Abstract
Immunodeficient mice have been used as recipients of human peripheral blood mononuclear cells (PBMC) for in vivo analyses of human xeno-graft-versus-host disease (GVHD). This xeno-GVHD model system in many ways mimics the human disease. The model system is established by intravenous or intraperitoneal injection of human PBMC or spleen cells into unconditioned or irradiated immunodeficient recipient mice. Recently, the development of several stocks of immunodeficient Prkdc scid (scid) and recombination activating 1 or 2 gene (Rag1 or Rag2) knockout mice bearing a targeted mutation in the gene encoding the IL2 receptor gamma chain (IL2rγ) have been reported. The addition of the mutated IL2rγ gene onto an immunodeficient mouse stock facilitates heightened engraftment with human PBMC. Stocks of mice with mutations in the IL2rγ gene have been studied in several laboratories on NOD-scid, NOD-Rag1 null, BALB/c-Rag1 null, BALB/c-Rag2 null, and Stock-H2d-Rag2 null strain backgrounds. Parameters to induce human xeno-GVHD in H2d-Rag2 null IL2rγ null mice have been published, but variability in the frequency of disease and kinetics of GVHD were observed. The availability of the NOD-scid IL2rγ null stock that engrafts more readily with human PBMC than does the Stock-H2d-Rag2 null IL2rγ null stock should lead to a more reproducible humanized mouse model of GVHD and for the use in drug evaluation and validation. Furthermore, GVHD in human PBMC-engrafted scid mice has been postulated to result predominately from a human anti-mouse major histocompatibility complex (MHC) class II reactivity. Our recent development of NOD-scid IL2rγ null β2m null and NOD-scid IL2rγ null Ab null stocks of mice now make it possible to investigate directly the role of host MHC class I and class II in the pathogenesis of GVHD in humanized mice using NOD-scid IL2rγ null stocks that engraft at high levels with human PBMC and are deficient in murine MHC class I, class II, or both classes of MHC molecules.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Alderuccio, F., Siatskas, C., Chan, J., Field, J., Murphy, K., Nasa, Z. and Toh, B. H. (2006). Haematopoietic stem cell gene therapy to treat autoimmune disease. Curr. Stem Cell Res. Ther. 1: 279–287.
Passweg, J. and Tyndall A. (2007). Autologous stem cell transplantation in autoimmune diseases. Semin. Hematol. 44: 278–285.
Ringden, O. and Le Blanc, K. (2005). Allogeneic hematopoietic stem cell transplantation: state of the art and new perspectives. APMIS 113: 813–830.
Welniak, L. A., Blazar B. R. and Murphy W. J. (2007). Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu. Rev. Immunol. 25: 139–170.
Demirer, T., Barkholt, L., Blaise, D., Pedrazzoli, P., Aglietta, M., Carella, A. M., Bay, J. O., Arpaci, F., Rosti, G., Gurman, G., Niederwieser, D. and Bregni, M. (2008). Transplantation of allogeneic hematopoietic stem cells: an emerging treatment modality for solid tumors. Nat. Clin. Pract. Oncol. 5: 256–267.
Bhatia, M. and Walters, M. C. (2008). Hematopoietic cell transplantation for thalassemia and sickle cell disease: past, present and future. Bone Marrow Transplant. 41: 109–117.
Lebensburger, J. and Persons, D. A. (2008). Progress toward safe and effective gene therapy for beta-thalassemia and sickle cell disease. Curr. Opin. Drug Discov. Devel. 11: 225–232.
Pinto, F. O. and Roberts, I. (2008). Cord blood stem cell transplantation for haemoglobinopathies. Br. J. Haematol. 141: 309–324.
Kawase, T. Matsuo, K., Kashiwase, K., Inoko, H., Saji, H., Ogawa, S., Kato, S., Sasazuki, T., Kodera, Y. and Morishima, Y. (2008). HLA mismatch combinations associated with decreased risk of relapse: implications for molecular mechanism. Blood. On line publication, December, 2008.
Gale, R. P., Horowitz, M. M. and Butturini, A. (1991). Autotransplants in acute leukaemia. Br. J. Haematol. 78: 135–137.
Porter, D. and Levine, J. E. (2006). Graft-versus-host disease and graft-versus-leukemia after donor leukocyte infusion. Semin. Hematol. 43: 53–61.
Foss, F. M. (2006). The role of purine analogues in low-intensity regimens with allogeneic hematopoietic stem cell transplantation. Semin. Hematol. 43: S35–S43.
Mosier, D. E., Gulizia, R. J., Baird, S. M. and Wilson, D. B. (1988). Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 335: 256–259.
Mosier, D. E., Baird, S. M. and Kirven, M. B. (1990). EBV-associated B-cell lymphomas following transfer of human peripheral blood lymphocytes to mice with severe combined immune deficiency. Curr. Top. Microbiol. Immunol. 166: 317–323.
Tary-Lehmann, M., Lehmann, P. V., Schols, D., Roncarolo, M. G. and Saxon, A. (1994). Anti-SCID mouse reactivity shapes the human CD4+ T cell repertoire in hu-PBL-SCID chimeras. J. Exp. Med. 180: 1817–1827.
Tary-Lehmann, M. and Saxon, A. (1992). Human mature T cells that are anergic in vivo prevail in SCID mice reconstituted with human peripheral blood. J. Exp. Med. 175: 503–516.
Hoffmann-Fezer, G., Gall, C., Zengerle, U., Kranz, B. and Thierfelder, S. (1993). Immunohistology and immunocytology of human T-cell chimerism and graft-versus-host disease in SCID mice. Blood 81: 3440–3448.
Shultz, L. D., Schweitzer, P. A., Christianson, S. W., Gott, B., Schweitzer, I. B., McKenna, S., Mobraaten, L., Rajan, T. V., Greiner, D. L. and Leiter, E. H. (1995). Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J. Immunol. 154: 180–191.
Christianson, S. W., Greiner, D. L., Hesselton, R. M., Leif, J. H., Wagar, E. J., Schweitzer, I. B., Rajan, T. V., Gott, B., Roopenian, D. C. and Shultz, L. D. (1997). Enhanced human CD4+ T cell engraftment in b2-microglobulin-deficient NOD-scid mice. J. Immunol. 158: 3578–3586.
Nervi, B., Rettig, M. P., Ritchey, J. K., Wang, H. L., Bauer, G., Walker, J., Bonyhadi, M. L., Berenson, R. J., Prior, J. L., Piwnica-Worms, D., Nolta, J. A. and DiPersio, J. F. (2007). Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID beta2mnull mice. Exp. Hematol. 35: 1823–1838.
Shultz, L. D., Ishikawa, F. and Greiner, D. L. (2007). Humanized mice in translational biomedical research. Nat. Rev Immunol. 7: 118–130.
Cao, X., Shores, E. W., Hu-Li, J., Anver, M. R., Kelsall, B. L., Russell, S. M., Drago, J., Noguchi, M., Grinberg, A., Bloom, E. T., Paul, W. E., Katz, S. I., Love, P. E. and Leonard, W. J. (1995). Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2: 223–238.
van Rijn, R. S., Simonetti, E. R., Hagenbeek, A., Hogenes M. C., de Weger, R. A., Canninga-van Dijk, M. R., Weijer, K., Spits, H., Storm, G., van Bloois, L., Rijkers, G., Martens, A. C. and Ebeling, S. B. (2003). A new xenograft model for graft-versus-host disease by intravenous transfer of human peripheral blood mononuclear cells in RAG2-/- gammac-/- double-mutant mice. Blood 102: 2522–2531.
Ito, M., Hiramatsu, H., Kobayashi, K., Suzue, K., Kawahata, M., Hioki, K., Ueyama, Y., Koyanagi, Y., Sugamura, K., Tsuji, K., Heike, T. and Nakahata, T. (2002). NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood 100: 3175–3182.
Shultz, L. D., Lyons, B. L., Burzenski, L. M., Gott, B., Chen, X., Chaleff, S., Gillies, S. D., King, M., Mangada, J., Greiner, D. L., and Handgretinger, R. (2005). Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2rg null mice engrafted with mobilized human hematopoietic stem cell. J. Immunol. 174: 6477–6489.
King, M., Pearson, T., Shultz, L. D., Leif, J., Bottino, R., Trucco, M., Atkinson, M. A., Wasserfall, C., Herold, K. C., Woodland, R. T., Schmidt, M. R., Woda, B. A., Thompson, M. J., Rossini, A. A. and Greiner, D. L. (2008). A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene. Clin. Immunol. 126: 303–314.
Golovina, T. N., Mikheeva, T., Suhoski, M. M., Aqui, N. A., Tai, V. C., Shan, X., Liu, R., Balcarcel, R. R., Fisher, N., Levine, B. L., Carroll, R. G., Warner, N., Blazar, B. R., June, C. H. and Riley, J. L. (2008). CD28 costimulation is essential for human T regulatory expansion and function. J. Immunol. 181: 2855–2868.
King, M., Pearson, T., Rossini, A. A., Shultz, L. D. and Greiner, D. L. (2008). Humanized mice for the study of type 1 diabetes and beta cell function. Ann. NY. Acad. Sci. 1150: 46–53.
Pearson, T., Shultz, L. D., Miller, D., King, M., Laning, J., Fodor, W., Cuthbert, A., Burzenski, L., Gott, B., Lyons, B., Foreman, O., Rossini, A. A. and Greiner, D. L. (2008). Non-obese diabetic-recombination activating gene-1 (NOD-Rag1 null) interleukin (IL)-2 receptor common gamma chain (IL2r gamma null) null mice: a radioresistant model for human lymphohaematopoietic engraftment. Clin. Exp. Immunol. 154: 270–284.
Takenaka, K., Prasolava, T. K., Wang, J. C., Mortin-Toth, S. M., Khalouei, S., Gan, O. I,. Dick, J. E. and Danska, J. S. (2007). Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat. Immunol. 8: 1313–1323.
Mosier, D. E. (1991). Adoptive transfer of human lymphoid cells to severely immunodeficient mice: models for normal human immune function, autoimmunity, lymphomagenesis, and AIDS. Adv. Immunol. 50: 303–325.
Rothenberg, B. E. and Voland, J. R. (1996). Beta2 knockout mice develop parenchymal iron overload: a putative role for class I genes of the major histocompatibility complex in iron metabolism. Proc. Natl. Acad. Sci. USA 93: 1529–1534.
Junghans, R. P. and Anderson, C. L. (1996). The protection receptor for IgG catabolism is the b2-microglobulin-containing neonatal intestinal transport receptor. Proc. Natl. Acad. Sci. USA 93: 5512–5516.
Torbett, B. E., Picchio, G. and Mosier, D. E. (1991). hu-PBL-SCID mice: a model for human immune function, AIDS, and lymphomagenesis. Immunol. Rev. 124: 139–164.
Banuelos, S. J. Shultz, L. D., Greiner, D. L., Burzenski, L. M., Gott, B., Lyons, B. L., Rossini, A. A. and Appel, M. C. (2004). Rejection of human islets and human HLA-A2.1 transgenic mouse islets by alloreactive human lymphocytes in immunodeficient NOD-scid and NOD-Rag1 null Prf1 null mice. Clin. Immunol. 112: 273–283.
Acknowledgment
We thank Jean Leif, Linda Paquin, Amy Cuthbert, Celia Hartigan, Amy Sands, Allison Ingalls, and Candy Knoll for their technical assistance. We also thank the participation of the Clinical Trials Unit at the University of Massachusetts Medical School. This work was supported by National Institutes of Health Grants AI46629, DK072473, CA34196, an institutional Diabetes Endocrinology Research Center (DERC) grant DK32520, RR-07068, the Beta Cell Biology Consortium, and grants from the Juvenile Diabetes Foundation, International, including a grant through the nPOD program. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Humana Press, a part of Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Pino, S. et al. (2010). Development of Novel Major Histocompatibility Complex Class I and Class II-Deficient NOD-SCID IL2R Gamma Chain Knockout Mice for Modeling Human Xenogeneic Graft-Versus-Host Disease. In: Proetzel, G., Wiles, M. (eds) Mouse Models for Drug Discovery. Methods in Molecular Biology, vol 602. Humana Press. https://doi.org/10.1007/978-1-60761-058-8_7
Download citation
DOI: https://doi.org/10.1007/978-1-60761-058-8_7
Published:
Publisher Name: Humana Press
Print ISBN: 978-1-60761-057-1
Online ISBN: 978-1-60761-058-8
eBook Packages: Springer Protocols