Project Summary / Abstract The mission of the ITN is to advance the clinical application of immune tolerance by performing high quality clinical trials of emerging therapeutics based upon testable mechanistic hypotheses. The ITN is structured in order to interrogate different diseases across the immunologic spectrum, with integration of innovative clinical studies and cutting edge immunology laboratory analysis. The ITN approach—clinical assessment of novel tolerance therapeutics, while we simultaneously evaluate the cellular, genetic, and immunologic mechanisms of disease and how they are altered in response to therapy—creates a framework for advancing cross-disease and cross-discipline knowledge, all designed to accelerate therapeutic options for major diseases. The existing scientific and operational framework enables the ITN to successfully enhance the development of tolerance therapies in transplantation, autoimmunity, and allergy. ITN has outlined a process to evolve our current strategies into the next generation of planned trials, as well as to operate a nimble, future-focused organization, poised to lead and adopt innovations that are currently unknown. The ITN has a collaborative structure involving hundreds of investigators, advisors, and clinical sites working in tandem with a core group of ITN staff, operating a program that is both scientifically and financially efficient. Several new innovations recently adopted by the ITN encourage widespread involvement from academic investigators, including expanded resource sharing and data sharing operations. With lead institutional commitment from the Benaroya Research Institute and the University of California San Francisco, and participation of more than 20 other major institutions represented in leadership and major advisory roles, the ITN strives to continue to successfully pioneer high impact clinical trials and mechanistic studies in areas of unmet medical need.