Upload
donald-e-mosier
View
216
Download
1
Embed Size (px)
Citation preview
Introduction: Humanizing the mouseDonald E. Mosier
THIS VOLUME SUMMARIZES almost a decade of progressin refining xenotransplant models for studyinghuman hematopoietic or lymphoid cell function inimmunodeficient mice. Three distinct protocols, withminor variations, for generating these models haveproven useful. Mice with the severe combined immu-nodeficiency (SCID) mutation are the most populartransplant recipients. Human hematopoietic progeni-tors contained in fetal liver or bone tissue grafts arecoimplanted with fetal thymus tissue to create theSCID-hu model. This model allows continued differ-entiation of lymphoid and myeloid lineages for up toa year, and supports differentiation of injected CD34+
human progenitor cells into mature lymphocytes.Alternatively, purified human hematopoietic precur-sor cells can be injected into SCID mice with orwithout human bone marrow stromal cells or hemato-poietic growth factors to create a SCID mouserepopulating cell assay. One important goal of thesemodels is to generate a biologic assay for the humanstem cell, which previously has been assessed by avariety of in-vitro methods with severe limitations.Serial transplantation of SCID repopulating humanprogenitors with successful long term repopulation ofsecondary recipients is tantalizingly close, yet thereare important differences of opinion about whetherthis has or has not been achieved. If such a cell is notthe long-term culture initiating cell, then the SCIDmodels will have provided an invaluable service indefining the elusive human stem cell. The thirdxenotransplant model consists of injecting maturehuman lymphoid cells (most commonly obtainedfrom peripheral blood) into SCID mice to create thehu-PBL-SCID model. This is most appropriately char-acterized as an adoptive transfer system modeled onthe pioneering work of Avrion Mitchison in transfer-ring mouse lymphocytes to lethally irradiated recipi-
ents. The PBL graft is not self renewing and functionsfor a limited time span, generally less than six months.The mature human T lymphocytes are not tolerant tomouse xenoantigens, as are fetal T cells maturing inthe mouse environment, and some degree of graft-versus-host reaction appears to favor survival of thehuman PBL, while too much xenoreactivity can leadto clinical graft-versus-host disease and death. SCIDmice are almost totally devoid of T and B lymphocytes,but they have normal levels of natural killer cells andother elements of the innate immune system. Thesecells influence the success of the PBL graft and haveled to attempts to modify the recipient to increase thenumber of human cells engrafted and the duration ofengraftment. Immune responses in the hu-PBL-SCIDmodel are generally secondary responses to antigensencountered by the PBL donor, although someprimary antibody responses have been reported.
This volume attempts to highlight both the pro-gress made with these models, and the currentproblems that require further work. Both SCID-huand hu-PBL-SCID mice have been very useful forstudies of human immunodeficiency virus (HIV)infection, so, whatever their limitations, they havemore than fulfilled the original expectations thatmotivated their creation. The better definition of therepopulating cell for SCID-hu mice and extending theduration of function are important problems. Under-standing the biologic consequences of xenoreactivityin the hu-PBL-SCID model is essential, and improvingthe model to more readily obtain primary cellular andhumoral immune responses remains an importantpractical need. As xenotransplantation and genetherapy inexorably approach clinical application, theneed for predictive animal models grows daily. Theability to craft the ideal mouse xenotransplant recipi-ent with gene knockout and transgenic technology isthe next step in overcoming the current limitations ofthese models. The contributions in this volumerepresent an excellent starting point for movingtowards that goal.From the Department of Immunology, Scripps Research Institute,
La Jolla, CA, USA©1996 Academic Press Ltd
seminars in IMMUNOLOGY, Vol 8, 1996: p 185
185