Overview

Spontaneous mutations that cause defects in immunological function in mice have provided important research tools with which to investigate the development and regulation of the immune system. A number of these mutations serve as models for specific human diseases and provide critical tools to increase the understanding of human immunodeficiency diseases, autoimmunity and leukemia. Spontaneous as well as targeted immunological mutations also provide mouse models that support engraftment with human stem cells and with human peripheral blood lymphocytes. These "humanized" mice have provided critical models for experimental investigation of human immune diseases without putting individuals at risk. Our recent research has leveraged these mouse models for studies on diabetes, bone development, autoimmunity, malignancy, anemia, thrombocytopenia, infectious diseases, transplantation tolerance and asthma.

Scientific report

Development of Humanized SCID Mice and Studies of Single Gene Models for Human Hematological Diseases

Advances in our understanding of the development and regulation of the immune system in normal and pathologic states rely heavily on studies of mice with genetically determined immunodeficiency and autoimmunity. Research in our laboratory encompasses (1) basic studies focused on elucidating the mechanisms underlying immunodeficiency, autoimmunity, and hematological diseases; and (2) applied studies focused on the development of effective immunodeficient mouse models that support heightened engraftment with human hematopoietic stem cells. These "humanized SCID mice" will facilitate studies of human immunity, regenerative medicine, and neoplasia. Examples of the studies carried out over the last year are summarized below:

Development of Humanized Mice for Translational Biomedical Research

Complex biological processes often require in vivo analysis, and important research advances have been obtained using mice as a model system for the study of many biological systems. However, mice are not humans, and the study of human biology in vivo is severely limited by ethical and technical constraints. There is a growing need for animal models to carry out in vivo studies on human cells, tissues, and organs without putting individuals at risk. Humanized mice, or mouse–human chimeras, have been developed to overcome these limitations and have become an important research tool for the in vivo study of human cells and tissues. We have developed a NOD-Prkdcscid (NOD/SCID) mouse strain harboring a null mutation of the common cytokine receptor γ chain (Il2rgtm1Wjl) (NOD/SCID/IL2rγnull) (full name NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ). In collaboration with Dale Greiner and his colleagues at The University of Massachusetts Medical School along with Fumihiko Ishikawa and his colleagues at The Riken Research Center for Allergy and Immunology, we have shown that these mice can efficiently support development of all myelo-erythroid components and functional lymphoid cells following human hematopoietic stem cell (HSC) engraftment. Development of mice that are ‘humanized’ by engraftment of human tissues, HSCs, and peripheral-blood mononuclear cells (PBMCs) provides an opportunity to study human biological processes in vivo that would otherwise not be possible. The new generations of humanized mice are proving to be powerful tools in preclinical testing and in the investigation of many human biological processes. The culmination of decades of research on humanized mice is leading to advances in our understanding of human hematopoiesis, innate and adaptive immunity, autoimmunity, infectious diseases, cancer biology, and regenerative medicine. The potential for new advances in our understanding of human biological systems provided by studies in humanized mice remains promising. The development of humanized mice based on immunodeficient IL2rγnull hosts has overcome many of the limitations and constraints of previously available models.

The Mouse Mutation "Thrombocytopenia and Cardiomyopathy" (trac) is within the Abcg5 Gene: A Single Gene Model for Human Mediterranean Macrothrombocytopenia

Homozygosity for a new spontaneous mouse mutation named "thrombocytopenia and cardiomyopathy" (trac) results in thrombocytopenia, dilated cardiomyopathy, and infertility. A/J-trac/trac mice show a precipitous drop in platelet numbers and increases in platelet volume by 4 weeks of age. By 2-3 months of age, trac/trac mice have a 20-fold decrease in platelet number, a 3-fold increase in platelet volume, and a greatly increased bleeding time. Blood smears showed abnormally large platelets and megakaryocytoid cells. The trac/trac mice also developed mild microcytic anemia accompanied by the presence of stomatocytes, a doubling of reticulocyte numbers, and a two-fold decrease in WBC counts. Increased numbers of megakaryocytes were present in bone marrow, spleen, and lungs. Ultrastructural studies of trac/trac megakaryocytes showed a poorly developed demarcation system and a failure to form platelet territories. The trac/trac platelets were enlarged, spherical, and contained numerous small alpha granules. The thrombocytopenia was not associated with defects intrinsic to bone marrow progenitor cells. Although thrombopoietin (TPO) levels were decreased, TPO treatment failed to reverse the thrombocytopenia. To identify the responsible gene, we produced a fine-structure genetic map of a 5-megabase interval containing the trac locus on mouse chromosome 17. The human syntenic region is Chr 2p21-p22. Analyses of 1100 F2 progeny from intercross matings of (A/J x C57BL/6J) F1 +/trac mice narrowed the interval to 0.3 Mb containing 4 genes. Sequencing of these genes revealed a G-to-A mutation at base 1435 (refseq nm031884) of Abcg5 (ATP-binding cassette sub-family G, member 5). This G>A base change results in a tryptophan codon (UGG) at amino acid position 463(uniprot) being changed to a premature stop codon (UAG). The transmembrane helices prediction program, TMHMM, predicts that the premature stop codon would truncate the last four of the six transmembrane domains of the ABCG5 protein. No DNA alterations were found in any of the other candidate genes. Genetic crosses of +/trac mice with mice doubly transgenic for the closely linked human ABCG5 and ABCG8 genes (stock B6SJL-Tg(ABCG5/ABCG8)14-2Hobb/J) showed that the transgenes normalized platelet counts and volumes in trac/trac mice. ABCG5 (sterolin-1) functions as part of a heterodimer, with ABCG8, that regulates plant sterol uptake. The trac/trac mutant mice have greatly elevated plasma levels of plant sterols. When placed on a phytosterol-free diet, the thrombocytopenia was reversed. Recent studies have shown that Mediterranean Macrothrombocytopenia is caused by mutations in ABCG5 or ABCG8. Identification of the molecular basis of the mouse Abcg5trac mutation provides a new model for studying the role of phytosterols in pathogenic changes in the hematopoietic, cardiovascular, and reproductive systems.

Lab staff

Principal Investigator: Leonard D. Shultz, Ph.D.
Postdoctoral Fellow: Vishnu Hosur, Ph.D., Mohit Verma, Ph.D.
Research Assistant II: Lisa Carney, B.S.
Research Assistant I: Bruce Gott
Laboratory Technician III
: Michelle Farley 
RAF Primary Room Technician: Allison Ingalls
Research Administrative Assistant:
Norma D. Buckley

Publication listings

2014

Roderick JE, Tesell J, Shultz LD, Brehm MA, Greiner DL, Harris MH, Silverman LB, Sallan SE, Gutierrez A, Look AT, Qi J, Bradner JE, Kelliher MA. 2014. c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells. Blood [Epub ahead of print].

Guendel I. Lordanskiy S, Van Dyne R, Kehn-Hall K, Saifuddin M, Das R, Jaworski E, Sampey GC, Senina S, Shultz L, Narayanan A, chen H, Lepene B, Zeng C, Kashanchi F. 2014. Novel neuroprotective GSK-3beta inhibitor restricts Tat-mediated HIV-1 replication. J virol 88(2): 1189-1208.

Dou S, Wang Y, Barton B, Chen L, rusckowski M, Shultz LD, Greiner DL, Liu G. 2014. Comparison between two labeled agents in mice using a coinjection-ratio approach in contrast to a conventional group approach. Nucl Med Biol 41(1): 127-131. PMCID: PMC3855254 

2013

Jurczyk A, Dilorio P, Brostowin D, Leehy L, Yang C, Urano F, Harlan DM, Shultz LD, Greiner DL, Bortell R. 2013. Improved function and proliferation of adult human beta cells engrafted in diabetic immunodeficient NOD-scid IL2rgamma(null) mice treated with alogliptin. Diabetes Metab Syndr Obes 6: 493-499. PMCID: 3864939

Lee J, Brehm MA, Greiner D, Shultz LD, Kornfeld H. 2013. Engrafted human cells generate adaptive immune responses to Mycobacterium bovis BCG infection in humanized mice. BMC Immunol 14(1): 53

Covassin L, Jangalwe S, Jouvet N, Laning J, Burzenski L, Shultz LD, Brehm MA.  2013.  Human immune system development and survival of NOD-scid IL2rgamma(null) (NSG) mice engrafted with human thymus and autologous hematopoietic stem cells.  Clin Exp Immunol 174(3): 372-388. PMCID: PMC3826304

Schleifman EB, McNeer NA, Jackson A, Yamtich J, Brehm MA, Shultz LD, Greiner DL, Kumar P, Saltzman WM, Glazer PM. 2013. Site-specific genome editing in PBMCs with PLGA nanoparticle-delivered PNAs confers HIV-1 resistance in humanized mice. Mol Ther Nucleic Acids 2: 3135. PMCID: 3889188

Brehm MA, Shultz LD, Luban J, Greiner DL. 2013. Overcoming current limitations in humanized mouse research. J Infect Dis 208 Suppl 2: S125-130. PMCID: PMC3807974

Brehm MA, Jouvet N, Greiner DL, Shultz LD.  2013.  Humanized mice for the study of infectious diseases.  Curr Opin Immunol  25(4): 428-435. PMCID: PMC3775881

Wilson DW, Oslund KL, Lyons B, Foreman O, Burzenski L, Svenson KL, Chase TH, Shultz LD. 2013. Inflammatory dilated cardiomyopathy in Abcg5-deficient mice. Toxicol Pathol 41(6): 880-892

Hickey RD, Galivo F, Schug J, Brehm MA, Haft A, Wang Y, Benedetti E, Gu G, Magnuson MA, Shultz LD, Lagasse E, Greiner DL, Kaestner KH, Grompe M.  2013.  Generation of islet-like cells from mouse gall bladder by direct ex vivo reprogramming.  Stem Cell Res 11(1): 503-515.

Jimenez-Diaz MB, Viera S, Ibanez J, Mulet T, Magan-Marchal N, Garuti H, Gomez V, Cortes-Gil L, Martinez A, Ferrer S, Fraile MT, Calderon F, Fernandez E, Shultz LD, Leroy D, Wilson DM, Garcia-Bustos JF, Gamo FJ, Angulo-Barturen I.  2013.  A new in vivo screening paradigm to accelerate antimalarial drug discovery.  PLoS One 8(6): e66967.  PMCID: PMC3692522

McNeer NA, Schleifman EB, Cuthbert A, Brehm M, Jackson A, Cheng C, Anandalingam K, Kumar P, Shultz LD, Greiner DL, Saltzman MW, Glazer PM. 2013. Systemic delivery of triplex-forming PNA and donor DNA by nanoparticles mediates site-specific genome editing of human hematopoietic cells in vivo. Gene Ther 20(6): 658-669.  PMCID: PMC3713483

Yokota SJ, Facciponte JG, Kelleher RJ Jr, Shultz LD, Loyall JL, Parsons RR, Odunsi K, Frelinger JG, Lord EM, Gerber SA, Balu-Iyer SV, Bankert RB.  2013.  Changes in ovarian tumor cell number, tumor vasculature, and T cell function monitored in vivo using a novel xenograft model.  Cancer Immun 13: 11.  PMCID: PMC3721261

Saito Y, Yuki H, Kurantani M, Hashizume Y, Takagi S, Honma T, Tanaka A, Shirouzu M, Mikuni J, Handa N, Ogahara I, Sone A, Najima Y, Tomabechi Y, Wakiyama M, Uchida N, Tomizawa-Murasawa M, Kaneko A, Tanaka S, Suzuki N, Kajita H, Aoki Y, Ohara O, Shultz LD, Fukami T, Goto T, Taniguchi S, Yokoyama S, Ishikawa F.  2013.  A pyrrolo-pyrimidine derivative targets human primary AML stem cells in vivo.  Sci Transl Med 5(181): 181ra152.

Tanaka T, Fujita Y, Ueno M, Schultz LD, Yamashita T.  2013.  Suppression of SHP-1 promotes corticospinal tract sprouting and functional recovery after brain injury.  Cell Death Dis 4: e567.  PMCID: PMC3641325

Goel HL, Pursell B, Chang C, Shaw LM, Mao J, Simin K, Kumar P, Vander Kooi CW, Shultz LD, Greiner DL, Norum JH, Toftgard R, Kuperwasser C, Mercurio AM.  2013.  GLT1 regulates a novel neuropilin-2/alpha6Beta1 integrin based autocrine pathway that contributes to breast cancer initiation.  EMBO Mol Med 5(4): 488-508.  PMCID: PMC3628099

Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D, Shultz L, Bhatia R. 2013. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-beta-catenin signaling. Blood 121(10): 1824-1838. PMCID: 3591802

Seymour R, Shirley BJ, Hogenesch H, Shultz LD, Sundberg JP. 2013. Loss of function of the mouse sharpin gene results in Peyer's Patch regression. PLoS One 8(2): e55224. PMCID: PMC3570409

Hosur V, Cox ML, Burzenski LM, Riding RL, Alley L, Lyons BL, Kavirayani A, Martin KA, Cox GA, Johnson KR, Shultz LD. 2013. Retrotransposon insertion in the T-cell acute lymphocytic leukemia 1 (Tal1) gene is associated with severe renal disease and patchy alopecia in Hairpatches (Hpt) mice. PLoS One 8(1): e53426. PMCID: PMC3534690

2012

Shultz LD, Brehm MA, Garcia-Martinez JV, Greiner DL. 2013. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol 12(11): 786-798. PMCID: PMC3749872

Jaiswal S, Pazoles P, Woda M, Shultz LD, Greiner DL, Brehm MA, Mathew A. 2012. Enhanced humoral and HLA-A2 restricted dengue virus-specific T-cell responses in humanized BLT NSG mice. Immunology 136(3): 334-343. PMCID: PMC3385033

Liu G, Dou S, Akalin A, Rusckowski M, Streeter PR, Shultz LD, Greiner DL. 2012. Pretargeting vs direct targeting of human betalox5 islet cells subcutaneously implanted in mice using an anti-human islet cell antibody. Nucl Med Biol 39(5): 645-651. PMCID: PMC3361517

Tanaka S, Saito Y, Kunisawa J, Kurashima Y, Wake T, Suzuki N, Shultz LD, Kiyono H, Ishikawa F. 2012. Development of mature and functional human myeloid subsets in hematopoietic stem cell-engrafted NOD/SCID/IL2rgammaKO mice. J Immunol 188(12): 6145-6155. PMCID: PMC3370073

Robinson SN, Simmons PJ, Thomas MW, Brouard N, Javni JA, Trilok S, Shim JS, Yang H, Steiner D, Decker WK, Xing D, Shultz LD, Savoldo B, Dotti G, Bollard CM, Miller L, Champlin RE, Shpall EJ, Zweidler-McKay PA. 2012. Ex vivo fucosylation improves human cord blood engraftment in NOD-SCID IL-2Ry(null) mice. Exp Hematol 40(6): 445-456. PMCID: PMC3352960

Bernstein JM, Lehman H, Lis M, Sands A, Wilding GE, Shultz L, Bankert R, Bobek L. 2012. Humanized mouse model used to monitor MUC gene expression in nasal polyps and to preclinically evaluate the efficacy of montelukast in reducing mucus production. Ann Otol Rhinol Laryngol 121(5): 307-316.  PMCID: PMC3621975

Hosur V, Kavirayani A, Riefler J, Carney LM, Lyons B, Gott B, Cox GA, Shultz LD. 2012. Dystrophin and dysferlin double mutant mice: a novel model for rhabdomyosarcoma. Cancer Genet 205(5): 232-241. PMCID: PMC3372852

Brehm MA, Shultz LD. 2012. Human allograft rejection in humanized mice: a historical perspective. Cell Mol Immunol 9(3): 225-231. Review

Brehm MA, Powers AC, Shultz LD, Greiner DL. 2012. Advancing animal models of human type 1 diabetes by engraftment of functional human tissues in immunodeficient mice. Cold Spring Harb perspect Med 2(5): a007757. PMCID:  PMC3331686

Li M, Zhou M, Gong M, Ma J, Pei F, Beamer WG, Shultz LD, Hock JM, Yu X. 2012. A novel animal model for bone metastasis in human lung cancer. Oncol Lett 3(4): 802-806. PMCID: PMC3362336

Takagi S, Saito Y, Hijikata A, Tanaka S, Watanabe T, Hasegawa T, Mochizuki S, Kunisawa J, Kiyono H, Koseki H, Ohara O, Saito T, Taniguchi S, Shultz LD, Ishikawa F. 2012. Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation. Blood 119(12): 2768-2777. PMCID: PMC3327455

Brehm MA, Racki WJ, Leif J, Burzenski L, Hosur V, Wetmore A, Gott B, Herlihy M, Ignotz R, Dunn R, Shultz LD, Greiner DL. Engraftment of human HSC in non-irradiated newborn NOD-scid IL2rynull mice is enhanced by transgenic expression of membrane-bound human Scf. Blood 119(12): 2778-2788. PMCID: PMC3327456

Unger WW, Pearson T, Abreu JR, Laban S, van der Slik AR, der Kracht SM, Kester MG, Serreze DV, Shultz LD, Griffioen M, Drijfhout JW, Greiner DL, Roep BO. 2012. Islet-specific CTL cloned from a Type 1 diabetes patient cause beta-cell destruction after engraftment into HLA-A2 transgenic NOD/SCID/IL2RG null mice. PLoS One 7(11): e49213. PMCID: PMC3498321

Ippolito GC, Hoi KH, Reddy ST, Carroll SM, Ge X, Rogosch T, Zemlin M, Shultz LD, Ellington AD, Vandenberg CL, Georgiou G. 2012. Antibody repertoires in humanized NOD-scid-IL2Rgamma(null) mice and human B cells reveals human-like diversification and tolerance checkpoints in the mouse. PLoS One 7(4): e35497. PMCID: PMC3338711

2011

Greiner DL, Brehm MA, Hosur V, Harlan DM, Powers AC, Shultz LD. 2011. Humanized mice for the study of type 1 and type 2 diabetes. Ann N Y Acad Sci 1245: 55-58. PMCID: PMC3384500

Shultz LD, Brehm MA, Bavari S, Greiner DL. 2011. Humanized mice as a preclinical tool for infectious disease and biomedical research. Ann N Y Acad Sci 1245: 50-54

Duyne RV, Narayanan A, Kehn-Hall K, Saifuddin M, Shultz L, Kashanchi F. 2011. Humanized mouse models of HIV-1 latency. Curr HIV Res 9: 595-605. Review

Covassin L, Laning J, Abdi R, Langevin DL, Phillips NE, Shultz LD, Brehm MA. 2011. Human peripheral blood CD4 T cell-engrafted non-obese diabetic-scid IL2ry(null) H2-Ab1 (tm1Gru) Tg (human leucocyte antigen D-related 4) mice: a mouse model of human allogeneic graft-versus-host disease. Clin Exp Immunol 166: 269-280. PMCID: PMC3219902

deLorio P, Jurczyk A, Yang C, Racki WJ, Brehm MA, Atkinson MA, Powers AC, Shultz LD, Greiner DL, Bortell R. 2011. Hyperglycemia-induced proliferation of adult human beta cells engrafted into spontaneously diabetic immunodeficient NOD-Rag1 nul IL2rynull Ins2Akita mice. Pancreas 40: 1147-1149. PMCID: PMC3176417

Schleifman EB, Bindra R, Leif J, Del Campo J, Rogers FA, Uchil P, Kutsch O, Shultz LD, Kumar P, Greiner DL, Glazer PM. 2011. Targeted disruption of the CCR5 gene in human hematopoietic stem cells stimulated by peptide nucleic acids. Chem Biol 18: 1189-1198. PMCID: PMC3183429

Dorrell C, Grompe MT, Pan FC, Zhong Y, Canaday PS, Shultz LD, Greiner DL, Wright CV, Streeter PR, Grompe M. 2011. Isolation of mouse pancreatic alpha, beta, duct and acinar populations with cell surface markers. Mol Cell Endocrinol 339: 144-150. PMCID: PMC3112273

Liu G, Dou S, Cheng D, Leif J, Rusckowski M, Streeter PR, Shultz LD, Hnatowich DJ, Greiner DL. 2011. Human islet cell MORF/cMORF pretargeting in a xenogeneic murine transplant model. Mol Pharm 8: 767-773. PMCID: PMC3109173

Whitfield-Larry F, Young EF, Talmage G, Fudge E, Azam A, Patel S, Largay J, Byrd W, Buse J, Calikoglu AS, Shultz LD, Frelinger JA. 2011. HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/gammac{null}/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells. Diabetes 60: 1726-1733. PMCID: 3114397

Zhao L, Spassieva SD, Jucius TJ, Shultz LD, Shick HE, Macklin WB, Hannun YA, Obeid LM, Ackerman SL. 2011. A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation. PLoS Genet 7: e1002063. PMCID: PMC3098191

Foreman O, Kavirayani AM, Griffey SM, Reader R, Shultz LD. 2011. Opportunistic bacterial infections in breeding colonies of the NSG mouse strain. Vet Pathol 48:495-499. PMCID: PMC3101569

Dash Y, Ramesh M, Kalyanasundaram R, Munirathinam G, Shultz LD, Rajan TV. 2011. Granuloma formation around filarial larvae triggered by host responses to an excretory/secretory antigen. Infect Immun 79:838-845. PMCID: PMC3028858

Bankert RB, Balu-lyer SV, Odunsi K, Shultz LD, Kelleher RJ Jr, Barnas JL, Simpson-Abelson M, Parsons R, Yokota SJ. 2011. Humanized mouse model of ovarian cancer recapitulates patient solid tumor progression, ascites formation, and metastasis. PLoS One 6: e24420. PMCID: PMC3174163

2010

Brehm MA, Bortell R, Diiorio P, Leif J, Laning J, Cuthbert A, Yang C, Herlihy M, Burzenski L, Gott B, Foreman O, Powers AC, Greiner DL, Shultz LD. 2010. Human immune system development and rejection of human islet allograts in spontaneously diabetic NOD-Rag1null IL2rgammanull Ins2Akita mice. Diabetes 59:2265-2270. PMCID: PMC2927949

Brehm MA, Cuthbert A, Yang C, Miller DM, Dilorio P, Laning J, Burzenski L, Gott B, Foreman O, Kavirayani A, Herlihy M, Rossini AA, Shultz LD, Greiner DL. 2010. Parameters for establishing humanized mouse models to study human immunity: Analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rgamma(null) mutation. Clin Immunol 135:84-98. PMCID: PMC2835837

Brehm MA, Shultz LD, Greiner DL. 2010. Humanized mouse models to study human diseases. Curr Opin Endocrinol Diabetes Obes 17:120-125. PMCID: PMC2892284

Chase TH, Lyons BL, Bronson RT, Foreman O, Donahue LR, Burzenski LM, Gott B, Lane P, Harris B, Ceglarek U, Thiery J, Wittenburg H, Thon JN, Italiano JE Jr, Johnson KR, Shultz LD. 2010. The mouse mutation "thrombocytopenia and cardiomyopathy" (trac) disrupts Abcg5: a spontaneous single gene model for human hereditary phytosterolemia/sitosterolemia. Blood 115:1267-1276. PMCID: PMC2826237

Gori JL, Tian X, Swanson D. Gunther R, Shultz LD, McIvor RS, Kaufman DS. 2010. In vivo selection of human embryonic stem cell-derived cells expressing methotrexate-resistant dihydrofolate reductase. Gene Ther 17:238-249. PMCID: PMC2820606

Libby SJ, Brehm MA, Greiner DL, Shultz LD, McClelland M, Smith KD, Cookson BT, Karlinsey JE, Kinkel TL, Porwollik S, Canals R, Cummings LA, Fang FC. 2010. Humanized nonobese diabetic-scid IL2rgammanull mice are susceptible to lethal Salmonella Typhi infection. Proc Natl Acad Sci U S A 107:15589-15594. PMCID: PMC2932584

Moriceau G, Ory B, Mitrofan L, Riganti C, Blanchard F, Brion R, Charrier C, Battaglia S, Pilet P, Denis MG, Shultz LD, Monkkonen J, Redini F, Heymann D. 2010. Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (Everolimus): pivotal role of the prenylation process. Cancer Res 70:10329-10339. PMCID: PMC3097388

Morisot S, Wayne AS, Bohana-Kashtan O, Kaplan IM, Gocke CD, Hildreth R, Stetler-Stevenson M, Walker RL, Davis S, Meltzer PS, Wheelan SJ, Brown P, Jones RJ, Shultz LD, Civin CI. 2010. High frequencies of leukemia stem cells in poor-outcome childhood precursor-B acute lymphoblastic leukemias. Leukemia 24:1859-1866. PMCID: PMC3035974

Pino S, Brehm MA, Covassin-Barberis L, King M, Gott B, Chase TH, Wagner J, Burzenski L, Foreman O, Greiner DL, Shultz LD. 2010. Development of novel major histocompatibility complex class 1 and class 11-deficient NOD-SCID IL2R gamma chain knockout mice for modeling human xenogeneic graft-versus-host disease. Methods Mol Biol 602:105-117. Book chapter

Racki WJ, Covassin L, Brehm M, Pino S, Ignotz R, Dunn R, Laning J, Graves SK, Rossini AA, Shultz LD, Greiner DL. 2010. NOD-scid IL2rgamma(null) mouse model of human skin transplantation and allograft rejection. Transplantation 89:527-536. PMCID: PMC2901915

Saito Y, Kitamura H, Hijikata A, Tomizawa-Murasawa M, Tanaka S, Takagi S, Uchida N, Suzuki N, Sone A, Najima Y, Ozawa H, Wake A, Taniguchi S, Shultz LD, Ohara O, Ishikawa F. 2010. Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci Transl Med 2:17ra19. PMCID: PMC3005290

Saito Y, Uchida N, Tanaka S, Suzuki N, Tomizawa-Murasawa M, Sone A, Najima Y, Takagi S, Aoki Y, Wake A, Taniguchi S, Shultz LD, Ishikawa F. 2010. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol 28:275-280

Shultz LD, Saito Y, Najima Y, Tanaka S, Ochi T, Tomizawa M, Doi T, Sone A, Suzuki N, Fujiwara H, Yasukawa M, Ishikawa F. 2010. Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. Proc Natl Acad Sci U S A 107: 13022-13027. PMCID: PMC2919921

Subramanya S, Kim SS, Abraham S, Yao J, Kumar M, Kumar P, Haridas V, Lee SK, Shultz LD, Greiner D, Manjunath N, Shankar P. 2010. Targeted delivery of small interfering RNA to human dendritic cells to suppress dengue virus infection and associated proinflammatory cytokine production. J Virol 84:2490-2501. PMCID: PMC2820933

Zhang B, Strauss AC, Chu S, Li M, Ho Y, Shiang KD, Snyder DS, Huettner CS, Shultz L, Holyoake T, Bhatia R. 2010. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell 17:427-442. PMCID: PMC2873971

2009

Bernstein JM, Brooks SP, Lehman HK, Pope L, Sands A, Shultz LD, Bankert RB. 2009. Human nasal polyp microenvironments maintained in a viable and functional state as xenografts in NOD-scid IL2rgamma(null) mice. Ann Otol Rhinol Laryngol 118:866-875. PMCID: PMC3005296 

Chase TH, Cox GA, Burzenski L, Foreman O, Shultz LD. 2009. Dysferlin deficiency and the development of cardiomyopathy in a mouse model of limb-girdle muscular dystrophy 2B. Am J Pathol. 175:2299-2308. PMCID: PMC2789639

Chopra P, Diiorio P, Pino SC, Wilson SB, Phillips NE, Mordes JP, Rossini AA, Greiner DL, Shultz LD, Bortell R. 2009. Failure of alpha-galactosylceramide to prevent diabetes in virus-inducible models of type 1 diabetes in the rat. In Vivo 23:195-201. PMCID: PMC2718559

Jaiswal S, Pearson T, Friberg H, Shultz LD, Greiner DL, Rothman AL, Mathew A. 2009. Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scid IL2rgammanull mice. PLoS One 4:e7251. PMCID: PMC2749937

Jimenez-Diaz MB, Mulet T, Viera S, Gomez V, Garuti H, Ibanez J, Alvarez-Doval A, Shultz LD, Martinez A, Gargallo-Viola D, Angulo-Barturen I. 2009. Improved murine model of malaria using P. falciparum competent strains and non-myelodepleted NOD-scid IL2R{gamma} null mice engrafted with human erythrocytes. Antimicrob Agents Chemother 53:4533-4536. PMCID: PMC2764183

King MA, Covassin L, Brehm MA, Racki W, Pearson T, Leif J, Laning J, Fodor W, Foreman O, Burzenski L, Chase TH, Gott B, Rossini AA, Bortell R, Shultz LD, Greiner DL. 2009. Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex. Clin Exp Immunol 157:104-118. PMCID: PMC2710598

Mangada J, Pearson T, Brehm MA, Wicker LS, Peterson LB, Shultz LD, Serreze DV, Rossini AA, Greiner DL. 2009. Idd loci synergize to prolong islet allograft survival induced by costimulation blockade in NOD mice. Diabetes 58:165-173. PMCID: PMC2606867

Miller DM, Thornley TB, Pearson T, Kruger AJ, Yamazaki M, Shultz LD, Welsh RM, Brehm MA, Rossini AA, Greiner DL. 2009. TLR agonists prevent the establishment of allogeneic hematopoietic chimerism in mice treated with costimulation blockade. J Immunol 182:5547-5559. PMCID: PMC2721273

Tian X, Hexum MK, Penchev VR, Taylor RJ, Shultz LD, Kaufman DS. 2009. Bioluminescent imaging demonstrates that transplanted human embryonic stem cell-derived CD34(+) cells preferentially develop into endothelial cells. Stem Cells 27:2675-2685. PMCID: PMC2857550

Unisinger J, McDonough JS, Shultz LD, Ferguson TA, Hotchkiss RS. 2009. Sepsis-induced human lymphocyte apoptosis and cytokine production in "humanized" mice. J Leukoc Biol 86:219-227. PMCID: 2726769

2008

Agliano A, Martin-Padura I, Mancuso P, Marighetti P, Rabascio C, Pruneri G, Shultz LD, Bertolini F. 2008. Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rgamma null mice generate a faster and more efficient disease compared to other NOD/scid-related strains. Int J Cancer 123:2222-2227.

Croker BA, Lawson BR, Rutschmann S, Berger M, Eidenschenk C, Blasius AL, Moresco EM, Sovath S, Cengia L, Shultz LD, Theofilopoulos AN, Pettersson S, Beutler BA, 2008. Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and microbial trigger. Proc Natl Acad Sci USA 105:15028-15033. PMCID: PMC2567487

Gaines P, Tien CW, Olins AL, Olins DE, Shultz LD, Carney L, Berliner N. 2008. Mouse neutrophils lacking lamin B-receptor expression exhibit aberrant development and lack critical functional responses. Exp Hematol 36:965-976. PMCID: PMC2543941

Giassi LJ, Pearson T, Shultz LD, Laning J, Biber K, Kraus M, Woda BA, Schmidt MR, Woodland RT, Rossini AA, Greiner DL. 2008. Expanded CD34+ human umbilical cord blood cells generate multiple lymphohematopoietic lineages in NOD-scid IL2rgamma null mice. Exp Biol Med (Maywood) 233:997-1012. PMCID: PMC2757278

Harris MA, Yang H, Low BE, Mukherje J, Guha A, Bronson RT, Shultz LD, Israel MA, Yun K. 2008. Cancer stem cells are enriched in the side-population cells in a mouse model of glioma. Cancer Res 68:10051-10059. PMCID: PMC2841432

Ishikawa F, Saito Y, Shultz LD. 2008. Modeling human leukemia using immune-compromised mice. In: Mouse Models of Human Blood Cancers. Li S (Ed). Springer Press, New York.

Ishikawa F, Saito Y, Yoshida S, Harada M, Shultz LD. 2008. The differentiative and regenerative properties of human hematopoietic stem/progenitor cells in NOD-SCID/IL2rgamma(null) mice. Curr Top Microbiol Immunol 324:87-94.

King M, Pearson T, Rossini AA, Shultz LD, Greiner LD. 2008. Humanized mice for the study of type 1 diabestes and beta cell function. Ann N Y Acad Sci 1150:46-53. PMCID: PMC2620029

King M, Pearson T, Shultz LD, Leif J, Bottino R, Trucco M, Akinson MA, Wasserfall C, Herold KC, Woodland RT, Schmidt MR, Woda BA, Thompson MJ, Rossini AA, Greiner DL. 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.

Kong Y, Yoshida S, Saito Y, Doi T, Nagatoshi Y, Fukata M, Saito N, Yang SM, Iwamoto C, Okamura J, Liu KY, Huang XJ, Lu DP, Shultz LD, Harada M, Ishikawa F. 2008. CD34+CD38+CD19+ as well as CD34+CD38-CD19+ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL. Leukemia 22:1207-1213.

Kumar P, Ban HS, Kim SS, Wu H, Pearson T, Greiner DL, Laouar A, Yao J, Haridas V, Habiro K, Yang YG, Jeong JH, Lee KY, Kim YH, Kim SW, Peipp M, Fey GH, Manjunath N, Shultz LD, Lee SK, Shankar P. 2008. T cell-specific siRNA delivery supresses HIV-1 infection in humanized mice. Cell 134:577-586. PMCID: PMC2943428

le Viseur C, Hotfilder M, Bomken S, Wilson K, Rottgers S, Schrauder A, Rosemann A, Irving J, Stam RW, Shultz LD, Harbott J, Jurgens H, Schrappe M, Pieters R, Vormoor J. 2008. In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties. Cancer Cell 14:47-58. PMCID: PMC2572185

Mori K, Blanchard F, Charrier C, Battaglia S, Ando K, Duplomb L, Shultz LD, Redini F, Heymann D. 2008. Conditioned media from mouse osteosarcoma cells promote MC3T3-E1 cell proliferation using JAKs and PI3-K/Akt signal crosstalk. Cancer Sci 99:2170-2176.

Pearson T, Greiner DL, Shultz LD. 2008. Creation of "humanized" mice to study human immunity. Curr Protoc Immunol Chapter 15:Unit 15.21. PMCID: PMC3023233

Pearson T, Greiner DL, Shultz LD. 2008. Humanized SCID mouse models for biomedical research. Curr Top Microbiol Immunol 324:25-51. Review

Pearson T, Shultz LD, Lief J, Burzenski L, Gott B, Chase T, Foreman O, Rossini AA, Bottino R, Trucco M, Greiner DL. 2008. A new immunodeficient hyperglycaemic mouse model based on the Ins2 Akita mutation for analyses of human islet and beta stem and progenitor cell function. Diabetologia 51:1449-1456. PMCID: PMC2719841

Pearson T, Shultz LD, Miller D, King M, Laning J, Fodor W, Cuthbert A, Burzenski L, Gott B, Lyons B, Foreman O, Rossini AA, Greiner DL. 2008. Non-obese diabetic-recombination activating gene-1 (NOD-Rag 1null) interleukin (IL)-2 receptor common gamma chain (IL 2 r gammanull) mice: a radioresistant model for human lymphohaematopoietic enraftment. Clin Exp Immunol 154:270-284. PMCID: PMC2612717

Schmidt MR, Appel MC, Giassi LJ, Greiner DL, Shultz LD, Woodland RT. 2008. Human BLyS facilitates engraftment of human PBL derived B cells in immunodeficient mice. PLoS ONE: 3:e3192. PMCID: PMC2527131

Simpson-Abelson MR, Sonnenberg GF, Takita H, Yokota SJ, Conway TF, Jr., Kelleher RJ, Jr, Shultz LD, Barcos M, Bankert RB. 2008. Long-term engraftment and expansion of tumor-derived memory T cells following the implantation of non-disrupted pieces of human lung tumor into NOD-scid IL2Rgamma(null) mice. J Immunol 180:7009-7018.

Yamamoto T, Kaizu C, Kawasaki T, Hasegawa G, Umezu H, Ohashi R, Sakurada J, Jiang S, Shultz L, Naito M. 2008. Macrophage colony-stimulating factor is indispensable for repopulation and differentiation of Kupffer cells but not for splenic red pulp macrophages in osteopetrotic (op/op) mice after macrophage depletion. Cell Tissue Res 332:245-256.

2007

Dash Y, Ramesh M, Greiner D, Shultz LD, Klei TR, Rajan TV. 2007. Determinants of memory in experimental filarial infections in mice. Parasite Immunol 29:567-574.

Ishikawa F, Niiro H, Iino T, Yoshida S, Saito N, Onohara S, Miyamoto T, Minagawa H, Fujii SI, Shultz LD, Harada M, Akashi K. 2007. The developmental program of human dendritic cells is operated independently of conventional myeloid and lymphoid pathways. Blood 110: 3591-3600.

Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, Nakamura R, Tanaka T, Tomiyama H, Saito N, Fukata M, Miyamoto T, Lyons B, Ohshima K, Uchida N, Taniguchi S, Ohara O, Akashi K, Harada M, Shultz LD. 2007. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 25: 1315-1321.

King M, Pearson T, Shultz LD, Leif J, Bottino R, Trucco M, Atkinson M, Wasserfall C, Herold K, Mordes JP, Rossini AA, Greiner DL. 2007. Development of new generation HU-PBMC-NOD/SCID mice to study human islet alloreactivity. Ann N Y Acad Sci 1103: 90-93. 

Meyerrose TE, De Ugarte DA, Hofling AA, Herrbrich PE, Cordonnier TD, Shultz LD, Eagon JC, Wirthlin L, Sands MS, Hedrick MA, Nolta JA. 2007. In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models. Stem Cells 25: 220-227.

Ramesh M, Paciorkowski N, Dash Y, Shultz L, Rajan TV. 2007. Acute but not chronic macrophage recruitment in filarial infections in mice is dependent on C-C chemokine ligand 2. Parasite Immunol 29: 395-404.

Seymour RE, Hasham MG, Cox GA, Shultz LD, Hogenesch H, Roopenian DC, Sundberg JP. 2007. Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis. Genes Immun 8: 416-421.

Shultz LD, Ishikawa F, Greiner DL. 2007. Humanized mice in translational biomedical research. Nat Rev Immunol 7: 118-130.

Shultz LD, Pearson T, King M, Giassi L, Carney L, Gott B, Lyons B, Rossini AA, Greiner DL. 2007. Humanized NOD/LtSz-scid IL2 receptor common gamma chain knockout mice in diabetes research. Ann N Y Acad Sci 1103: 77-89.

Thornley TB, Phillips NE, Beaudette-Zlatanova BC, Markees TG, Bahl K, Brehm MA, Shultz LD, Kurt-Jones EA, Mordes JP, Welsh RM, Rossini AA, Greiner DL. 2007. Type 1 IFN mediates cross-talk between innate and adaptive immunity that abrogates transplantation tolerance. J Immunol 179: 6620-6629.

Yamazaki M, Pearson T, Brehm MA, Miller DM, Mangada JA, Markees TG, Shultz LD, Mordes JP, Rossini AA, Greiner DL. 2007. Different mechanisms control peripheral and central tolerance in hematopoietic chimeric mice. Am J Transplant 7: 1710-1721.

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