Inhibition of pathogenic Inhibition of proinflammatory pathogenic autoreactive 7 Ce!l proinflammatory all or ¿-active T cell

Creation of a protective microenvi ronment in the graft

Inhibition of pathogenic Inhibition of proinflammatory pathogenic autoreactive 7 Ce!l proinflammatory all or ¿-active T cell

Inhibition of

Creation of a protective microenvi ronment in the graft

Fig. E3.3. Schematic representation of how tolerance induction to autoantigens might prevent or delay graft rejection. See text for details.

of pathogenic T cells, thereby preventing tissue injury. Overall, the experimental data suggest that one can harness the naturally developing, autoreactive regulatory cell repertoire, and that expansion of these T cells to a sufficient degree, can result in a regulatory immune repertoire capable of controlling or preventing the development of a pathogenic alloimmune response.

Autoimmunity by design as outlined, does not account for the presence of autoantibody-mediated processes, although analogous regulatory features could be envisioned (through controlling complement activation or signaling through inhibitory Fc receptors expressed on macrophages). Overall, while the idea of protective, autoimmunity by design is consistent with much of the published literature, there remain a number of unanswered questions (Table E3.2). The hypothesis would be bolstered by more experimental data clearly identifying the phenotypes, mechanisms of action, and origins of regulatory T cells, and of autoreactive, regulatory T cells in specific. Experiments designed to better test whether the numbers of pathogenic versus tolerogenic, autoreactive T cells affect the threshold for the expression of organ pathology/rejection, as well as experiments focusing on further isolation, characterization and mechanistic analysis of tolerogenic APCs are also needed.

The autoimmunity by design paradigm provides a conceptual framework through which to consider experimental results and requires a shift in thinking about why autoreactive T cells are present in a host. Instead of functioning as escaped prisoners that are dangerous to the community, this hypothesis suggests that autoreactive T cells act more like your friendly, local police department, constantly patrolling the neighborhood for signs of commotion, reinforcing the walls

Table E3.2. Questions raised by the autoimmunity by design theory

• Can naive T cell precursors differentiate into multiple phenotypes of proinflammatory versus regulatory cells? If so, what influences the decision?

• Can one routinely isolate autoreactive regulatory T cells from normal organs?

• Do autoreactive, regulatory T cells proliferate and alter expression of cell surface markers upon activation?

• What signals attract regulatory cells to normal organs and do these signals differ from those that attract proinflammatory cells? Do regulatory T cells cross endothelial cell barriers and if so, how?

• Can autoreactive regulatory T cells be converted into pathogenic proinflammatory T cells or are they at an end-differentiated stage of development?

• Can one alter the expression of protective genes in parenchymal cells and affect the proinflammatory versus tolerant state of the organ?

• Do the relative numbers of regulatory versus proinflammatory autoreactive T cells contribute to the development of inflammation at a given site?

• What are the mechanisms employed by regulatory T cells? Bystander suppression? Prevention of precursor differentiation into proinflammatory effectors? Upregulation of protective genes on parenchymal cells?

• Can certain cells, other than T cells, transfer tolerance? If so, what are the phenotypic markers that define these cells, how are they induced, and how do they function?

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