Organ transplant rejection, prevention

Corticosteroids also exert inhibitory effects on the overall immune process. These drugs impair the function of the leukocytes responsible for antibody production and destruction of foreign cells. As a result, corticosteroids are also used therapeutically in the prevention of organ transplant rejection. 

Prevention of organ transplant rejection PO Loading dose 6 mg. Maintenance 2 mg/day. 

Mechanism of Action An immunologic agent that inhibits T-lymphocyte activation by binding to intracellular proteins, forming a complex, and inhibiting phosphatase activity. Therapeutic Effect Suppresses the immunologically mediated inflammatory response prevents organ transplant rejection. 

Muromonoab-CD3 is used for the treatment of acute organ transplant rejection. It is effective in preventing graft rejection after kidney, heart or liver transplantation. Muromonoab-CD3 is effective in patients who after acute cardiac or liver allograft rejection do not respond to steroid therapy. It is administered intravenously and with a dose of 5 mg/day, a general concentration range of 400-1500 ng/ml can be achieved. A serum concentration of 600-1150 ng/ml in renal transplant patients produces desirable immunosuppressive effects. The levels of CD3 expression, their production and antibodies to the drug determine its rate of clearance. In the absence of antibodies to muromonoab-CD3, its half-life is about 18 h. 

Immunosuppression or enhancement can be associated with two distinct groups (1) Drugs intended to modulate immune function for therapeutic purposes (e.g. to prevent organ transplant rejection) where adverse immunosuppression can be considered exaggerated pharmacodynamics. (2) Drugs not intended to affect immune function but cause immunotoxicity due, for instance, to necrosis or apoptosis of immune cells or interaction with cellular receptors shared by... 

Tacrolimus is a macrohde immunosuppressive agent indicated for the prevention of organ transplant rejection and useful as an alternative treatment in severe recalcitrant psoriasis. Tacrolimus, like cyclosporine, inhibits T-ceU activation. ... 

Therapeutic Uses Azathioprine is indicated as an adjunct for prevention of organ transplant rejection and in severe rheumatoid arthritis. Although the dose of azathioprine required to prevent organ rejection and minimize toxicity varies, 3-5 mg/kg/day is the usual starting dose. Lower initial doses (1 mg/kg/day) are used for rheumatoid arthritis. Complete blood count and Uver function tests should be monitored. 

Therapeutic Uses Muromonab-CD3 is indicated for treatment of acute organ transplant rejection. The recommended dose is 5 mg/day (in adults less for children) in a single intravenous bolus (<1 minute) for 10-14 days. Antibody levels increase over the first 3 days and then plateau. Circulating T cells disappear from the blood within minutes of administration and return within 1 week after cessation of therapy. Repeated use of muromonab-CD3 results in the immunization of the patient against the mouse determinants of the antibody, which can neutralize and prevent its immunosuppressive efficacy. Thus, repeated treatment with the muromonab-CD3 or other mouse monoclonal antibodies generally is contraindicated. 

Azathioprine (Imuran) Converted to 6-mercaptopurine ribose phosphate which inhibits purine synthesis. Because DNA RNA synthesis requires proteins, all proliferating cells are inhibited (B-cells, T-cells, nonimmune cells). Prevention of organ transplant rejection. Gl distress, bone marrow depression, infections, mild leukopenia and thrombocytopenia. 

Methotrexate (e.g., Mexate) Inhibits dihydrofolate reductase, an enzyme that catalyzes the synthesis of thymidine. DNA synthesis is thus impaired. Prevention of organ transplant rejection, severe psoriasis. Bone marrow depression, Gl ulceration, nephrotoxicity, hepatotoxicity, pulmonary infiltration, skin toxicity. 

Lymphocyte immune-, anti -thymocyte-globulin (Atgam) Horse IgG antibodies which selectively suppress T-lymphocytes (cell-mediated immunity) and humoral immunity. Prevention of organ transplant rejection, aplastic anemia. Fever, chills, leukopenia, throm -bocytopenia, skin reactions. Less often arthralgia, chest or back pain, dyspnea, nausea, vomiting, headache, night sweats (serum sickness). 

Farnesyl pyrophosphate (Fig. 30.2) is an intermediate in the biosynthesis of cholesterol, ubiquinone, and dolichol phosphates. Based on their site of action, HMGRis will decrease the availability of all four of these compounds and, thus, decrease cell proliferation. Potential applications of this antiproliferative effect include the prevention of restenosis following angioplasty, prevention of glomerular injury in renal disease, treatment of malignant disease, and prevention of organ transplantation rejection (40). 

Basiliximab Chimeric IgGlK Sp2/0 a chain IL-2 receptor (CD25) Reduces T cell activation Prevent organ transplant rejection Simulect ... 

Cyclosporine A (CsA) is an inhibitor of intracellular calcineurin, thereby inhibiting the production and release of interleukin-2 (IL-2) which subsequently limits clonal activation and expansion of T-lymphocytes. CsA is FDA-approved for the prevention of solid organ transplant rejection (kidney, liver) and keratoconjunctivitis sicca. Non-FDA labeled indications include, but are not limited to, the autoimmime diseases systemic lupus erythematosus rheumatoid arthritis myasthenia gravis. 

After these initial approaches in animal models, ECP has been used in humans for the prevention and/or treatment of several solid organ transplant rejections, including kidney, heart, lung, pancreas, and liver. The year of introduction of ECP for treating rejection of each type of transplant is indicated in Table 5. Importantly, ECP is effective for patients resistant to conventional treatment, particularly if started early. Besides reversal of allograft rejection, a reduction in immunosuppressive therapy has also been frequently achieved [173,174]. 

Another biomedical appHcation of mictocapsules is the encapsulation of Hve mammalian ceUs for transplantation into humans. The purpose of encapsulation is to protect the transplanted ceUs or organisms from rejection by the host. The capsule sheU must prevent entrance of harmful agents into the capsule, aUow free transport of nutrients necessary for ceU functioning into the capsule, and aUow desirable ceUular products to freely escape from the capsule. This type of encapsulation has been carried out with a number of different types of Hve ceUs, but studies with encapsulated pancreatic islets or islets of Langerhans ate most common. The alginate—poly(L-lysine) encapsulation process originally developed in 1981 (54) catalyzed much of the ceU encapsulation work carried out since. A discussion of the obstacles to the appHcation of microencapsulation in islet transplantation reviewed much of the mote recent work done in this area (55). Animal ceU encapsulation has also been researched (56). 

Successful outcomes in solid-organ transplantation generally are measured in terms of several separate end points (1) preventing acute rejection (2) increasing 1-year graft survival ... 

Solid organ transplant recipients have a blunted immune response to vaccines because the immunosuppressive regimens used to prevent organ rejection inhibit both T- and B-cell proliferation. Many of these patients will also have secondary hypogammaglobulinemia post-transplantation. Prior to transplant, children should complete primary immunization schedules if possible accelerated schedules may be used. Adults should have all vaccinations updated prior to transplantation.16... 

Allograft Tissue or organ transplanted from a donor of the same species but different genetic makeup the recipient s immune system must be suppressed to prevent rejection of the allograft (graft). 

In some surgical procedures, such as organ transplantation, the success of that procedure will be only as great as the course of pharmacotherapy that follows. Organ transplant recipients are required to continue drug therapy for the balance of their lives for control of their immune systems and to prevent organ rejection. 

Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant useful in the prevention of rejection in organ transplants and grafting procedures. Ciclosporin is markedly nephrotoxic. Vincristine is a vinca alkaloid cytotoxic agent fluorouracil and methotrexate are both antimetabolite cytotoxic agents and bleomycin is a cytotoxic antibiotic. 

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