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antigen stimulation. As lymphocytes are prevented from being activated, AICD does not occur. In that respect the new immunosupressive drug rapamycin might be a good alternative. It does not interfere with activation and AICD. It rather functions by arresting the cell cycle, rendering lymphocytes insensitive to prolif-erative signals. Therefore, although CsA prevents tolerance induction with anti-CD40L antibodies, rapamycin does not affect tolerance in this system.39 One can predict that also anti-CD4 tolerance induction might be achieved in spite of concomitant administration of rapamycin.

Another issue to bear in mind is the practical feasibility of any therapeutic strategy. Some of the experimental protocols might be too complex or involve potential side-effects too risky for widespread clinical use. The ideal agent should be easily administered and with low impact on the immune system as a whole.

A potentially simple approach that has not yet been exploited, though offering therapeutic potential, is linked suppression. Although very little is known of its mechanisms, it can mediate powerful immuregulatory effects: for example, after tolerance induction with non-depleting CD4 and CD8 mAbs to a minor mismatched skin, tolerant animals subsequently accept skin from donors that in addition to the tolerised minors have a major histocompatibility mismatch.27 In practise one might be able to "tolerise" to a series of polymorphic allo-antigens in advance of a transplant to pre-expand regulatory cells. Following organ transplantation this first cohort of regulatory cells may facilitate spread of tolerance to clones reactive to the "linked" antigens. Thus inducing tolerance to the whole organ.

The administration of epitopes by oral,42,43 nasal44 and even intra-peritoneal45 routes can lead to tolerance. It is also possible to modify the characteristics of the peptide, such as the affinity for the MHC, to modulate this effect.46

As we get to know some of the most important or dominant epitopes involved in graft rejection, we may be able to use them to induce transplantation tolerance. Furthermore, tolerance induced with a few dominant epitopes might then "spread" by linked suppression to other epitopes that are also present in the graft. It should therefore be possible to "build tolerance in stages": it is probably not necessary to tolerise to the whole set of major and minor antigens of the allograft, since tolerance to a few dominant ones will subsequently spread to the rest. Ultimately it might be possible to identify a group of dominant epitopes that could be used as a universal therapy to induce transplantation tolerance in any host-donor combination.

Aknowledgements

This work was funded by grants from the Medical Research Council (UK). LG is supported by a scholarship from the Gulbenkian Foundation and the Portuguese Foundation for Science and Technology.

This article is reprinted from Graft 2001; Vol. 4, No. 3:174-179, with permission from the authors.

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