Tissue rejection

Tissue/organ transplantation in which the donor is not genetically identical to the recipient (i.e. in cases other than identical twins). The recipient will mount an immune response against the transplanted tissue, culminating in tissue rejection unless immunosuppressive agents are administered. 

Water-miscible solvents alone can be used when the drug is chemically unstable in the presence of any water. The number of solvents available for this purpose is extremely limited. The classic review of this subject was made in 1963 (Spiegel and Noseworthy), and some 30 years later, no additional solvents are available. This is unlikely to change in the near future due to the extensive effort necessary to determine the safety of a solvent used as a vehicle. When a nonaqueous vehicle is used, one can invariably expect some degree of pain upon injection, and subsequent tissue destruction is possible. This damage may be due to the heat of solution as vehicle mixes with body fluids it may be associated with tissues rejecting the solvent or, it may be an inherent property of the solvent. 

Recently, it has been possible to grow cells of the human immune system in special mice. These mice carry a genetic defect called severe combined immunodeficiency (SCID), which leaves them with crippled immune systems, much like those in AIDS patients. Because SCID mice lack functional cellular immunity, it is possible to implant them with human cells without tissue rejection taking place. Researchers have recently developed techniques to implant human fetal tissues containing stem cells for the blood into SCID mice. It is then possible to reconstitute these mice with functional human immune system cells, including T lymphocytes and B lymphocytes. They have also found that if these SCID mice are infected by HIV, the virus will establish infection in the human tissue and destroy the T helper lymphocytes, just as it does in humans. Thus, it may be possible to study some of the mechanisms by which HIV attacks the immune system in these mice. In addition, they may be very useful for testing potential antiviral drugs. 

Mycophenolate mofetil has a more specific effect on lymphocytes than on other cells. It inhibits inosine monophosphate dehydrogenase, which catalyzes purine synthesis in lymphocytes. It is used in acute tissue rejection responses. 

Nitrofurazone, a topical antibiotic, is occasionally used in the treatment of burns or skin grafts in which bacterial contamination may cause tissue rejection. 

The main clinical uses of immunosuppressive drugs are suppression of organ and tissue rejection after transplant surgery and the treatment of diseases with an autoimmune component. Thses include renal diseases, e.g. glomerulonephritis, some nephrotic syndromes, connective tissue diseases, such as systemic lupus erythematosus rheumatoid arthritis, and systemic vasculitis. 

Azathioprine is a cytotoxic inhibitor of purine synthesis effective for the control of tissue rejection in organ transplantation. It is also used in the treatment of autoimmune diseases. Its biologically active metabolite, mercaptopurine, is an inhibitor of DNA synthesis. Mercaptopurine undergoes further metabolism to the active antitumour and immunosuppressive thioinosinic acid. This inhibits the conversion of purines to the corresponding phosphoribosyl-5 phosphates and hypoxanthine to inosinic acid, leading to inhibition of cell division and this is the mechanism of the immunosuppression by azathioprine and mercaptopurine. Humans are more sensitive than other species to the toxic effects of the thiopurines, in particular those involving the haematopoietic system. The major limiting toxicity of the thiopurines is bone marrow suppression, with leucopenia and thrombocytopenia. Liver toxicity is another common toxic effect. 

The major classes of immunosuppressive drugs employed in clinical practice to avoid tissue rejection include calcineurin inhibitors, target of rapamycin (TOR) inhibitors, sphingosine-1 -phosphate receptor (S1P-R) modulators, cytotoxic agents, glucocorticoids and monoclonal antibodies. These drugs need to be used on a lifelong basis and have major undesirable side effects. 

Daclizumab is used for the prophylaxis of acute rejection in patients receiving kidney transplants. A dose of 1 mg/kg is sufficient to completely block all the IL-2 receptors. It is administered in five doses at a 2-week interval where its elimination half-life is about 20 days. A combination of several other immunosuppressive agents including cyclosporine (or tacrolimus, rapamycin), mycophenolate mofetil and corticosteroids can be used with daclizumab. When it is used in combination with tacrolimus, the doses of tacrolimus are reduced. After tissue transplantation, the addition of daclizumab to the standard immunosuppressive regimen produces reduction in tissue rejection up to 50%. Daclizumab can cause hypersensitivity reactions, but it does not cause cytokine-release syndrome. There is a low incidence of... 

Basiliximab is used for the prophylaxis of acute rejection for patients undergoing kidney transplantation where it is employed in combination with other standard immunosuppressive therapy regimens. After tissue transplantation, its addition to the standard immunosuppressive regimen results in inhibiting tissue rejection up to approximately 30%. Both daclizumab and basiliximab have similar effects on the expression of IL-2a and -(3 chains. 

Azathioprine (Imuran) is an immunosuppressant drug that is often used to prevent tissue rejection following organ transplants. Because of its immunosuppressant properties, this drug has been employed in treating... 

Clinical Use. Cyclophosphamide (Cytoxan, Neosar) is an anticancer alkylating agent that is commonly used in a variety of neoplastic disorders (see Chapter 36). This drug may also be helpful in suppressing the immune response in certain autoimmune diseases, such as multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis.12 43 High doses of cyclophosphamide are also used to prevent tissue rejection in patients receiving bone marrow transplants and other organ transplants. 

Our knowledge of how the immune system functions in both normal and disease states has increased dramatically over the last several decades, and we now have drugs that can moderate the effects of the immune response in certain clinical situations. Immunosuppressants are a mainstay in preventing tissue rejection, and much of the current success of organ transplants is due to the judicious use of immunosuppressive drugs. These drugs are also beneficial in a number of diseases that have an autoimmune basis, and immunosuppressants can help alleviate symptoms or possibly even reverse the sequelae of certain diseases... 

The immune system defends the body against invading organisms, foreign antigens, and host cells that have become neoplastic. In addition, the immune system is an active participant in autoimmune diseases, hypersensitivity reactions, and transplant tissue rejections. 

IV. Anti-T-cell Immune serum is obtained from animals immunized with human T-lymphocytes. The antibodies bind to and damage T cells and can thus be used to attenuate tissue rejection. 

Transplantation of islets of Langerhans as a means of treating insulin-dependent diabetes mellitus has become an important field of interest [217-219]. However, tissue rejection and relapse of the initial autoimmune process have limited the success of this treatment. Immunoisolation of islets in semipermeable microcapsules has been proposed to prevent their immune destruction [220, 221]. Nevertheless, a pericapsular cellular reaction eventually develops around micro-encapsulated islets, inducing graft failure [222]. Since empty microcapsules elicit a similar reaction [223], the reaction is not related to the presence of islets within the capsule but is, at least partially, caused by the capsule itself. Consequently, microcapsule biocompatibility appears to constitute a major impediment to the successful microencapsulated islet transplantation. 

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