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Issues in immunosuppression

Improving the survival of  the patient and the transplant are the obvious targets for immunosuppression in the next millennium. In addition, there will be increased pressure to adopt regimens that optimize the Three Cs of Treatment: Co-morbidity (quality of life), Cost and Convenience.
For instance, with respect to Cost, in the US, managed care companies are already stipulating the drogs that can be prescribed for transplant patients enrolled in their plans. lncreasingly throughout the world cost-containment strategies wilI be brought to bear on transplantation treatments.
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Figure 1. The Three Fates

" The future goals of immunssuppressive therapy must be Synergy, Selectivity and Specificity "


With respect to Convenience, increased ease of administration and simplification of the immuno- suppressive regimen are essential If transplantation is to advance. For example, once immunosuppressants selective for alloimmune responses are developed, anfibiotic prophyliaxis might be dropped trom the regimen as the host's defenses against infection are not impaired by such agents.

With respect to Co-morbidity, the selection of agents souhld eventualy be tailored to each patient to
achieve minimal morbidity, taking into account each Individoal drug's therapeutic window of effect versus toxicity specific for that patient

Primary strategy of transplant drug development

Targeted drug design will be the primary strategy of transplant drug development. As knowledge of the intercellular pathways of antigen signal reception, transduction and activation increases, critical regulatory molecules for the emergence of alloaggression wilI be targeted for structural modeling by thee design of second generation inhibitory drugs. The futore goals of immunosuppressive therapy must be Synergy, Selectyvity, and Specificify. These goals are metaphorically represented by the Three Fates in the logo of the congress (Figure 1).

Table1: New drugs for immunosupression
Target Agetn
Endothelium Anti-ICAM-I
antisense oligonucleotoides
Lymphocyte homing FTY 720
Cytokine signal
transducction
RAPA/RAD

Synergy Cilinicians will need to ensure fhat they achieve the most optimal and synergistic immunosoppressive regimens forr individual patients. The combination of rapamycin and Neoral is a good example of a synergistic interaction. It bas reduced
the rate of acute rejection episodes by 75 per cent. It enables the clinician to use lowerr doses of Neoral and/or to withdraw steroids. The combination of  Neoral and the new monoclonal antibody, Simulect© (basiliximab), has produced a moderate (30 per cent) decrease in the rate of occurrence of acute rejection episodes (The Lancet 1997; 350: 1193-1198).
Although this is not drug synergy, it is a useful  additive eftect. Indeed, the combination of Neoral,
rapamycin (or RAD) and Simulect will Iikely be the standard therapies to the year 2000. These examples show how therapies that interact synergistically, or at least jo an additive way, can boost etficacy and cost eftectiveness of  treatment regimens.

Selectivity An iremune-suppressive agent must not only inhibit the body's immune reactinos against the graft, but also spare host resistance toward infections. Selectivity is the most important property of an optimal immunosuppresive drug regimen.

Specificity Finaily, an immunesuppressive agent, prbably used in combination with another
immunomodulator, needs to be developed te produce donor specific tolerance.
Achieving these goals wiIl be critical to achieve efficacious aud safe immunosuppression in the new millenium. Pagos 4-5 look at some of  the important immunosuppressants that are coming into use.