Development of a Human Adaptive Immune System in Cord Blood Cell-Transplanted Mice

Abstract

Because ethical restrictions limit in vivo studies of the human hemato-lymphoid system, substitute human to small animal xenotransplantation models have been employed. Existing models, however, sustain only limited development and maintenance of human lymphoid cells and rarely produce immune responses. Here we show that intrahepatic injection of CD34+ human cord blood cells into conditioned newborn Rag2-/-gammac-/- mice leads to de novo development of B, T, and dendritic cells; formation of structured primary and secondary lymphoid organs; and production of functional immune responses. This provides a valuable model to study development and function of the human adaptive immune system in vivo.

EBV-Induced Human CD8+ NKT Cells Synergise CD4+ NKT Cells Suppressing EBV-Associated Tumours Upon Induction of Th1-Bias

“…The challenge was repeated once after 6 days. The hu-thym-SCID chimaeras were maintained for 4 weeks (unless otherwise stated) (22). In some cases, CD4 + or/and CD8 + NKT cells (1  10 5 cells/mouse) were purified from thymi of EBV-exposed hu-thym-SCID chimaeras (at week 4 post-establishment), mixed with syngeneic CD3 + CD56 -CD161 -T cells (2  10 6 cells/mouse) purified from the spleens of EBV-exposed hu-thym-SCID chimaeras and antigen presenting cells (DCs, 0.5  10 6 cells/mouse), and i.v.…”

Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

“…The recent advances in the development of HIS mice provide a new model to experimentally dissect human lymphocyte biology that may eventually allow us to bridge the knowledge gap between murine and human in vivo studies of immune responses. One welldescribed HIS mouse model involves engraftment of newborn Balb/c Rag2 À/À g c À/À mice with human fetal liver or cord blood haematopoietic stem cells (HSCs), which seed the murine BM and thymus and in turn differentiate into an almost complete spectrum of mature human myeloid and lymphoid cell subsets [1][2][3]. Human B-cell development predominates in this model, with T cells encompassing o10% of the peripheral lymphocyte pool [1][2][3].…”

“…One welldescribed HIS mouse model involves engraftment of newborn Balb/c Rag2 À/À g c À/À mice with human fetal liver or cord blood haematopoietic stem cells (HSCs), which seed the murine BM and thymus and in turn differentiate into an almost complete spectrum of mature human myeloid and lymphoid cell subsets [1][2][3]. Human B-cell development predominates in this model, with T cells encompassing o10% of the peripheral lymphocyte pool [1][2][3]. The reasons for the reduced T-cell homeostasis is not known, but could involve central and/or peripheral mechanisms.…”

“…turnover rate yet fail to accumulate [1][2][3][4][5]. On the other hand, interaction of haematopoietic precursors with murine thymic epithelial cell (TEC) ligands or soluble factors during thymopoiesis and subsequent selection of T cells on murine major histocompatibility complexes (MHC) may generate suboptimal signals for T-cell maintenance.…”

“…Mice were maintained in isolators with autoclaved food and water. Mice with a HIS were generated as previously described [1][2][3]40]. Briefly, newborn (3-5-day-old) mice received sub-lethal (3.3 Gy) total body irradiation from a Cs source, and were injected intra-hepatic (i.h.)…”