Overview:

The ITN has a unique mandate, namely to focus on immune tolerance, distinct from immunosuppression and immune modulation strategies, across a broad range of medical/surgical disciplines—transplantation, autoimmunity, and allergy. Over 175 clinical sites on 3 continents are involved with the ITN in this effort, as are thousands of human subjects and numerous clinical and laboratory investigators. Success in clinical trials of tolerance therapies is measured by gaining new insight into the immunologic mechanisms of clinical tolerance, drug action and/or disease that help explain the clinical shortcomings, guide next generation therapeutic development, identify subpopulations of sensitive individuals, or provide the basis for new surrogate/biomarkers of tolerance or disease. This philosophy underpins the ITN’s biomarker efforts. But there are significant clinical challenges: the lack of well-defined markers of immune system unresponsiveness; the inability to routinely sample some in vivo sites of immune activity (i.e., sampling is often limited to the blood); difficulty in correctly evaluating the clinical impact of tolerance-promoting agents where a background of immunosuppression is ethically necessary; the design of drug withdrawal studies in which no reliable markers of tolerance yet exist; and in some cases the inability to distinguish a specific immune response in diseased versus normal individuals. Such substantial challenges require a sophisticated, flexible and comprehensive approach that guidesthe ITN in designing its technological and operational capabilities and in turn permits the investigation of the mechanisms of tolerance in humans. The infrastructure developed by the ITN supports the integration of mechanistic studies into each clinical trial -- acquiring multiple clinical specimens at multiple time-points, applying a wide range of assays, each standardized and optimized for these human specimens, and integrating immunologic, cellular and genetic hypotheses concurrently in a highly quality controlled environment. This talk will describe the mechanistic assay infrastructure that the ITN has built to develop and conduct integrated biomarker and mechanistic studies. This includes a broad range of activities related to mechanistic assays, such as: development of mechanistic study plans and associated specimen collection tables; identification, validation and monitoring of ITN core facilities; management of ITN specimen tracking and storage, supporting data systems; clinical site training and assay kit development; and managing and monitoring mechanistic assay quality assurance (QA) / quality control (QC). Examples will be given; successes and cautionary tales.