Immune Response of Transplanted Kidney Tissues Assembled from Organoid Building Blocks

The increasing scarcity of organs and the significant morbidity linked to dialysis requires the development of engineered kidney tissues from human-induced pluripotent stem cells. To accomplish this, integrative approaches that synergize scalable kidney organoid differentiation, tissue biomanufacturing, and comprehensive assessment of their immune response and host integration are essential. Here, we create engineered human kidney tissues composed of kidney organoid building blocks (OBBs) and transplant them into mice reconstituted with allogeneic human immune cells. We assess their host vascular integration, in vivo maturation, and their ability to trigger human immune responses. Tissue-infiltrating human immune cells are composed of effector T cells and innate cells. This immune infiltration leads to kidney tissue injury characterized by reduced microvasculature, enhanced kidney cell apoptosis, and a unique inflammatory gene signature comparable to kidney organ transplant rejection in humans. Upon treatment with the immunosuppressive agent Rapamycin, the induced immune response is greatly suppressed. Our model serves as a translational platform to study engineered kidney tissue immunogenicity and develop novel therapeutic targets for kidney rejection. ### Competing Interest Statement J.A.L. serves on the Scientific Advisory Board of Trestle Biotherapeutics. R.M. is an inventor on a patent related to this work filed by the President and Fellows of Harvard College and Mass General Brigham (PCT/US2018/036677 licensed to Trestle Biotherapeutics). R.M. holds a stock option in Trestle Biotherapeutics. R.M. served as a consultant to Toray Industries, and Ajinomoto.