Immune recognition and rejection of allogeneic skin grafts

Abstract

The transplantation of allogeneic skin grafts is associated with a potent inflammatory immune response leading to the destruction of donor cells and the rejection of the graft. Shortly after transplantation, skin dendritic cells (DCs) migrate out of the graft through lymphatic vessels and infiltrate the recipient's draining lymph nodes where they present donor antigens via two mechanisms: the direct pathway, in which T cells recognize intact donor MHC antigens on donor DCs; and the indirect pathway, involving T-cell recognition of donor peptides bound to self-MHC molecules on recipient DCs. Some recent studies have suggested that T cells can become activated via recognition of donor MHC molecules transferred on recipient antigen-presenting cells (semidirect pathway). Activation of T cells via direct or indirect allorecognition is sufficient to trigger acute rejection of allogeneic skin grafts. In addition, allospecific antibodies contribute to the rejection process either by killing allogeneic targets in a complement-dependent fashion or by opsonizing donor cells and forming immune complexes. Finally, several studies demonstrate that NK cells, activated due to missing self-MHC class I molecules on allogeneic cells, are involved in allogeneic skin graft rejection via direct killing of donor cells and through the production of proinflammatory cytokines including IFN-γ and TNF-α.

Figure 1. Antigen-presenting cell and T-cell trafficking following skin transplantation

At 3–4 days following placement of skin allografts, when the blood and lymphatic circulation is restored, graft APCs (bone marrow-derived MHC class II⁺ cells) migrate to the draining lymph nodes of the recipient where they can activate T cells through the direct pathway. Once activated, these T cells can now migrate to the site of the graft through the blood vasculature and participate in graft rejection. APC: Antigen-presenting cell; DC: Dendritic cell; LC: Langerhans cell; LN: Lymph node.

Figure 2. Pathways of T-cell allorecognition

Following skin transplantation, recipient alloreactive T cells can be activated to donor antigens presented via three distinct pathways: the direct pathway, in which T cells recognize intact allo-MHC molecules on donor APCs; the indirect pathway, in which recipient T cells recognize processed donor antigens (MHC and minor antigen peptides) presented by self-MHC molecules on host APCs; and the semidirect pathway, in which recipient T cells can be activated by acquired donor MHC molecules displayed on recipient APCs. APC: Antigen-presenting cell; TCR: T-cell receptor.

Figure 3. Alloresponses mediated by B cells and NK cells after skin transplantation

Following skin transplantation, B cells and NK cells can contribute to alloimmunity and allograft rejection via several mechanisms. Antidonor antibodies can directly kill donor cells via complement-dependent cytotoxicity or opsonize allogeneic cells (i.e., target cells for ADCC). NK cells can kill donor cells lacking expression of self-MHC class I molecules (missing self), or can contribute to DTH reactions and activation of cytolytic cells by producing proinfammatory cytokines including IFN-γ and TNF-α. ADCC: Antibody-dependent cell-mediated cytotoxicity; APC: Antigen-presenting cell; DTH: Delayed type hypersensitivity.