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Zihai Li, MD, PhD
Professor of Microbiology & Immunology
College of Medicine
MUSC

Email: zihai@musc.edu
 
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Zihai Li, MD, PhD

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Research Interest:

My laboratory has primarily been interested in the mechanism of immune regulation by the innate immune system in the context of cancer. My research team has made seminal contributions to understanding the immunological properties of heat shock proteins in cancer immunotherapy and immune tolerance. We provided the first genetic evidence linking the heat shock response to antigen cross-presentation and adaptive immunity; pioneered the use of autologous tumor-derived HSP70-peptide complex for the immunotherapy of human leukemia; and discovered that gp96 (known also as grp94 and HSP90b1) in the endoplasmic reticulum is the master molecular chaperone for Toll-like receptors (TLRs). Furthermore, through transgenic mouse models, we have illuminated the importance of the subcellular localization of gp96 in regulating T cell tolerance and systemic lupus erythematosus. Using a combination of genetic, cell biological, biochemical and immunological tools, our laboratory is pinpointing the precise mechanism of gp96-TLR interaction to understand the implications of such in hematopoiesis, autoimmunity and cancer, as well as in the functions of various cellular components of the immune system. This work has broad implications in understanding how the immune system operates physiologically and how it might be harnessed for the prevention and treatment of human diseases such as cancer in light of the critical role of TLRs in the evolution, function and regulation of the immune system.

Honors:
Sally Abney Rose Endowed Chair in Stem Cell Biology & Therapy, SmartState Center of Economic Excellence

Positions:
Leader, Cancer Immunology Program, Hollings Cancer Center, Medical University of South Carolina
Chair, Department of Microbiology & Immunology, Medical University of South Carolina

Selected Publications:

1.Rachidi S, Wallace K, Day TA, Alberg AJ, Li Z. Lower circulating platelet count and antiplatelet therapy independently predict better outcomes in patients with head and neck squamous cell carcinoma. J Hematol Oncol. .7(1):65, 2014.
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2.Seidler PM, Shinsky SA, Hong F, Li Z, Cosgrove MS, Gewirth DT. Characterization of the Grp94/OS-9 Chaperone-Lectin Complex. J Mol Biol. ., 2014.
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3.Rachidi S, Sun S, Li Z. Endoplasmic reticulum heat shock protein gp96/grp94 is a pro-oncogenic chaperone not a tumor suppressor. Hepatology. ., 2014.
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4.Guo B, Li Z. Endoplasmic reticulum stress in hepatic steatosis and inflammatory bowel diseases. Front Genet. .5:242, 2014. PMCID: PMC4110625
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5.Zhang L, Luo Z, Sieg SF, Funderburg NT, Yu X, Fu P, Wu H, Jiao Y, Gao Y, Greenspan NS, Harding CV, Kilby JM, Li Z, Lederman MM, Jiang W. Plasmacytoid Dendritic Cells Mediate Synergistic Effects of HIV and Lipopolysaccharide on CD27+ IgD- Memory B Cell Apoptosis. J Virol. .88(19):11430-41, 2014.
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6.Bailey SR, Nelson MH, Himes RA, Li Z, Mehrotra S, Paulos CM. Th17 cells in cancer: the ultimate identity crisis. Front Immunol. .5:276, 2014. PMCID: PMC4060300
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7.Thaxton JE, Liu B, Zheng P, Liu Y, Li Z. Deletion of CD24 impairs development of heat shock protein gp96-driven autoimmune disease through expansion of myeloid-derived suppressor cells. J Immunol. .192(12):5679-86, 2014.
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8.Zhang J, Fu S, Sun S, Li Z, Guo B. Inflammasome activation has an important role in the development of spontaneous colitis. Mucosal Immunol. .7(5):1139-50, 2014. PMCID: PMC4115056
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9.Li Z, Chen L, Rubinstein MP. Cancer immunotherapy: are we there yet? Exp Hematol Oncol. .2(1):33, 2013.
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10.Morales C, Rachidi S, Hong F, Sun S, Ouyang X, Wallace C, Zhang Y, Garret-Mayer E, Wu J, Liu B, Li Z. Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis. Cancer Res. .74(2):446-59, 2013. PMCID: PMC4002507
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11.Kellner J, Liu B, Kang Y, Li Z. Fact or fiction--identifying the elusive multiple myeloma stem cell. J Hematol Oncol. .6:91, 2013. PMCID: PMC4029203
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12.Zhang Y, Helke KL, Coelho SG, Valencia JC, Hearing VJ, Sun S, Liu B, Li Z. Essential role of the molecular chaperone gp96 in regulating melanogenesis. Pigment Cell Melanoma Res. .27(1):82-9, 2013. PMCID: PMC4002504
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13.Hua Y, White-Gilbertson S, Kellner J, Rachidi S, Usmani SZ, Chiosis G, Depinho R, Li Z, Liu B. Molecular chaperone gp96 is a novel therapeutic target of multiple myeloma. Clin Cancer Res. .19(22):6242-51, 2013. PMCID: PMC3851294
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14.Liu G, Lu S, Wang X, Page ST, Higano CS, Plymate SR, Greenberg NM, Sun S, Li Z, Wu JD. Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis. J Clin Invest. .123(10):4410-22, 2013. PMCID: PMC3784540
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15.An N, Lin YW, Mahajan S, Kellner JN, Wang Y, Li Z, Kraft AS, Kang Y. Pim1 serine/threonine kinase regulates the number and functions of murine hematopoietic stem cells. Stem Cells. .31(6):1202-12, 2013. PMCID: PMC3664117
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16.Hong F, Liu B, Chiosis G, Gewirth DT, Li Z. a7 helix region of aI domain is crucial for integrin binding to endoplasmic reticulum chaperone gp96: a potential therapeutic target for cancer metastasis. J Biol Chem. .288(25):18243-8, 2013. PMCID: PMC3689966
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17.Liu B, Staron M, Hong F, Wu BX, Sun S, Morales C, Crosson CE, Tomlinson S, Kim I, Wu D, Li Z. Essential roles of grp94 in gut homeostasis via chaperoning canonical Wnt pathway. Proc Natl Acad Sci U S A. .110(17):6877-82, 2013. PMCID: PMC3637754
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18.Rachidi SM, Qin T, Sun S, Zheng WJ, Li Z. Molecular profiling of multiple human cancers defines an inflammatory cancer-associated molecular pattern and uncovers KPNA2 as a uniform poor prognostic cancer marker. PLoS One. .8(3):e57911, 2013. PMCID: PMC3607594
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19.Pandey JP, Li Z. The forgotten tale of immunoglobulin allotypes in cancer risk and treatment. Exp Hematol Oncol. .2(1):6, 2013. PMCID: PMC3598368
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20.Liu B, Staron M, Li Z. Murine but not human basophil undergoes cell-specific proteolysis of a major endoplasmic reticulum chaperone. PLoS One. .7(6):e39442, 2012. PMCID: PMC3377640
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21.Maitra U, Deng H, Glaros T, Baker B, Capelluto DG, Li Z, Li L. Molecular mechanisms responsible for the selective and low-grade induction of proinflammatory mediators in murine macrophages by lipopolysaccharide. J Immunol. .189(2):1014-23, 2012. PMCID: PMC3392521
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22.Barton ER, Park S, James JK, Makarewich CA, Philippou A, Eletto D, Lei H, Brisson B, Ostrovsky O, Li Z, Argon Y. Deletion of muscle GRP94 impairs both muscle and body growth by inhibiting local IGF production. FASEB J. .26(9):3691-702, 2012. PMCID: PMC3425820
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23.Wu S, Dole K, Hong F, Noman AS, Issacs J, Liu B, Li Z. Chaperone gp96-independent inhibition of endotoxin response by chaperone-based peptide inhibitors. J Biol Chem. .287(24):19896-903, 2012. PMCID: PMC3370174
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24.Li Z, Hsueh CT, Liu D. Publish, not perish: Introducing Experimental Hematology & Oncology. Exp Hematol Oncol. .1(1):1, 2012. PMCID: PMC3506992
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25.Wu S, Hong F, Gewirth D, Guo B, Liu B, Li Z. The molecular chaperone gp96/GRP94 interacts with Toll-like receptors and integrins via its C-terminal hydrophobic domain. J Biol Chem. .287(9):6735-42, 2012. PMCID: PMC3307303
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26.Staron M, Wu S, Hong F, Stojanovic A, Du X, Bona R, Liu B, Li Z. Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex. Blood. .117(26):7136-44, 2011. PMCID: PMC3143555
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27.Li X, Zhang K, Li Z. Unfolded protein response in cancer: the physician's perspective. J Hematol Oncol. .4:8, 2011. PMCID: PMC3060154
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28.Audouard C, Le Masson F, Charry C, Li Z, Christians ES. Oocyte-targeted deletion reveals that hsp90b1 is needed for the completion of first mitosis in mouse zygotes. PLoS One. .6(2):e17109, 2011. PMCID: PMC3039677
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29.Usmani SZ, Bona RD, Chiosis G, Li Z. The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1. J Hematol Oncol. .3:40, 2010. PMCID: PMC2974653
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30.Liu B, Yang Y, Qiu Z, Staron M, Hong F, Li Y, Wu S, Li Y, Hao B, Bona R, Han D, Li Z. Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone. Nat Commun. .1:79, 2010. PMCID: PMC2982182
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31.Han JM, Kwon NH, Lee JY, Jeong SJ, Jung HJ, Kim HR, Li Z, Kim S. Identification of gp96 as a novel target for treatment of autoimmune disease in mice. PLoS One. .5(3):e9792, 2010. PMCID: PMC2843739
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32.Liu B, Nash J, Runowicz C, Swede H, Stevens R, Li Z. Ovarian cancer immunotherapy: opportunities, progresses and challenges. J Hematol Oncol. .3:7, 2010. PMCID: PMC2831814
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33.McAleer JP, Liu B, Li Z, Ngoi SM, Dai J, Oft M, Vella AT. Potent intestinal Th17 priming through peripheral lipopolysaccharide-based immunization. J Leukoc Biol. .88(1):21-31, 2010. PMCID: PMC2892526
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34.Li Y, Zeng H, Xu RH, Liu B, Li Z. Vaccination with human pluripotent stem cells generates a broad spectrum of immunological and clinical responses against colon cancer. Stem Cells. .27(12):3103-11, 2009.
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35.Staron M, Yang Y, Liu B, Li J, Shen Y, Zúñiga-Pflücker JC, Aguila HL, Goldschneider I, Li Z. gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis. Blood. .115(12):2380-90, 2009. PMCID: PMC2845896
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36.Morales C, Wu S, Yang Y, Hao B, Li Z. Drosophila glycoprotein 93 Is an ortholog of mammalian heat shock protein gp96 (grp94, HSP90b1, HSPC4) and retains disulfide bond-independent chaperone function for TLRs and integrins. J Immunol. .183(8):5121-8, 2009. PMCID: PMC2856694
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37.Usmani SZ, Bona R, Li Z. 17 AAG for HSP90 inhibition in cancer--from bench to bedside. Curr Mol Med. .9(5):654-64, 2009.
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38.Dai J, Liu B, Li Z. Regulatory T cells and Toll-like receptors: what is the missing link? Int Immunopharmacol. .9(5):528-33, 2009. PMCID: PMC2856690
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39.Goldstein MG, Li Z. Heat-shock proteins in infection-mediated inflammation-induced tumorigenesis. J Hematol Oncol. .2:5, 2009. PMCID: PMC2644312
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40.Qiao Y, Liu B, Li Z. Activation of NK cells by extracellular heat shock protein 70 through induction of NKG2D ligands on dendritic cells. Cancer Immun. .8:12, 2008. PMCID: PMC2935777
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41.Dhodapkar MV, Dhodapkar KM, Li Z. Role of chaperones and FcgammaR in immunogenic death. Curr Opin Immunol. .20(5):512-7, 2008. PMCID: PMC3224819
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42.Liu B, Li Z. Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin. Blood. .112(4):1223-30, 2008. PMCID: PMC2515121
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43.Wang Z, Liu B, Wang P, Dong X, Fernandez-Hernando C, Li Z, Hla T, Li Z, Claffey K, Smith JD, Wu D. Phospholipase C beta3 deficiency leads to macrophage hypersensitivity to apoptotic induction and reduction of atherosclerosis in mice. J Clin Invest. .118(1):195-204, 2008. PMCID: PMC2129238
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44.Li W, Cui H, Meng FQ, Chang XH, Zhang G, Liu B, Li ZH. New T cell epitopes identified from an anti-idiotypic antibody mimicking ovarian cancer associated antigen. Cancer Immunol Immunother. .57(2):143-54, 2007.
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45.Han JM, Park SG, Liu B, Park BJ, Kim JY, Jin CH, Song YW, Li Z, Kim S. Aminoacyl-tRNA synthetase-interacting multifunctional protein 1/p43 controls endoplasmic reticulum retention of heat shock protein gp96: its pathological implications in lupus-like autoimmune diseases. Am J Pathol. .170(6):2042-54, 2007. PMCID: PMC1899434
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46.Gorusu M, Benn P, Li Z, Fang M. On the genesis and prognosis of variant translocations in chronic myeloid leukemia. Cancer Genet Cytogenet. .173(2):97-106, 2007.
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47.Dai J, Liu B, Cua DJ, Li Z. Essential roles of IL-12 and dendritic cells but not IL-23 and macrophages in lupus-like diseases initiated by cell surface HSP gp96. Eur J Immunol. .37(3):706-15, 2007.
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48.Dai J, Liu B, Ngoi SM, Sun S, Vella AT, Li Z. TLR4 hyperresponsiveness via cell surface expression of heat shock protein gp96 potentiates suppressive function of regulatory T cells. J Immunol. .178(5):3219-25, 2007.
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49.Yang Y, Liu B, Dai J, Srivastava PK, Zammit DJ, Lefrançois L, Li Z. Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity. .26(2):215-26, 2007. PMCID: PMC2847270
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50.Liu B, Yang Y, Dai J, Medzhitov R, Freudenberg MA, Zhang PL, Li Z. TLR4 up-regulation at protein or gene level is pathogenic for lupus-like autoimmune disease. J Immunol. .177(10):6880-8, 2006.
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51.Yang Y, Li Z. Roles of heat shock protein gp96 in the ER quality control: redundant or unique function? Mol Cells. .20(2):173-82, 2005.
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52.Pritchard MT, Li Z, Repasky EA. Nitric oxide production is regulated by fever-range thermal stimulation of murine macrophages. J Leukoc Biol. .78(3):630-8, 2005.
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53.Li Z, Qiao Y, Liu B, Laska EJ, Chakravarthi P, Kulko JM, Bona RD, Fang M, Hegde U, Moyo V, Tannenbaum SH, Ménoret A, Gaffney J, Glynn L, Runowicz CD, Srivastava PK. Combination of imatinib mesylate with autologous leukocyte-derived heat shock protein and chronic myelogenous leukemia. Clin Cancer Res. .11(12):4460-8, 2005.
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54.Gale RP, Horowitz MM, Talpaz M, Scheinberg DA, Molldrem J, Li Z, Baccarani M, Goldman JM, Tura S. Immune therapy of chronic myelogenous leukemia. Leuk Res. .29(5):583-6, 2005.
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55.Zheng H, Li Z. Cutting edge: cross-presentation of cell-associated antigens to MHC class I molecule is regulated by a major transcription factor for heat shock proteins. J Immunol. .173(10):5929-33, 2004.
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56.Lee SJ, Myers L, Muralimohan G, Dai J, Qiao Y, Li Z, Mittler RS, Vella AT. 4-1BB and OX40 dual costimulation synergistically stimulate primary specific CD8 T cells for robust effector function. J Immunol. .173(5):3002-12, 2004.
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57.DeFillipo AM, Dai J, Li Z. Heat shock-induced dendritic cell maturation is coupled by transient aggregation of ubiquitinated proteins independently of heat shock factor 1 or inducible heat shock protein 70. Mol Immunol. .41(8):785-92, 2004.
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58.Li Z. In vitro reconstitution of heat shock protein-peptide complexes for generating peptide-specific vaccines against cancers and infectious diseases. Methods. .32(1):25-8, 2004.
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59.Liu B, Dai J, Zheng H, Stoilova D, Sun S, Li Z. Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases. Proc Natl Acad Sci U S A. .100(26):15824-9, 2003. PMCID: PMC307652
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60.Millar DG, Garza KM, Odermatt B, Elford AR, Ono N, Li Z, Ohashi PS. Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nat Med. .9(12):1469-76, 2003.
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61.Zheng H, Benjamin IJ, Basu S, Li Z. Heat shock factor 1-independent activation of dendritic cells by heat shock: implication for the uncoupling of heat-mediated immunoregulation from the heat shock response. Eur J Immunol. .33(6):1754-62, 2003.
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62.Dai J, Liu B, Caudill MM, Zheng H, Qiao Y, Podack ER, Li Z. Cell surface expression of heat shock protein gp96 enhances cross-presentation of cellular antigens and the generation of tumor-specific T cell memory. Cancer Immun. .3:1, 2003.
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63.Liu B, DeFilippo AM, Li Z. Overcoming immune tolerance to cancer by heat shock protein vaccines. Mol Cancer Ther. .1(12):1147-51, 2002.
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64.Li Z, Dai J, Zheng H, Liu B, Caudill M. An integrated view of the roles and mechanisms of heat shock protein gp96-peptide complex in eliciting immune response. Front Biosci. .7:d731-51, 2002.
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65.Li Z, Menoret A, Srivastava P. Roles of heat-shock proteins in antigen presentation and cross-presentation. Curr Opin Immunol. .14(1):45-51, 2002.
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66.Zheng H, Dai J, Stoilova D, Li Z. Cell surface targeting of heat shock protein gp96 induces dendritic cell maturation and antitumor immunity. J Immunol. .167(12):6731-5, 2001.
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67.Bilgrami S, Bona RD, Edwards RL, Li Z, Naqvi B, Shaikh A, Furlong F, Fox J, Clive J, Tutschka PJ. Dexamethasone, paclitaxel, etoposide, cyclophosphamide (d-TEC) and G-CSF for stem cell mobilisation in multiple myeloma. Bone Marrow Transplant. .28(2):137-43, 2001.
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68.Ménoret A, Li Z, Niswonger ML, Altmeyer A, Srivastava PK. An endoplasmic reticulum protein implicated in chaperoning peptides to major histocompatibility of class I is an aminopeptidase. J Biol Chem. .276(36):33313-8, 2001.
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69.Caudill MM, Li Z. HSPPC-96: a personalised cancer vaccine. Expert Opin Biol Ther. .1(3):539-47, 2001.
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70.Li Z, Gooley T, Applebaum FR, Deeg HJ. Splenectomy and hemopoietic stem cell transplantation for myelofibrosis. Blood. .97(7):2180-1, 2001.
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71.Li Z, Deeg HJ. Pros and cons of splenectomy in patients with myelofibrosis undergoing stem cell transplantation. Leukemia. .15(3):465-7, 2001.
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72.Li Z, Groh V, Strong RK, Spies T. A single amino acid substitution causes loss of expression of a MICA allele. Immunogenetics. .51(3):246-8, 2000.
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73.Blachere NE, Li Z, Chandawarkar RY, Suto R, Jaikaria NS, Basu S, Udono H, Srivastava PK. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med. .186(8):1315-22, 1997. PMCID: PMC2199095
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74.Li Z. Priming of T cells by heat shock protein-peptide complexes as the basis of tumor vaccines. Semin Immunol. .9(5):315-22, 1997.
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75.Li Z, Srivastava PK. A critical contemplation on the role of heat shock proteins in transfer of antigenic peptides during antigen presentation. Behring Inst Mitt. .(94):37-47, 1994.
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76.Srivastava PK, Udono H, Blachere NE, Li Z. Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics. .39(2):93-8, 1994.
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77.Blachere NE, Udono H, Janetzki S, Li Z, Heike M, Srivastava PK. Heat shock protein vaccines against cancer. J Immunother Emphasis Tumor Immunol. .14(4):352-6, 1993.
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78.Li Z, Srivastava PK. Tumor rejection antigen gp96/grp94 is an ATPase: implications for protein folding and antigen presentation. EMBO J. .12(8):3143-51, 1993. PMCID: PMC413580
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