E3

Pathogenic Autoreactive Myosin-specific

Myosin-derived P

donor-derived myosin peptides to recipient autoreactive T cells in the proinflammatory environment of the transplant

T cell

Overcomes regulator)' mechanisms in graft and contributes to graft destruction BUT

donor-derived myosin peptides to recipient autoreactive T cells in the proinflammatory environment of the transplant

Protective microenvironment of native heart prevents host heart pathology

Fig. E3.2. Schematic depiction of the development of pathogenic autoreactive T cells following heart transplantation. See text for details.

cells recognize donor-derived antigenic determinants complexed to recipient MHC molecules expressed on recipient APCs.31 This indirect pathway of allorecognition represents the usual method of immune recognition by T cells—the exogenous antigen is engulfed by the host's APCs, processed into peptide fragments, shunted through the MHC processing pathways and expressed on the antigen presenting cell surface. While many of the indirectly presented peptides derive from donor MHC molecules, any antigen found in donor cells (including so-called "minor" antigens and even nonpolymorphic antigens common to both donor and recipient) could theoretically be processed and presented by recipient APCs. The proinflammatory state of the transplanted organ (due, in part to surgical trauma and ischemia reperfusion injury), along with the enormous anti-allograft T cell immune response focused towards donor MHC molecules (direct pathway) could easily overcome the hypothesized tolerogenic state of the donor organ, permitting priming of autoreactive T cells, and facilitating/accelerating the migration to, and pathologic function of these autoreactive T cells in the transplant. The ability of such primed T cells to contribute to destruction of an allograft would also be anticipated, as the autoreactive T cells infiltrating the donor allograft could re-encounter self-antigens expressed on infiltrating self-APCs and mediate local tissue injury through release of pro-inflammatory cytokines, induction of delayed type hypersensitivity reactions and through initiation of other, secondary, macrophage-mediated effector mechanisms.

The experimental data show that despite the development of pathogenic autoimmunity directed towards transplanted organs (including isografts), the autoreactive T cells do not cause injury to the native organs of the recipient (see accompanying articles). The endogenous host tissues seem to maintain a non-pathogenic microenvironment (theoretically due to the reciprocal interactions between regulatory T cells and the host tissue), and an absence of chemoattractant signals to attract pathogenic T cells. Although pathogenic autoreactive T cells are activated as a component of the alloimmune response, these cells seem to be preferentially attracted to the transplanted graft and do not accumulate in the native organ in large numbers. Small numbers of rogue, activated T cells that enter the normal tissue could theoretically be controlled by the permissive/tolerogenic microenvironment, preventing the development of diffuse autoimmune disease in the native tissues. If this hypothesis is true, then expression of inflammatory signals within an otherwise normal organ could precipitate organ-specific autoimmune disease. Indeed, studies in which TNFa was genetically over-expressed in islet cells confirmed that local production of this proinflammatory molecule could result in islet inflammation and diabetes.32 Another potential test of the hypothesis would be to induce injury of the native heart (for example, by ischemia reperfusion via tying off a coronary vessel) at the time of heart allograft placement, with the premise being that the induced injury would result in attraction of primed, autoreactive (i.e., myosin-specific) T cells and thereby precipitate myocarditis of the native heart.

The autoimmunity by design hypothesis additionally provides a potential explanation for the intriguing observation that induction of tolerance to the organ-specific autoantigen prior to transplantation can delay or even prevent rejection of a subsequently placed allograft (Fig. E3.3). Experimental tolerization (for example, by administration of antigen in incomplete Freund's adjuvant) would expand the population of endogenous autoreactive regulatory T cells, creating a permissive microenvironment in the host through interaction with normal host tissues, and may be dependent on T cell mediated induction of "tolerant" APCs. Following transplant surgery, the expanded repertoire of tolerant APCs and regulatory T cells would inhibit priming or effector function of any pathogenic alloreactive T cells (functioning either in the secondary lymphoid organs and/or in the graft). In addition, this increased number of regulatory cells would partially restore the microenvironment of the inflamed graft towards a protective state, thereby raising the threshold number of pathogenic T cells required to mediate graft rejection. Prevention of graft rejection would be thus be dependent on the relative numbers of regulatory cells versus pathogenic T cells infiltrating the graft as well as the phenotype of the graft itself. In some cases (as outlined in the accompanying articles), tolerance induction may sufficiently raise the number of regulatory cells to fully prevent rejection of an allograft. In other situations the induced tolerance to autoantigens may expand the number of regulatory cells but not to a sufficient degree to prevent the eventual effects of a potent alloimmune response (and thus only delay, not prevent rejection). The hypothesis is again supported by recent results in the models of skin graft tolerance,15 autoimmune dia-betes33 and experimental autoimmune encephalomyelitis34 in which expanded populations of regulatory T cells (in some cases shown to be autoreactive) can localize to the target organ and can inhibit the development and effector function

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