Immunological considerations and challenges for regenerative cellular therapies

The central goal of regenerative medicine is to replace damaged or diseased tissue with cells that integrate and function optimally. The capacity of pluripotent stem cells to produce unlimited numbers of differentiated cells is of considerable therapeutic interest, with several clinical trials underway. However, the host immune response represents an important barrier to clinical translation. Here we describe the role of the host innate and adaptive immune responses as triggers of allogeneic graft rejection. We discuss how the immune response is determined by the cellular therapy. Additionally, we describe the range of available in vitro and in vivo experimental approaches to examine the immunogenicity of cellular therapies, and finally we review potential strategies to ameliorate immune rejection. In conclusion, we advocate establishment of platforms that bring together the multidisciplinary expertise and infrastructure necessary to comprehensively investigate the immunogenicity of cellular therapies to ensure their clinical safety and efficacy. In this Review, Petrus-Reurer et al describe the roles of both innate and adaptive immune responses in allogeneic graft rejection, in addition to discuss how such responses are determined by the cellular therapy of interest. They also describe the range of in vitro and in vivo approaches used to examine the immunogenicity of cellular therapies and consider potential confounders and strategies that can be employed to ameliorate immune rejection.