On December 18, 2018, NIAID, in coordination with the NIH Office of the Director and HHS, organized a workshop to assess recent advances and opportunities in the development and use of humanized immune system (HIS) mouse models, in which the immune system of the mouse is partially replaced with human immune cells and tissues. Participants included leading scientists in the fields of immune system development and function, transplant immunology, autoimmunity, and infectious disease research. Adm Brett Giroir, Assistant Secretary of HHS, welcomed the participants and described HHS interest in this area, including a clearer understanding of the limitations and adequacy of existing HIS models, and the possibility of developing scientifically validated alternatives to the use of human fetal tissue. Dr. Daniel Rotrosen, Director of the Division of Allergy, Immunology and Transplantation at NIAID, provided an overview of the workshop goals and expected outcomes, including: evaluation of the features, strengths and limitations of current HIS mouse models; procedures to compare HIS models made from fetal and non-fetal tissue sources; and studies that would be required to fully characterize and standardize these models. Dr. Lawrence Tabak, NIH Principal Deputy Director, provided brief introductory comments on behalf of NIH.
Dr. Leonard Shultz provided a comprehensive summary of HIS mouse model development and usage from 1988 to the present. In following breakout sessions, participants discussed the strengths and limitations of various HIS mouse models and provided opinions on ways to optimize HIS models for the development of vaccines and therapeutics for infectious and immune-mediated diseases and cancer. The meeting participants reconvened for reports from the two breakout groups and a final discussion, that resulted in the following summary points:
- Major scientific advances have been made in understanding infectious disease pathogenesis and development of therapeutics using HIS mouse models made with human fetal tissues.
- No single humanized immune system model is universally appropriate or optimal for all applications.
- Various models can recapitulate key aspects of human T cell immunity; existing models are less able to recapitulate human innate immunity and antibody responses regardless of tissue source. Improvements in modeling antibody responses should be a focus of future work and may be particularly important for advances in vaccinology; and in modeling infectious, autoimmune, and allergic diseases.
- Few direct comparisons have been conducted of HIS mice derived using fetal vs. non-fetal human tissue sources.
- Meeting participants included investigators working on fetal tissue-derived and non-fetal tissue-derived HIS models. Considering published data and other information shared at this meeting, participants expressed the opinion that fetal tissue-derived HIS models remain the “gold standard” to which other model systems should be compared. This preference is based on the preponderance of data indicating superior engraftment, differentiation, survival and function of the adaptive immune cells (particularly T cells) in fetal tissue-derived models.
- Following the breakout sessions, there was strong opinion that work should proceed on a variety of models derived with fetal tissues or from alternative sources.