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Current Research

Scientific Overview


Moriya  Tsuji
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Moriya Tsuji, M.D., Ph.D.
Professor

Research Activities

Project 1 - Humanized Mouse Models for Vaccine/Adjuvant Research
My laboratory has recently established a humanized mouse model by using a novel approach to introduce human genes encoding cytokines and HLA molecules by adeno-associated virus serotype 9 (AAV9) vector-mediated delivery. This human gene transduction to immunodeficient NSG mice facilitates the reconstitution of human immune system (HIS) that includes functional human CD8+ T cell, CD4+ T cells and B cells in NSG mice, upon engraftment of human hematopoietic stem cells (HSCs) [ref. 1, 2, 3, 4, 5, 6].  Briefly, NSG mice transduced with AAV9 encoding certain HLAs and selected human cytokines, such as human GMCSF, IL-3 and IL-15, resulted in a high level (>85%) of reconstitution of human CD45+ cells without significant mouse to mouse variation. Furthermore, the transduction of HLAs/hucytokines has led HIS mice to induce a potent human T-cell response, as well as human IgG response, against antigens derived from human pathogens. Most recently, we have succeeded in generating a novel humanized mouse model, in which both human CD1d and HLA-A2 are co-expressed by way of AAV9 vectors [ref. 7]. These humanized mice can mount functional human invariant natural killer T (iNKT) cells, as well as human CD8+ T cells, thus enabling us to study the function of CD1d-binding NKT-stimulating glycolipids in the context of our Project 2 (see below).

Project 2 – A CD1d-binding NKT Stimulating Glycolipid as Cancer Immunotherapy
From a glycolipid library consisting of more than 100 α-galactosylceramide analogs, we have previously identified a clinical lead, called 7DW8-5, which can exert potent stimulatory activity on iNKT cells and dendritic cells, while displaying an adjuvant effect superior to that of α-GalCer [ref. 8, 9, 10, 11].  Our 7DW8-5 not only potently stimulates human iNKT cells and induces the maturation of dendritic cells, but also displays a binding affinity to human and murine CD1d molecules, which are superior to those of α-GalCer. 7DW8-5 has demonstrated an excellent safety profile and potent immune enhancing activity in non-human primate studies [ref. 12] and also highly localized biodistribution in the draining lymph nodes upon intramuscular injection in a mouse model [ref 13, 14]. We are currently testing 7DW8-5 as an immunotherapy agent against cancer, such as ovarian and breast cancers using our novel humanized mouse model (Project 1) [ref. 7] in a preclinical setting. 

Project 3 – Modified Adenoviral Vector for Malaria Vaccine
In the past, my team had shown for the first time that adenovirus (Ad) is an excellent vector for inducing a protective cell-mediated immunity against malaria [ref. 15, 16]. However, the recombinant Ad expressing a malaria antigen was unable to induce a potent humoral response against malaria. Because Ad, particularly Ad serotype 5 (Ad5), is known to elicit a strong pre-existing immunity that is primarily against its capsid proteins, we decided to insert a B-cell epitope of Plasmodium yoelii circumsporozoite protein (PyCSP) into the capsid proteins of Ad5. After multiple immunization of capsid-modified or unmodified AdPyCSP, we found that AdPyCSP expressing the B epitope in the HVR1 of the Hexon of AdPyCSP induces a higher level of protective anti-malarial immunity than unmodified AdPyCS [ref. 17]. After having identified HVR1 as an optimal site to circumvent pre-existing anti-Ad immunity and improve the immunogenicity of AdPyCSP, we have switched to a human malaria antigen, P. falciparum CSP (PfCSP), as a transgene to express. In addition to the PfCSP transgene, we inserted B-cell, as well as CD4+ T-cell, epitopes of PfCSP into the capsid protein (Hexon) and the core protein VII (pVII) of Ad, respectively. We found that the doubly modified adenovirus vaccine can induce both humoral and cellular immune responses potently, and ultimately, protected a majority of mice from challenge with highly infectious transgenic rodent parasites that express PfCSP, PfCSP/Py sporozoites [ref. 18]. Hexon and pVII-modified adenoviral malaria vaccine that express not only PfCSP but also its B-cell and CD4+ T-cell epitopes, is a promising candidate as a next generation malaria vaccine.

Project 4 – PD1 Inhibitory Peptides to Improve Malaria Vaccine
In malaria-infected individuals, PD-1 is highly elevated on CD4+ T cells suggesting that PD-1-mediated immune dysfunction may limit protective immunity against the parasite. In a rodent malaria model, PD-1 was shown to severely dampen CD8+ T cell proliferation and prolong chronic infection. Leidos, Inc. has recently identified several PD-1 peptides that bind both human and mouse PD-1. In order to determine whether PD-1 inhibitory peptides can enhance the immunogenicity of a malaria vaccine, we immunized a group of mice with a recombinant adenovirus expressing P. yoelii circumsporozoite protein (AdPyCSP) [ref. 15, 16], followed by the injection of PD-1 inhibitory peptides. Another groups of mice received AdPyCSP alone. When we compared the immunogenicity of the two groups of mice, we found that PD-1 inhibitory peptides could significantly enhance the level of PyCSP-specific CD8+ T-cell response, ultimately leading to a more potent protective immunity against rodent malaria infection in a mouse model. We are currently determining the mechanisms by which PD-1 inhibitory peptides display their immunomodulating effect. 

References

  1. Huang J, Li X, Coelho-dos-Reis JGA, Wilson JM, Tsuji M. 2014. An AAV vector-mediated gene delivery approach facilitates reconstitution of functional human CD8+ T cells in mice. PLOS ONE   9: e88205.
  2. Sharma A, Wu W, Sung B, Huang J, Tsao T, Li X, Gomi R, Tsuji M, Worgall S. 2016. RSV Pulmonary Infection in Humanized Mice Induces Human Anti-RSV Immune Responses and Pathology. J Virol. 90: 5068-5074.  Co-corresponding author.
  3. Huang J, Li X, Coelho-dos-Reis JGA, Zhang M, Mitchell R, Tayar-Nogueira R, Tsao T, Noe AR, Ayala R, Sahi V, Gutierrez GM, Nussenzweig V, Wilson JM, Nardin EH, Nussenzweig RS, Tsuji M. 2015. Human immune system mice immunized with Plasmodium falciparum circumsporozoite protein induce protective human humoral immunity against malaria.  J Immunol Methods 427:42-50. 
  4. Li X, Huang J, Zhang M, Funakoshi R, Sheetij D, Spaccapelo R, Crisanti A, Nussenzweig V, Nussenzweig RS, Tsuji M. 2016. Human CD8+ T cells mediate protective immunity induced by a human malaria vaccine in human immune system mice. Vaccine 34:4501-6.
  5. Saito A, Henning MS, Serrao E, Dubose BN, Teng S, Huang J, Li X, Saito N, Roy SP, Siddiqui MA, Ahn J, Tsuji M, Hatziioannou T, Engelman AN, Yamashita M. 2016 Optimal capsid interactions with CPSF6 are dispensable but selected during HIV-1 replication. J Virol. 90:6918-35. 
  6. Nogueira RT, Sahi V, Huang J, Tsuji M. 2017. Human IgG repertoire of malaria antigen-immunized human immune system (HIS) mice. Immunol Lett. 188: 46-52.
  7. Li X, Huang J, Kaneko I, Zhang M, Iwanaga S, Yuda M, Tsuji M. 2017. A potent adjuvant effect of a CD1d-binding NKT cell ligand in human immune system mice.  Expert Rev Vaccines 16:73-80.
  8. Li X, Fujio M, Imamura M, Wu D,Vasan S, Wong C-H, Ho DD, Tsuji M.  2010. Design of a novel CD1d-binding NKT cell ligand as a vaccine adjuvant. Proc. Natl. Acad. Sci. USA. 107: 13010-13015.
  9. Padte NN, Li X, Tsuji M, Vasan S. 2011. Clinical Development of a Novel CD1d-binding NKT Cell Ligand as a Vaccine Adjuvant.  Clin. Immunol. 140: 142-151.
  10. Venkataswamy MM, Ng TW, Kharkwal SS, Carreño LJ, Johnson AJ, Kunnath-Velayudhan S, Liu Z, Bittman R, Jervis PJ, Cox LR, Besra GS, Wen X, Yuan W, Tsuji M, Li X, Ho DD, Chan J, Lee S, Frothingham R, Haynes BF, Panas MW, Gillard GO, Sixsmith JD, Korioth-Schmitz B, Schmitz JE, Larsen MH, Jacobs WR Jr, Porcelli SA. 2014. Improving Mycobacterium bovis bacillus Calmette-Guèrin as a vaccine delivery vector for viral antigens by incorporation of glycolipid activators of NKT cells. PLoS One. 9: e108383.
  11. Coelho-dos-Reis JG, Huang J, Tsao T, Pereira FV, Funakoshi R, Nakajima H, Sugiyama H, Tsuji M. 2016. Co-administration of a-GalCer analog and TLR4 agonist induces robust CD8+ T-cell responses to PyCS protein and WT-1 antigen and activates memory-like effector NKT cells.  Clin Immunol. 168: 6-15.
  12. Padte NN, Boente-Carrera M, Andrews CD, McManus J, Grasperge BF, Gettie A, Coelho-dos-Reis JGA, Li X, Levenkova N, Wu D, Bruder JT, Sedegah M, Patterson N, Richie TL, Wong CH, Ho DD, Vasan S, Tsuji M. 2013 A glycolipid adjuvant, 7DW8-5, enhances CD8+ T cell responses induced by an adenovirus-vectored malaria vaccine in non-human primates. PLOS ONE   8: e78407.
  13. Li X, Kawamura A, Andrews CD, Miller JL, Wu D, Tsao T, Zhang M, Oren D, Padte NN, Porcelli SA, Wong CH, Kappe SHI, Ho DD, Tsuji M. 2015. The co-localization of a CD1d-binding glycolipid with a radiation-attemuated sporozoites vaccine in LN-resident DCs for a robust adjuvant effect. J Immunol  195: 2710-2721. 
  14. Li X, Huang J, Kawamura A, Funakoshi R, Porcelli SA, Tsuji M. 2017. Co-localization of a CD1d-binding glycolipid with an adenovirus-based malaria vaccine for a potent adjuvant effect. Vaccine. 35: 3171-3177.
  15. Rodrigues EG, Zavala F, Eichinger D, Wilson JM, Tsuji M.  1997.  Single immunizing dose of recombinant adenovirus efficiently induces CD8+ T cell-mediated protective immunity against malaria.  J. Immunol.  158: 1268-74.
  16. Rodrigues EG, Zavala F, Nussenzweig RS, Wilson JM, Tsuji M.  1998.  Efficient induction of protective anti-malaria immunity by recombinant adenovirus. Vaccine  16: 1812-17.
  17. Shiratsuchi T, Kraus A, Worgall S, Tsuji M.  2010. Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents pre-existing immunity to adenovirus in mice.  J. Clin. Inv. 120: 3688-3701.
  18. Shiratsuchi T, Rai U, Kaneko I, Zhang M, Iwanaga S, Yuda M, Tsuji M. 2017. A potent malaria vaccine based on adenovirus with dual modifications at Hexon and pVII. Vaccine.  In press.