JO VOL. 12 N. 1, Jan-Jun, 2020
BONE MARROW AND IMMUNITY IN HUMANIZED MICE
Author: R. Ross
Affiliation: University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
Transplant rejection is an adverse effect that involves the bone marrow and often leads to death. For this reason the cells or the organ to be transplanted need careful treatment. Stem cell therapy today is very promising for the treatment of diseases difficult to cure with drug therapies (1). Allogeneic transplantation, for example that with blood cells, can present serious immune reactions, with damage to organs and tissues. Many cytokines are secreted in the Graft-versus-host reaction involving T cells, where donor cells attack host cells and organs (2). These important and useful studies are carried out in mice to which different types of cells are injected – experiments which are not possible in humans. Human lymphocytes implanted in the mouse lead to death of the transplanted animal, but in humanized mice the reactions are very different and milder, and represent an ideal model for the study of the immune reaction (3). Therefore, humanized animal models are very important for the study of transplant rejection. Mouse models that receive human cells can give important immune and inflammatory reactions that can confuse the researcher in reaching the final goal (4). Now, even more in biomedical research, humanized mice are used to avoid or alleviate these adverse reactions. Humanized mice are made with immunodeficient mice which are injected with human CD34+ haematopoietic stem cells, normally coming from the human umbilical cord, with the addition of the cytokine GM-CSF (granulocyte – macrophage colony-stimulating factor) (1). The graft depends on various factors such as the injection route, the origin of the donor, the murine strain, etc. (2) Cytokine treatment of humanized mice allows the study of cell differentiation, in particular mouse myeloid cells. However, immune cell reconstitution in the humanized mouse is very low, such as grafting CD68+ macrophages (1). However, recently, new strains of humanized mice seem to be better at producing hematopoietic cells important for immune responses (5). Adaptive immune responses are well studied in humanized mice and allow a beneficial immune study. CD4 and CD8 cells are fairly well tolerated and engrafted, and the donor cell memory is sufficiently conserved in the humanized mouse (6). Transgenic mice can express human leukocyte antigen (HLA) that does not change in maturation of T cells, although there is a certain difference related to different HLA (7). The engraftment of human cells in humanized mice leads to a cytokine reaction between those produced by human cells and those generated by the mouse, influencing cell differentiation.
- Skelton JK, Ortega-Prieto AM, Dorner M. A Hitchhiker’s guide to humanized mice: new pathways to studying viral infections. Immunology 2018; 154(1):50-61.
- Huang F, Cao FL, Zheng SG. Update of humanized animal disease models in studying Graft-versus-host disease. Hum Vaccin Immunother 2018; 14(11):2618-23.
- Laudanski K, Stentz M, DiMeglio M, Furey W, Steinberg T, Patel A. potential pitfalls of the humanized mice in modeling sepsis. Int J Inflam 2018; 2018:6563454.
- Campbell KS, Cohen AD, Pazina T. Mechanisms of NK cell activation and clinical activity of the therapeutic SLAMF7 antibody, elotuzumab in multiple myeloma. Front Immunol 2018; 9:2551.
- Jewett A, Kos J, Fong Y, et al. NK cells shape pancreatic and oral tumor microenvironments; role in inhibition of tumor growth and metastasis.Semin Cancer Biol 2018; 53:178-88.
- Kozlowska AK, Kaur K, Topchyan P, Jewett A. Novel strategies to target cancer stem cells by NK cells; studies in humanized mice. Front Biosci (Landmark Ed) 2017; 22:370-84.
- Morton JJ, Bird G, Refaeli Y, Jimeno A. Humanized mouse xenograft models: narrowing the tumor-microenvironment gap. Cancer Res 2016; 76(21):6153-58.