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Leonard Shultz, Ph.D.

Professor
The Jackson Laboratory
Immunology

600 Main Street
Bar Harbor, ME 04609
USA

p. 207-288-6405
f. 207-288-6079
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Leonard Shultz, Ph.D. - Investigator Profile

Complex biological processes often require in vivo analysis. Our lab has focused on the molecular and cellular basis for spontaneous mutations that disrupt the development or regulation of the hematopoietic and immune systems. We have applied the knowledge gained in these studies to investigations of type 1 diabetes (T1D). The study of human diabetes 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 autoimmune systems to investigate the etiology and pathogenesis of human T1D and to investigate new therapeutic interventions without putting individuals at risk. We have developed humanized mice, or mouse–human chimeras, to overcome these limitations. This research focuses on the development, optimization and validation of humanized mouse models that support engraftment with human hematopoietic cell populations and with human islets. These studies began in 1988 with our report of the SCID-hu mouse model. Over the ensuing two decades we have improved humanized mouse strains, and have optimized the technologies used for stem cells engraftment. Our recent research has leveraged these mouse models for translational studies on human hematopoiesis, immunity, diabetes, regenerative medicine, transplantation tolerance and cancer. We have developed the NOD/SCID mouse strain harboring a null mutation of the IL2 cytokine receptor common g chain and have shown that these mice, referred to as NOD/SCID/Gamma (NSG) mice, can efficiently support development of functional lymphoid and myeloid cells following human hematopoietic stem cell (HSC) engraftment. Development of NSG mice that are ‘humanized’ by engraftment of human tissues, HSCs, and peripheral blood mononuclear cells (PBMCs) has provided an opportunity to study human biological processes in vivo that would otherwise not be possible. The new generations of humanized mice expressing human HLA and cytokine transgenes and carrying additional targeted mutations that further depress host innate immunity are powerful tools in the investigation of T1D as well as other human diseases. 

Scientific Interests/Keywords

Humanized mouse model for studying diabetes, bone development, autoimmunity

Professor, Shultz Lab

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Publication Citation
22611244 Tanaka S, Saito Y, Kunisawa J, Kurashima Y, Wake T, Suzuki N, Shultz LD, Kiyono H, Ishikawa F Development of mature and functional human myeloid subsets in hematopoietic stem cell-engrafted NOD/SCID/IL2rγKO mice. (2012) J Immunol 188: 6145-55 (Added 2012-08-24 07:28:30.617401)
22558161 Ippolito GC, Hoi KH, Reddy ST, Carroll SM, Ge X, Rogosch T, Zemlin M, Shultz LD, Ellington AD, Vandenberg CL, Georgiou G Antibody repertoires in humanized NOD-scid-IL2Rγ(null) mice and human B cells reveals human-like diversification and tolerance checkpoints in the mouse. (2012) PLoS One 7: e35497 (Added 2012-08-24 07:28:38.146169)
22553498 Brehm MA, Powers AC, Shultz LD, Greiner DL Advancing animal models of human type 1 diabetes by engraftment of functional human tissues in immunodeficient mice. (2012) Cold Spring Harb Perspect Med 2: a007757 (Added 2012-08-24 07:28:44.323034)
22384859 Jaiswal S, Pazoles P, Woda M, Shultz LD, Greiner DL, Brehm MA, Mathew A Enhanced humoral and HLA-A2-restricted dengue virus-specific T-cell responses in humanized BLT NSG mice. (2012) Immunology 136: 334-43 (Added 2012-08-24 07:28:49.211274)
22327213 Brehm MA, Shultz LD Human allograft rejection in humanized mice: a historical perspective. (2012) Cell Mol Immunol 9: 225-31 (Added 2012-08-24 07:28:59.226292)
22316614 Liu G, Dou S, Akalin A, Rusckowski M, Streeter PR, Shultz LD, Greiner DL Pretargeting vs. direct targeting of human betalox5 islet cells subcutaneously implanted in mice using an anti-human islet cell antibody. (2012) Nucl Med Biol 39: 645-51 (Added 2012-08-24 07:29:02.069951)
22306295 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 Ex vivo fucosylation improves human cord blood engraftment in NOD-SCID IL-2Rγ(null) mice. (2012) Exp Hematol 40: 445-56 (Added 2012-08-24 07:29:08.462008)
22279057 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 Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation. (2012) Blood 119: 2768-77 (Added 2012-08-24 07:29:13.165707)
22246028 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 HSCs in nonirradiated newborn NOD-scid IL2rγ null mice is enhanced by transgenic expression of membrane-bound human SCF. (2012) Blood 119: 2778-88 (Added 2012-08-24 07:29:24.157688)
22211979 Shultz LD, Brehm MA, Bavari S, Greiner DL Humanized mice as a preclinical tool for infectious disease and biomedical research. (2011) Ann N Y Acad Sci 1245: 50-4 (Added 2012-08-24 07:29:32.978128)
21985373 Covassin L, Laning J, Abdi R, Langevin DL, Phillips NE, Shultz LD, Brehm MA Human peripheral blood CD4 T cell-engrafted non-obese diabetic-scid IL2rγ(null) H2-Ab1 (tm1Gru) Tg (human leucocyte antigen D-related 4) mice: a mouse model of human allogeneic graft-versus-host disease. (2011) Clin Exp Immunol 166: 269-80 (Added 2012-08-24 07:29:36.660932)
21944757 Schleifman EB, Bindra R, Leif J, del Campo J, Rogers FA, Uchil P, Kutsch O, Shultz LD, Kumar P, Greiner DL, Glazer PM Targeted disruption of the CCR5 gene in human hematopoietic stem cells stimulated by peptide nucleic acids. (2011) Chem Biol 18: 1189-98 (Added 2012-08-24 07:29:57.694362)
21926555 Diiorio P, Jurczyk A, Yang C, Racki WJ, Brehm MA, Atkinson MA, Powers AC, Shultz LD, Greiner DL, Bortell R Hyperglycemia-induced proliferation of adult human beta cells engrafted into spontaneously diabetic immunodeficient NOD-Rag1null IL2rγnull Ins2Akita mice. (2011) Pancreas 40: 1147-9 (Added 2012-08-24 07:30:05.614259)
21539888 Dorrell C, Grompe MT, Pan FC, Zhong Y, Canaday PS, Shultz LD, Greiner DL, Wright CV, Streeter PR, Grompe M Isolation of mouse pancreatic alpha, beta, duct and acinar populations with cell surface markers. (2011) Mol Cell Endocrinol 339: 144-50 (Added 2013-03-14 16:24:18.452249)
21521873 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 HLA-A2-matched peripheral blood mononuclear cells from type 1 diabetic patients, but not nondiabetic donors, transfer insulitis to NOD-scid/γc(null)/HLA-A2 transgenic mice concurrent with the expansion of islet-specific CD8+ T cells. (2011) Diabetes 60: 1726-33 (Added 2012-08-24 07:30:37.504967)
21361360 Liu G, Dou S, Cheng D, Leif J, Rusckowski M, Streeter PR, Shultz LD, Hnatowich DJ, Greiner DL Human islet cell MORF/cMORF pretargeting in a xenogeneic murine transplant model. (2011) Mol Pharm 8: 767-73 (Added 2012-08-24 07:30:50.716163)
20615947 Shultz LD, Saito Y, Najima Y, Tanaka S, Ochi T, Tomizawa M, Doi T, Sone A, Suzuki N, Fujiwara H, Yasukawa M, Ishikawa F Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. (2010) Proc Natl Acad Sci U S A 107: 13022-7 (Added 2011-03-02 10:39:33.928539)
20570944 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 Human immune system development and rejection of human islet allografts in spontaneously diabetic NOD-Rag1null IL2rgammanull Ins2Akita mice. (2010) Diabetes 59: 2265-70 (Added 2011-03-07 14:19:43.874428)
20150806 Brehm MA, Shultz LD, Greiner DL Humanized mouse models to study human diseases. (2010) Curr Opin Endocrinol Diabetes Obes 17: 120-5 (Added 2011-03-02 10:37:09.631124)
20134397 Racki WJ, Covassin L, Brehm M, Pino S, Ignotz R, Dunn R, Laning J, Graves SK, Rossini AA, Shultz LD, Greiner DL NOD-scid IL2rgamma(null) mouse model of human skin transplantation and allograft rejection. (2010) Transplantation 89: 527-36 (Added 2011-03-02 10:36:38.28702)
20096637 Brehm MA, Cuthbert A, Yang C, Miller DM, DiIorio P, Laning J, Burzenski L, Gott B, Foreman O, Kavirayani A, Herlihy M, Rossini AA, Shultz LD, Greiner DL 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. (2010) Clin Immunol 135: 84-98 (Added 2011-03-07 14:19:43.88485)
20012395 Pino S, Brehm MA, Covassin-Barberis L, King M, Gott B, Chase TH, Wagner J, Burzenski L, Foreman O, Greiner DL, Shultz LD 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. (2010) Methods Mol Biol 602: 105-17 (Added 2011-03-02 10:35:37.612289)
19659776 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 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. (2009) Clin Exp Immunol 157: 104-18 (Added 2011-03-02 10:35:01.65211)
19120266 King M, Pearson T, Rossini AA, Shultz LD, Greiner DL Humanized mice for the study of type 1 diabetes and beta cell function. (2008) Ann N Y Acad Sci 1150: 46-53 (Added 2009-04-21 09:47:33)
18785974 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 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. (2008) Clin Exp Immunol 154: 270-84 (Added 2009-04-21 09:46:49)
18784835 Schmidt MR, Appel MC, Giassi LJ, Greiner DL, Shultz LD, Woodland RT Human BLyS facilitates engraftment of human PBL derived B cells in immunodeficient mice. (2008) PLoS One 3: e3192 (Added 2011-03-02 10:34:30.879123)
18653783 Giassi LJ, Pearson T, Shultz LD, Laning J, Biber K, Kraus M, Woda BA, Schmidt MR, Woodland RT, Rossini AA, Greiner DL Expanded CD34+ human umbilical cord blood cells generate multiple lymphohematopoietic lineages in NOD-scid IL2rgamma(null) mice. (2008) Exp Biol Med (Maywood) 233: 997-1012 (Added 2011-03-02 10:33:42.838857)
18563383 Pearson T, Shultz LD, Lief J, Burzenski L, Gott B, Chase T, Foreman O, Rossini AA, Bottino R, Trucco M, Greiner DL A new immunodeficient hyperglycaemic mouse model based on the Ins2Akita mutation for analyses of human islet and beta stem and progenitor cell function. (2008) Diabetologia 51: 1449-56 (Added 2009-04-21 09:46:25)
18491294 Pearson T, Greiner DL, Shultz LD Creation of "humanized" mice to study human immunity. (2008) Curr Protoc Immunol Chapter 15: Unit 15.21 (Added 2011-03-02 10:33:13.034752)
18481451 Pearson T, Greiner DL, Shultz LD Humanized SCID mouse models for biomedical research. (2008) Curr Top Microbiol Immunol 324: 25-51 (Added 2009-04-21 09:43:50)
18096436 King M, Pearson T, Shultz LD, Leif J, Bottino R, Trucco M, Atkinson MA, Wasserfall C, Herold KC, Woodland RT, Schmidt MR, Woda BA, Thompson MJ, Rossini AA, Greiner DL 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. (2008) Clin Immunol 126: 303-14 (Added 2011-03-02 10:32:43.247619)
17376822 King M, Pearson T, Shultz LD, Leif J, Bottino R, Trucco M, Atkinson M, Wasserfall C, Herold K, Mordes JP, Rossini AA, Greiner DL Development of new-generation HU-PBMC-NOD/SCID mice to study human islet alloreactivity. (2007) Ann N Y Acad Sci 1103: 90-3 (Added 2011-03-02 10:15:25.201403)
17332083 Shultz LD, Pearson T, King M, Giassi L, Carney L, Gott B, Lyons B, Rossini AA, Greiner DL Humanized NOD/LtSz-scid IL2 receptor common gamma chain knockout mice in diabetes research. (2007) Ann N Y Acad Sci 1103: 77-89 (Added 2009-04-21 09:43:05)
17259968 Shultz LD, Ishikawa F, Greiner DL Humanized mice in translational biomedical research. (2007) Nat Rev Immunol 7: 118-30 (Added 2009-04-21 09:43:20)
Resource ID Name Contributed on Primary Contributor
209 Autosomal beta-cell toxigene strain Dec 21, 2007 Yes
210 X-linked toxigene strain Dec 21, 2007 Yes
211 NOD-Rag-Perforin Akita Dec 21, 2007 Yes
212 not available Dec 21, 2007 Yes
214 not available Dec 26, 2007 Yes
1261 NOD-Rag1nullIL2rgnullIns2Akita Mar 13, 2009 Yes
1262 NOD-scidIL2gnull Mar 16, 2009 Yes
1421 NOD-Rag1nullPrf1null Apr 20, 2009 Yes
4142 NOD-scid IL2Rγnull Nov 11, 2011 Yes
4143 NOD-Rag IL2rγnull Ins2Akita Nov 15, 2011 Yes
4290 Breed NOD-scid IL2rynull GLUT4null, and NOD-scid IL2rynull ob/ob mice. Mar 15, 2012
11 completed resources viewable