This project focuses on direct comparisons and immunological analyses of humanized immune system (HIS) mice made from fetal vs neonatal human tissue sources. The neonatal HIS model will be optimized to better recapitulate systemic and tissue-specific human innate and adaptive immunity and lymphoid tissue development. Two novel humanized mouse host strains will be developed and evaluated for their ability to generate robust human immune cell engraftment and function without irradiation. The models developed will be assessed by studying T cell-mediated transplant allorejection responses and by examining infectious disease pathology using Epstein Barr Virus (EBV). Dr. Matthew Brown will serve as the PI; the work will be done in collaboration with the University of Massachusetts (Dr. Michael Brehm) and Jackson Laboratory (Dr. Leonard Shultz). Previously cryopreserved fetal tissue in their possession will be used for these studies. No new fetal tissue will be procured for this study.