Dendritic Cells in Xenotransplantation: Shaping the Cellular Immune Response Toward Tolerance

The molecular barriers that cause acute xenograft rejection have been identified and addressed by generating genetically modified (GM) animals, knocked out for specific xenoantigens (xenoAgs), and expressing regulatory molecules for both complement and coagulation pathways among others. The focus of xenotransplantation research now lies in delayed xenograft rejection. Dendritic cells (DC) are a specific subpopulation of professional antigen-presenting cells (APC) that play a crucial role in the context of organ transplantation. DCs, originating from both the xenograft and the recipient, have the capacity to present xenoAgs to the recipient's immune system via their respective major histocompatibility complex (MHC) molecules leading to rejection. These processes are known as direct and indirect presentation, respectively. However, under certain microenvironmental conditions, DC develops into anti-inflammatory regulatory cells that can induce immunological tolerance. The purpose of this review is to summarize current knowledge on the general characteristics and functions of DC from species relevant to xenotransplantation, specifically humans, non-human primates (NHP), and pigs. It will also cover the process of xenoAg presentation, different methods for generating DC with regulatory properties in vitro, and finally, discuss the current strategies for using regulatory DC to improve xenograft acceptance by inducing tolerance.