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Generation of primary antigen-specific human T- and B-cell responses in immunocompetent SCID-hu mice

Nature Medicine volume 6, pages 103–106 (2000)Cite this article

The development and effector functions of human leukocytes are regulated by a complex network of interactions mediated through the binding of specific receptors on these cells with soluble or membrane-bound ligands present in the microenvironment. The complexity of such interactions cannot be completely mimicked in vitro, and therefore preclinical testing of vaccines, pathogens and new therapeutic compounds modulating the immune system has relied extensively on the use of rodents and nonhuman primates. Unfortunately, findings in these animal models cannot always be extrapolated to man. Therefore, attempts have been made to reconstitute a functional human immune system in mice with severe combined immunodeficiency1 (SCID mice). These mice have a defect in their DNA recombinase system, which renders them unable to express rearranged antigen receptors. Consequently, SCID mice lack functional T and B cells and are therefore excellent recipients for xenografts of human cells2,3 and tissues4 (SCID-hu mice).

Although the current SCID-hu mouse models are excellent for studying human lymphopoiesis and hematopoiesis5,6 they are not suitable for the induction of primary immune responses after immunization. SCID mice transplanted with human fetal thymus and liver under the kidney capsules sustain human T lymphopoiesis for more than 1 year, but do not generate mature B cells5,7. In contrast, SCID mice transplanted with human fetal bones generate human B lymphocytes and cells of the myeloerythroid lineages, but not T cells7,8. Both mature human T and B lymphocytes, as well as macrophages and other cells derived from myeloid and erythroid lineages, develop in SCID mice simultaneously transplanted with human fetal thymus and bone9. These last SCID-hu mice generate all classes of human Ig, indicating that the different human leukocyte populations in these mice interact in response to environmental antigens and induce B cells to undergo Ig switching9. Although natural immune responses could be measured in vivo , extensive efforts to immunize these mice actively, including administration of different antigens, or peptide-loaded autologous dendritic cells in the presence of different adjuvants using various routes of immunization, have failed to induce detectable antigen-specific antibody production (J.M.C, unpublished data). These results indicate that transplantation of liver, thymus and bone provides SCID mice with an environment capable of maintaining human hematopoiesis, but these human hematopoietic tissues are not sufficient to support the development of human immune responses after immunization. We therefore investigated whether transplantation of additional, non-hematopoietic human tissues was necessary to recruit, activate and expand the relevant human leukocyte populations involved in the generation of primary human T cell-dependent B-cell responses.

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Figure 1: Histological analysis of human Sk-LN grafts of SCID-hu IC mice, 3 months after transplantation.
Figure 2: Histological analysis of human Sk-LN grafts of SCID-hu IC mice after immunization with TT.
Figure 3: Histological analysis of the B-cell populations in the Sk-LN grafts of SCID-hu IC mice after immunization with TT.
Figure 4: Antibody responses in SCID-hu IC mice.
Figure 5: TT-specific proliferation of T-cell lines isolated from the Sk-LN grafts of SCID-hu IC mice immunized with TT.

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Acknowledgements

We thank I. Lindley, Novartis Research Institute, for critical reading of the manuscript. DNAX Research Institute of Molecular & Cellular Biology is supported by Schering-Plough Corporation.

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Authors and Affiliations

  1. Department of Immunology, Novartis Research Institute, Brunner Strasse 59, Vienna, A-1235, Austria

    José M. Carballido, Nicole Carballido-Perrig & Jan E. de Vries

  2. Department of Human Immunology, DNAX Research Institute of Molecular and Cellular Biology, 901 California Ave, Palo Alto, 94304-91104, California, USA

    Reiko Namikawa & Svetlana Antonenko

  3. Telethon Institute for Gene Therapy, Hospital San Raffaelle, Via Olgettina 58, Milan, I-20132, Italy

    Maria-Grazia Roncarolo

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  1. José M. Carballido
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Correspondence to José M. Carballido or Jan E. de Vries.

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Carballido, J., Namikawa, R., Carballido-Perrig, N. et al. Generation of primary antigen-specific human T- and B-cell responses in immunocompetent SCID-hu mice. Nat Med 6, 103–106 (2000). https://doi.org/10.1038/71434

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