State of the Art: Role of the Dendritic Cell in Induction of Allograft Tolerance

Abstract

Despite decades of research, the induction and maintenance of long-term allograft tolerance without immunosuppression remains an elusive goal in the field of solid organ and cell transplantation. Immunosuppressive medications frequently prevent or minimize acute cellular rejection but have failed to halt antidonor antibody production and chronic organ rejection. Past efforts aimed at promoting lasting allograft tolerance have focused primarily on peripheral T-cell depletion, augmentation of regulatory T cells, or induction via simultaneous hematopoietic stem cell transplantation and facilitation of donor chimerism. So far, none of these methods have led to consistently safe, feasible and long lasting donor organ acceptance. Over the course of the past 4 decades, the study of a unique population of antigen-presenting cells known as dendritic cells has shown promise for breaking new ground in achieving indefinite allograft survival without immunosuppression and its associated adverse effects. In this review, we discuss the discovery and early investigations of dendritic cells and chronicle some of the key studies demonstrating their role in transplantation, particularly in indirect allorecognition, the immunologic pathway thought to drive chronic rejection and perhaps tolerance induction.

Figure 1

Timeline represen;ng changes in the understanding of visceral allograO immunogenicity. (Tx, transplant; DC, dendri;c cell)

Figure 2

Schema;c representa;on of myeloid- (bone marrow) and monocyte-derived dendri;c cell development, including a simplified comparison of surface markers and other characteris;cs present at different stages of matura;on. (imDC, immature dendri;c cell; mDC, mature dendri;c cell; MHC, major histocompa;bility complex; CD, cluster of differen;a;on; IL, interleukin

Figure 3

Schema;c representa;on of the post-transplant immunologic response, from both the direct and indirect pathways of allorecogni;on. (DC, dendri;c cell; Ag, an;gen; MHC, major histocompatability complex; Th1, Type 1 T helper cell; Th2, Tupe 2 T helper cell)

Figure 4

Flow chart comparing the basic func;ons of mature versus immature dendri;c cells and their contribu;ons to immunologic s;mula;on versus tolerance. (DC, dendri;c cell)