Organ transplantation acute rejection

Even if tissue types are dosely matched, transplanted organs are usually rejected unless preventive measures are taken. Rejection, if it occurs, can begin soon after transplantation - acute rejection - but can... 

Acute rejection is a cell-mediated process that generally occurs within 5 to 90 days of the transplant procedure however, it can occur at any time after transplantation. This reaction is mediated through alloreactive T cells, as outlined previously. Organ-specific signs and symptoms of acute rejection are listed in Table 52-2. 

The induction agents are highly immunosuppressive and, when given prior to some organ transplants (e.g., kidney transplant), allow for significant reductions in acute rejection... 

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 ... 

This includes patients with Banff grade II acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, or with serum creatinine greater than 4.5 mg/dL, black patients, retransplants, multi-organ transplants, or patients with high panel of reactive antibodies. 

Muromonab-CD3 (Orthoclone OKT3) [Immunosuppressant/ Monoclonal Antibody] WARNING Can cause anaphylaxis monitor fluid status Uses Acute rejection following organ transplantation Action Murine Ab, blocks T-cell Fxn Dose Per protocol Adults. 5 mg/d IV for 10-14 d Peds. 0.1 mg/kg/d IV for 10-14 d Caution [C, /-] w/ Hx Szs, PRG, uncontrolled HTN Contra Murine sensitivity, fluid overload Disp Inj SE Anaphylaxis, pulm edema, fever/chills w/ 1st dose (premedicate w/ stCToid/APAP/antihistamine) Interactions t Effects W/ immunosuppressives t effects OF live virus vaccines t risk of CNS effects encephalopathy W/ indomethacin EMS Monitor for S/Sxs of Infxn monitor resp Fxn, known to... 

Mycophenolate mofetil is used together with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients undergoing allogeneic renal, or hepatic transplants. Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is rapidly hydrolyzed to mycopheno-lic acid, its active metabolite. Mycophenolic acid is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an important enzyme for the de novo synthesis of purines. As lymphocytes have little or no salvage pathway for purine... 

Early clinical trials indicate that mycophenolate mofetil in conjunction with cyclosporine and corticosteroids is a more effective regimen than azathioprine in preventing the acute rejection of transplanted organs. GI side effects are most common. 

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. 

Pinderski LJ, Kirklin JK, McGiffin D, Brown R, et al. 2005. Multi-organ transplantation Is there a protective effect against acute and chronic rejection J Heart Lung Transplant. 24 1828-1833. 

Recently, biologicals such as anti-CD3 monoclonal antibody have been used to combat acute rejection. Chronic rejection usually occurs months or even years after transplantation. It is characterized by thickening and fibrosis of the vasculature of the transplanted organ, involving both cellular and humoral immunity. Chronic rejection is treated with the same drugs as those used for acute rejection. 

The first therapeutic antibody approved (Orthoclone OKT-3 or Muromonab CD3, 1986) was indicated not for cancer treatment, but for controlling acute rejection of transplanted organs (kidney, heart, and liver). Nowadays, other clinical indications such as asthma, rheumatoid arthritis, psoriasis, and Crohn s disease are treated with mAbs (see Chapter 17) (Antibody Engineering and Manufacture, 2005 Monoclonal Antibodies and Therapies, 2004 Hot Drugs, 2004 Walsh, 2004). 

Tacrolimus, a macrolide derivative, has similar immunosuppressive properties to ciclosporin and has effects on T lymphocytes by inhibiting interleukin-2 production. On a weight basis, tacrolimus is about 100 times more potent than ciclosporin. In view of the outcome of several multicenter trials, it has been used as an alternative to ciclosporin as a baseline regimen for the prophylaxis of renal and liver transplant rejection and in the treatment of acute rejection (SED-13,1130) (SEDA-21, 390) (1). The clinical pharmacology, clinical use, and adverse effects profile of tacrolimus in organ transplantation have been extensively reviewed (2). 

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