In parallel with major recent advances in basic immunology, opportunities for clinical exploitation of this understanding have broadened, as has our ability to perform direct assessment of immunological mechanisms in humans. This is a cornerstone of the Immune Tolerance Network (ITN) approach - clinical assessment of novel tolerance therapeutics, while simultaneously evaluating the cellular, genetic and immunologic mechanisms of disease and how they are altered in response to therapy. In this renewal application, we describe the scientific and operational framework that we propose to enable the ITN to successfully accelerate the development of tolerance therapies in transplantation, autoimmunity, and allergy. We will outline a process to evolve our current strategies into the next generation of planned trials, as well as how we plan to operate a nimble, future-focused organization, poised to lead and adopt future innovations that are currently unknown. We propose 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 will encourage widespread involvement from academic investigators, including expanded resource sharing and data sharing operations. Three major institutions, the Benaroya Research Institute at Virginia Mason, Massachusetts General Hospital, and the University of California, San Francisco, form the administrative backbone for this application, with another twenty institutions represented in leadership and major advisory roles.

Public Health Relevance

The proposed Immune Tolerance Network (ITN) grant addresses major unmet health needs. In the United States, autoimmune diseases affect >5% of the population, and allergic diseases affect another ~15%. Transplantation is a life-saving intervention for organ failure, but it comes with a significant burden and risk, in each area, pre-clinical studies show that immune tolerance should be an achievable therapeutic prospect for many affected individuals. Successful tolerance offers the possibility of long-term freedom from immunosuppressive therapy, bringing a radical improvement in terms of quality of life, disease burden, and health care cost.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Thomas, Leighton A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Benaroya Research Institute at Virginia Mason
United States
Zip Code
Savage, Thomas M; Shonts, Brittany A; Obradovic, Aleksandar et al. (2018) Early expansion of donor-specific Tregs in tolerant kidney transplant recipients. JCI Insight 3:
Santos, Alexandra F; Couto-Francisco, Natália; Bécares, Natalia et al. (2018) A novel human mast cell activation test for peanut allergy. J Allergy Clin Immunol 142:689-691.e9
Newell, Kenneth A; Adams, Andrew B; Turka, Laurence A (2018) Biomarkers of operational tolerance following kidney transplantation - The immune tolerance network studies of spontaneously tolerant kidney transplant recipients. Hum Immunol 79:380-387
Gill, Michelle A; Liu, Andrew H; Calatroni, Agustin et al. (2018) Enhanced plasmacytoid dendritic cell antiviral responses after omalizumab. J Allergy Clin Immunol 141:1735-1743.e9
Renand, Amedee; Shamji, Mohamed H; Harris, Kristina M et al. (2018) Synchronous immune alterations mirror clinical response during allergen immunotherapy. J Allergy Clin Immunol 141:1750-1760.e1
Weir, Gordon C; Ehlers, Mario R; Harris, Kristina M et al. (2018) Alpha-1 antitrypsin treatment of new-onset type 1 diabetes: An open-label, phase I clinical trial (RETAIN) to assess safety and pharmacokinetics. Pediatr Diabetes 19:945-954
Harris, Kristina M; Lu, Tingting; Lim, Noha et al. (2018) Challenges and Opportunities for Biomarkers of Clinical Response to AHSCT in Autoimmunity. Front Immunol 9:100
du Toit, George; Sayre, Peter H; Roberts, Graham et al. (2018) Allergen specificity of early peanut consumption and effect on development of allergic disease in the Learning Early About Peanut Allergy study cohort. J Allergy Clin Immunol 141:1343-1353
Sykes, Megan (2018) Immune monitoring of transplant patients in transient mixed chimerism tolerance trials. Hum Immunol 79:334-342
Feng, Sandy; Bucuvalas, John C; Demetris, Anthony J et al. (2018) Evidence of Chronic Allograft Injury in Liver Biopsies From Long-term Pediatric Recipients of Liver Transplants. Gastroenterology 155:1838-1851.e7

Showing the most recent 10 out of 55 publications