Accommodation and related conditions in vascularized composite allografts

Abstract

Purpose of review: The outcome of vascularized composite allografts (VCA) often appear unrelated to the presence of donor-specific antibodies (DSA) in blood of the recipient or deposition of complement in the graft. The attenuation of injury and the absence of rejection in other types of grafts despite manifest donor-specific immunity have been explained by accommodation (acquired resistance to immune-mediated injury), adaptation (loss of graft antigen) and/or enhancement (antibody-mediated antigen blockade). Whether and how accommodation, adaptation and/or enhancement impact on the outcome of VCA is unknown. Here we consider how recent observations concerning accommodation in organ transplants might advance understanding and resolve uncertainties about the clinical course of VCA.

Recent findings: Investigation of the mechanisms through which kidney allografts avert antibody-mediated injury and rejection provide insights potentially applicable to VCA. Interaction of DSA can facilitate replacement of donor by recipient endothelial cells, modulate or decrease synthesis of antigen, mobilize antigen that in turn blocks further immune recognition and limit the amount of bound antibody, allowing accommodation to ensue. These processes also can explain the apparent dissociation between the presence and levels of DSA in blood, deposition of C4d in grafts and antibody-mediated rejection. Over time the processes might also explain the inception of chronic graft changes.

Summary: The disrupted tissue in VCA and potential for repopulation by endothelial cells of the recipient establish conditions that potentially decrease susceptibility to acute antibody-mediated rejection. These conditions include clonal suppression of donor-specific B cells, and adaptation, enhancement and accommodation. This setting also potentially highlights heretofore unrecognized interactions between these 'protective' processes.

Figure 1. Mechanisms that could avert antibody-mediated rejection of vascularized composite allografts

Vascularized composite allografts (VCA), like skin grafts, probably evoke powerful donor-specific T cell and B cell responses and production of large amounts of donor specific antibodies (DSA) (a lymphocyte, either T cell or B cell, with antigen receptor is shown in the figure). (A) Direct surgical or spontaneous anastomosis of recipient blood vessels with donor blood vessels should allow DSA to directly contact donor cells, eventuating is antibody-mediated rejection (AMR), as seen in organ transplants. However, AMR is observed less often in VCA than in organ allografts, particularly kidney allografts, and might be less severe. Decreased incidence and/or severity of AMR in VCA might be explained by one or more of several mechanisms. (B) Where the endothelial lining of blood vessels in VCA derives from the recipient (by ingrowth of recipient vessels or migration of endothelial cell precursors), DSA will not bind and rejection will not ensue. Recipient blood vessels can be attacked however by alloreactive T cells recognizing donor peptide associated with self-MHC (not shown). (C) Tissue injury associated with the transplant procedure could liberate donor antigen, which, in sufficient amounts, might interact with B cell antigen receptor causing suppression of function (clonal suppression). The smaller amounts of DSA subsequently produced could cause donor antigen to be modulated or liberated, increasing clonal suppression. The liberated antigen associated with self- or donor-MHC (not shown) might block cognate recognition by alloreactive T cells (enhancement). The smaller amounts of DSA could also act on donor endothelium to induce accommodation (acquired resistance to immune and inflammatory injury). The decrease in donor antigen in the graft owing to adaption and the liberated antigen also weigh toward accommodation since less DSA can bind to donor blood vessels (due to less antigen and/or blocking by free antigen). Interaction of DSA with liberated antigen might also cause formation of immune complexes leading to some apparently reactive conditions of VCA (not shown).