid (MPA), the active metabolite, which then reversibly inhibits IMPDH. The lack of the controlled guanosine nucleotide pathway and reliance upon salvage synthesis leaves T and B lymphocytes particularly reliant upon GTP, and the rate of conversion of IMP to GTP may be rate-limiting for the proliferation of T and B lymphocytes. MPA reduces the total guanosine nucleotide pool as it inhibits new guanosine nucleotide synthesis, although there is a compensatory increase in deoxy guanosine nucleotide synthesis and therefore DNA replication in T and B lymphocytes. This reduction is thought to be the principal mechanism by which MMF inhibits the immune response. MPA is also reported to have certain cytostatic effects on T and B lymphocytes, R cells, and macrophages. The implications of the repopulation of the guanosine nucleotide pool and the longer-term effects of MPA are still to be fully elucidated.

Medical Uses of Imuran

Imuran is utilized in the treatment of autoimmune disease, including scleroderma, systemic lupus erythematosus, juvenile diabetes, dermatomyositis, rheumatoid arthritis, and autoimmune hepatitis. It is often helpful in the management of myasthenia gravis and the prevention of kidney graft rejection. Rheumatoid arthritis and a few of the autoimmune diseases are said to create an increased risk of lymphoma, a cancer of the immune cells. There is an elevated risk with Imuran. This must be balanced against the benefit in the treatment of arthritis. The data on the treatment of systemic lupus erythematosus (SLE) is fairly strong, and this is considered one of the more responsive diseases to Azathioprine. We would also like to investigate the benefits for patients who have lung or skin involvement specifically with scleroderma. In addition to treating the underlying autoimmune disease, we understand that patients are often being treated with high doses of steroids, and Imuran may be beneficial at allowing a steroid dose reduction. High doses of steroids are known to cause severe adverse events, and it is generally recommended to use the minimum possible dose for the shortest possible time. Azathioprine is effective in allowing a reduction of the steroid dose and more recently has been used to allow steroid-free remission.

Potential Side Effects and Precautions

Hepatotoxicity and Allopurinol: Azathioprine (AZA) can produce toxic effects on the liver. Development of liver fibrosis, cirrhosis, and a fulminant hepatic failure syndrome has been described in transplanted patients treated with AZA. The spectrum of hepatotoxicity varies from asymptomatic hyperbilirubinemia to hepatitis and jaundice, sometimes with fever and rash, to chronic active hepatitis or acute hepatic necrosis. In some patients, AZA-induced liver injury resolves when the dose is reduced - if the liver injury is mild, no chronic or continued therapy is needed. However, in severe cases it may be necessary to wait several months for the injury to resolve, and a higher dose of corticosteroids may be required to control the disease being treated. In rare cases, AZA must be stopped permanently because the risk of further liver injury is unacceptable. A proportion of patients with AZA-induced liver damage have been successfully treated with corticosteroid therapy, but the use of prednisone to treat the erythematosus or dermatomyositis may pose a risk of further HPA axis suppression. If treatment with AZA must be stopped, in most cases the liver injury will resolve with no irreversible effects of toxicity, and the outlook for the patient's SIJD is usually favourable.

The monitoring of the patient by the doctor is a necessity while the patient is having Imuran. The affected blood cells and potency of the drug makes it necessary as even withdrawal of the drug may not improve the condition. The bone-marrow depression can lead to a decrease in the production of the white and red blood cells which is a serious side effect. The functions of the T-cells and B-cells may take few months and years to get back to the normal level. As the B and T cells play an important role in the immunity of the human body, a decrease in their activity is an important factor. Anemia is also caused by this drug. Constant check on the blood cells is necessary so that if the drug is causing any problem, it may be detected at the early stage. The doses of the drug can be reduced, stopped or the patient may be switched to some other medicine.

Rapacan: A Target of Rapamycin (mTOR) Inhibitor

Despite the role of Rapamycin in inhibiting the immune system, it is inferior to Calcineurin inhibitors when used for induction therapy immediately post-transplantation to prevent acute rejection of the allograft. Moreover, the delay in organ function often associated with Rapamycin prevents its use in patients at high risk of acute rejection. As a result, it is likely that Rapamycin will be used in maintenance therapy, either as a replacement for a Calcineurin inhibitor due to nephrotoxicity, or in conjunction with a reduced dose of Calcineurin inhibitors with the aim of preventing chronic rejection. Due to its wide use in the transplant population, there is considerable interest in developing new drugs that act in synergy with Rapamycin. The production of inflammatory cytokines by T cells. A study by Kato et al. (2005) examined the effects of Rapamycin administration on gene transcript value in rat allografts. Significantly, genes involved in T cell activation and receptor signal transduction, as well as MHC antigens, showed downregulation in the Rapamycin-treated allografts. In contrast to the widespread effects of corticosteroids, the reduced MHC expression is of particular importance in that it reduces the risk of infection and malignancy by decreasing T cell recognition of foreign antigens.

Role of Rapacan in Immune System Modulation

Rapamycin (Sirolimus) is a novel immunosuppressant from the class of the macrolide antibiotics and has properties that are different from all other known immunosuppressive agents. After minimal processing, it inhibits the activity of the mammalian target of rapamycin (mTOR), a key regulatory kinase involved in the alloantigen-driven T cell activation that leads to T and B cell clonal expansion and ultimately to acute and chronic allograft rejection. Retroactive analyses of recent renal transplantation trials would suggest that the substitution of other immunosuppressants with a regimen containing rapamycin can greatly reduce the probability of acute nephrotoxicity. Its ability to reduce calcineurin inhibitor (CNI)-induced nephrotoxicity is secondary to the mTOR complex role involving the stabilization of HIF-1α (required for erythropoiesis and iron metabolism proteins) and vasoconstrictive effects of a low nitric oxide to reactive oxygen species ratio. Furthermore, the potential for steroid sparing is an attractive option in an attempt to completely withdraw corticosteroids or a selected few patients who remain sensitive to the effects of steroids. Data from a 2-year course of rapamycin-based CNI and corticosteroid withdrawal protocol would suggest continued and improved allograft function with a reduction of proteinuria and lipid profile in comparison to standard immunosuppression regimens. This contrasts from the effects of CNI withdrawal where it is often associated with increased acute rejection and poorer long-term graft function. CNI withdrawal with introduction of rapamycin has produced less evidence of rejection and effects on the long-term health of the transplant. On non-inferiority trials, though, it is shown that to improve the renal benefits of a patient is more than likely to increase the incidence of acute rejection somewhat, lowering hematocrit and serum lipid levels, reduction of proteinuria, and less chronic allograft nephropathy make it an attractive option for patients mainly with cardiovascular disease or those waiting for retransplantation. Nevertheless, further studies are required to determine the safety and dosage of rapamycin or newer analogues and support its part in a changing approach at prolonging the graft survival.

Applications of Rapacan in Transplantation

Rapamycin appears to be effective in patients receiving kidney, heart, and liver transplants. Although there does not appear to be a direct correlation between Rapamycin dose and plasma concentration, trough levels have been shown to have a definite relationship to renal function and graft outcome. A recent study suggests that a combined regimen of Rapamycin and a full dose of cyclosporine is detrimental to renal function at 6 months post-renal transplant, and it is advocated that the cyclosporine dose be reduced or withdrawn after 4-8 weeks and replaced with a low dose. This may have important implications for patients with pre-existing renal insufficiency at the time of transplant, who may benefit from a regimen involving no calcineurin inhibitor. An additional potential advantage of Rapamycin is its reported lack of nephrotoxicity, which opens the possibility of a calcineurin inhibitor-free regimen in the future.

Rapamycin, a newer generation rapalogue with even more specific mTOR inhibiting properties, has an important role as an immunosuppressive agent. It has been approved in the USA for the prevention of acute organ rejection in renal transplant patients at a low dose of cyclosporine and corticosteroids. The primary mode of action of Rapamycin in prolonging allograft survival is through its ability to arrest the cell cycle in T-cells and B-cells, which occurs in response to cytokines such as IL-2, and is a crucial step in the progression to cellular division and differentiation. By inhibiting IL-2 driven gene transcription, Rapamycin decreases synthesis and blocks the action of cytokines, leading to the specific inhibition of T-cell proliferation. The net result is the prevention of a cell-mediated immune response to the allograft. These unique properties of Rapamycin have been demonstrated both in animal models and clinical trials, making it an attractive alternative to current regimens of calcineurin inhibitors and antimetabolites.

Safety Considerations and Adverse Reactions

This is an elaborated form of information on content listed in Chapter 4.3. The information modulated the adverse effects caused by the Mycophenolate mofetil and MPA. As MMF and MPA predominantly act on T and B cells, their effect directly on the cells cause certain infections. There are sporadic cases of severe and fatal infections such as progressive multifocal leukoencephalopathy (PML) in patients diagnosed with SLE and lupus nephritis after taking high dose MPA for 3 years. The autopsy findings showed diffuse and multiple demyelination in the cerebrum and cerebellum. Effects from the immunosuppressive drug can also cause lymphoproliferative disorders. This is due to the drug limiting the replication of T and B cells and reducing their normal function. From that, defective cells accumulate and produce abnormal proteins, resulting in uncontrolled cell division and altered programmed cell death. This can lead to malignancy or tumors in lymphoid tissue, and in severe cases, it can result in cancers. A case report occurred in a 50-year-old woman with arthritis treated with MPA and SLE treated with prednisone. She complained of fever, night sweats, and abdominal pain. An examination showed hepatosplenomegaly and Hodgkin-like cells on liver biopsy, and the results revealed a diffuse large B-cell lymphoma.

Garza, Kristian, et al. “Framing the Community Data System Interface.” Proceedings of the 2015 British HCI Conference, ACM, 13 July 2015. Crossref.