immune repertoire such that only a few residual anti-virus, memory T cells remain in the host. It is hypothesized that normally, the number of autoreactive T cells activated during such infections is limited, and that this response also resolves, despite the fact that persistent self-antigens are always present (perhaps due to the persistence of the autoreactive regulatory repertoire already present in the host). Under extremely rare conditions, again determined by genetic predispositions of the host and various environmental factors, the autoreactive component of the proinflammatory immune repertoire may not fully resolve or may re-activate. In these latter instances, the target organ would not resolve back to the normal, quiescent, but actively protective state, with the end result being the development of self-perpetuating, organ-specific autoimmune disease.

It is intriguing to note that pathologic autoimmune reactions are generally organ-specific, and do not spread to involve other organs despite the fact that many normal tissues likely express some of the same autoantigens (although organ specific autoimmunity can be directed towards antigenic targets specifically found in a given organ and not another). The autoimmunity by design framework suggests a plausible explanation to account for this, based on the assumption that the various microenvironments of the host can differentially influence the autoimmune repertoire. The model would suggest that the noninvolved host tissues maintain a tolerant phenotype, consisting of infiltrating, autoreactive, regulatory T cells, a nonpathogenic microenvironment, and an absence of chemoattractant signals to attract pathogenic T cells. If small numbers of activated pathogenic T cells spill over into these tissues they would be controlled by the permissive microenvironment (just as outlined above for organs of the normal, noninfected host), thus preventing spread of the autoimmune disease to additional organs.

The development of pathogenic and protective autoreactivity within the conceptual context of autoimmunity by design can account for some recent observations in transplantation immunobiology as well. Emerging data, summarized in the accompanying articles by Benichou, Fedoseyeva and Wilkes (Editors of Graft will need to insert references here), provide convincing evidence that autoreactive T cells can contribute to destruction of a transplanted organ. Work by these investigators and by others showed that allograft transplantation primes pathogenic, recipient-MHC-restricted T cells specific for peptides derived from cardiac myosin (heart grafts), collagen V (lung transplants), heat shock proteins (skin grafts and heart grafts) and some unknown autoantigens.11,24-30 The primed autoreactive T cells were not simply innocent bystanders, because 1) they could be isolated from allografts undergoing rejection, 2) immunization with these autoantigens prior to transplantation could accelerate allograft rejection and 3) induction of a pathogenic immune response to these autoantigens through experimental immunization could precipitate rejection of an isograft. Interestingly, the primed, autoreactive T cells capable of rejecting a transplanted isograft did not seem to cause injury to the native organs of the recipient.

The detection of autoreactive T cells following transplantation should be anticipated (Fig. E3.2). In addition to direct recognition of donor cells, recipient T

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