E1

Figure E4.1. Demonstration of linked suppression. This requires the demonstration that tolerant animals accept grafts where a third party antigen is present in cells that also have the tolerated antigens (BxC), but reject third party grafts (C) if the tolerated antigen absent from the graft cells (even if a concomitant tolerated-type graft (B) is given). The animals that accept the grafts with the "linked" third party antigen (BxC) should accept later grafts of the third party (C).

autoimmunity models (reviewed in 29). Even among the T cell population of normal individuals T cells with the capacity of causing autoimmune disease have been identified, as well as regulatory cells that prevent this pathological autoaggression.30,31 It is therefore likely that, in addition to thymic tolerance, peripheral tolerance mechanisms operate to safeguard tolerance to extra-thymic antigens.

The phenotype of these regulatory cells, and their proposed mechanisms of action is not yet totally clear. Although it is possible to induce transplantation tolerance with mAbs in thymectomised mice,14,28 there is evidence suggesting that regulatory cells in some autoimmunity models are a defined lineage originating in the thymus (reviewed by Seddon & Mason32). This lineage was shown to have some distinctive surface markers: they are included in the CD45RClo population of CD4+ cells in the rat,30 or in the CD45RBlo in the mice.33 It also seems that expression of the IL2 receptor a-chain (CD25) reflects the presence of a putative regulatory CD4+ cell that further subdivide the CD45RBlo population.34,35 Given that CD25 seems to be a marker of suppressor cells it may seem paradoxical that an antibody targeting CD25 is licensed for use as immunosuppressive agent in clinical transplantation (reviewed in 36). A theoretical risk for a therapy that tar gets CD25 expressing cells might be the loss of potential to induce tolerance to the graft, as well as a possible disruption of normal regulatory mechanisms that prevent autoimmunity.

Other markers, such as L-selectin37 or CD3838 have also been suggested as possible surface markers of regulatory cells. It is hoped that purification and cloning of these elusive regulatory cells will allow a better understanding of their biology.

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