Table 2.

Remaining challenges and opportunities to address these challenges

Challenge	Opportunity
Many mouse cytokines do not fully support human lymphoid and myeloid development	Generate human cytokine transgenic and knockout mice, delivery of cytokines using viral vectors
Human mature T cell engraftment results in xenogeneic GVHD	Recipient MHC class I/II knockouts
Thymus education of human T cells occurs in the context of mouse MHC molecules resulting in H2-restricted human T cells	HLA class I and II transgenic mice in Hu-SRC-SCID model or use BLT model
Sensitivity to genotoxic drugs and radiation therapy	Use of Rag1null or Rag2null mice rather than Prkdcscid mice
Absence of hemolytic complement in immunodeficient mice on a NOD background due to lack of functional C5	Replace defective NOD Hc gene with functional C5 complement gene
Remaining host innate immunity	Further genomic editing to knockout genes contributing to innate immunity
Impaired humoral immune responses	Provide human growth factors needed for optimal T cell, B cell, and APC development and function Devise approaches for optimizing lymph node development and lymphoid architecture in IL2rgnull mice
Distinguish human from mouse stroma in recipients of human tissue grafts	eGFP transgenic mice