Info

Four of the seven classes are biologic agents, antibodies, directed against lymphocytes; the other three classes are chemical reagents, medium sized molecules of less than 1000 (kd) in molecular weight.

All four of the antibody classes are administered intravenously as short courses ranging from a single dose to intermittent dosing for as long as eight weeks. Two of the classes (polyclonal antithymocyte globulin and monoclonal antibodies against lymphocyte cell surface differentiation markers) act by destroying and depleting a wide array of T and B lymphocytes, monocytes, macrophages, and NK cells through cell lysis. The two remaining classes of biologic agents are also monoclonal antibodies; muromonab-CD3 blocks the T-lymphocyte receptor for antigen while daclizumab and basiliximab block the T lymphocyte receptor for IL-2. These last two classes of antibody interfere with T lymphocyte response to antigens introduced by the transplanted organ.

Immunosuppressive regimens throughout the past four decades have been divided into two camps: those that use only chemical reagents and those that combine chemical reagents with antibodies. Both camps included corticosteroids among the chemical reagents. Between 1964 and 1986 polyclonal anti-human lymphocyte globulin was the only antibody class available and chemical reagents consisted only of corticosteroids and azathioprine until 1983. The combination of antibody with steroids and azathioprine was superior to steroids and azathioprine alone. But after cyclosporine joined steroids and azathioprine in 1983 the two camps parted ways. Advocates of chemical reagents alone claimed graft and patient survival equal to that of drugs plus antibody. Advocates of adding antibody to drugs claimed that the combination permitted delayed onset of first rejection, lower early doses of cyclosporine with less nephrotoxicity and better renal function at no cost with respect to incidence of rejection episodes and graft survival. Moreover it simplified management of delayed graft function which affected up to one-third of cadaveric kidney transplants.

The two camps, drugs versus drugs plus antibody, still disagree. The drug camp has new drugs (tacrolimus, MMF and sirolimus) and the antibody camp has new antibodies. Both camps have learned to manage with less calcineurin inhibitor (so as to reduce nephrotoxicity) and both camps have largely replaced azathioprine with MMF, but corticosteroids, a relic from the 1960's that lacks any specificity for lymphocytes and is the most devastating of all immunosuppressive drugs with respect to long-term crippling side effects, persist as part of the regimen in both camps throughout the world.

0 0

Post a comment