time, signals from the regulatory T cells delivered to vascular cells, parenchymal cells, and/or bone marrow derived APCs of the organ would theoretically maintain its quiescent, tolerogenic state (possibly through upregulation of protective genes or inducing APCs to differentiate into a tolerogenic phenotype). The end result would be a self-perpetuating, protective microenvironment that is dependent on the interaction between the regulatory T cells and the induced protective state of the organ. It is hypothesized that the autoreactive regulatory T cells are required to induce the tolerant state, but may not be sufficient to maintain it; induced alterations in the peripheral organ tissue cells and/or APCs such that they have protective or tolerogenic properties would be necessary for maintenance. In contrast to standard paradigms, the hypothesis suggests that the lack of inflammation is an active process, involving an ever-evolving interaction between autoreactive (regulatory) T cells and the "normal" tissues of the peripheral organs. The immune system must overcome these active, protective processes in order to mediate local inflammation. Further implicit in this paradigm is the concept that individual microenvironments are regulated independently—how the immune system behaves in one location may not be identical to how it behaves at a different site in the organism (i.e., inflammation can be localized to a single site with the remainder of the host being unaffected).

Is the autoimmunity by design framework consistent with experimental observations made in tolerant animals? Certainly, normal hosts, presumably tolerant to self-antigens, have T cell repertoires containing autoreactive T cells, some of which are naïve and others of which seem to have regulatory properties.6-8 Increasing evidence is accumulating to show that regulatory T cells are detectable in both mice and humans and that depletion of certain subpopulations of regulatory T cells (i.e., CD25+ CD4+) can result in autoimmune pathology (although the specificity of these cells has not been defined in most studies) (reviewed in ref. 9). Studies from at least one transplant model show that normal, donor organs contain T cells with regulatory potential that have the capability of repopulating an immuno deficient recipient and can mediate tolerance.10 In vivo expansion of autoreactive T cells can be elicited experimentally and can result in either pathogenic autoimmunity or protective tolerance, depending on the experimental protocol utilized.11,12 Some induced regulatory populations of T cells can transfer tolerance to naïve animals.13-15 There is also evidence that transfer of regulatory T cells alone may not be sufficient to mediate tolerance in naïve animals but that tolerogenic APCs may be required.16,17 Finally, tolerance can be associated with end organ resistance, mediated by expression of protective gene products (i.e., heme oxyengase, indoleamine 2,3-dioxygenase, FasL) that, in turn, can be upregulated by interactions with primed T cells (some of which have been shown to be tolerogenic) or their secreted cytokines.18-20 Thus in a broad sense, the autoreactivity by design hypothesis is consistent with many experimental observations regarding tolerance.

How would the conceptual framework of autoreactivity by design explain the development of pathologic autoimmune disease? Firstly, it is notable that the development of autoimmune disease is a relatively rare event and that it is difficult

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