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A mightier mouse with human adaptive immunity

Nature Biotechnology volume 22, pages 684–685 (2004)Cite this article

Since the pioneering studies of Mosier et al.2 and McCune et al.3, stepwise progress has been made in generating chimeras in which the human immune system and hematopoiesis can be reconstituted and studied in a mouse. The original protocol of transplanting human peripheral blood lymphocytes (Hu-PBL) into severe combined immunodeficient (SCID) mice (to create so-called Hu-PBL-SCID mice) was quickly followed by attempts to increase the rate of successful xenogeneic engraftment through the use of alternative sources of human tissue, including fetal liver cells, fetal or adult bone marrow, fetal thymus and fetal lymph nodes. These initial studies identified the presence of a pluripotent CD34+ stem cell isolated from either human adult bone marrow or umbilical cord blood that provides long-term multilineage capacity when injected intravenously and is therefore referred to as the 'SCID repopulating cell' (SRC)4,5. Eventually, combining the scid mutation with the nonobese diabetic (NOD) mouse strain (NOD/SCID) was found to significantly increase the percentage of engrafted cells6,7,8, establishing this system as the model of choice.

As these mice suffered from a high incidence of thymic lymphomas, residual natural killer cell activity as well as spontaneous rearrangement in the murine lymphocytes that limited their applications, alternative mice strain combinations continued to be explored. NOD/SCID bred to β2 microglobulin knockout mice (bm2−/−)9 provided one such improved combination; and later, a strain in which the common cytokine receptor gamma chain knockout (γc−/−) mouse was backcrossed to the NOD/SCID mouse10 offered superior engraftment capacity. In parallel, the double-mutant mice combining the gene encoding recombinase activating gene 2 (RAG)-2 and common cytokine receptor gamma chain deficiencies (RAG2−/−γc−/−) were found to be a viable alternative11. These RAG2−/−γc−/− mice exhibit an alymphoid phenotype with no spontaneous tumor formation and acceptable hematopoietic engraftment following intravenous injection of hematopoietic stem cells that can be further enhanced by administration of exogenous human cytokines12.

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Figure 1: Model developed by Traggiai et al. permitting organogenesis and consequent human hematopoietic cell engraftment in mice with transplanted cord blood.

R. Henretta

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  1. NovImmune SA, 64 avenue de la Roseraie, Geneva, CH-1205, Switzerland

    Marie H Kosco-Vilbois

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  1. Marie H Kosco-Vilbois
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Kosco-Vilbois, M. A mightier mouse with human adaptive immunity. Nat Biotechnol 22, 684–685 (2004). https://doi.org/10.1038/nbt0604-684

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