[1] G. Trinchieri and D. Santoli, Anti-viral activity induced by culturing lymphocytes
with tumor-derived or virus-transformed cells. Enhancement of human natural killer
cell activity by interferon and antagonistic inhibition of susceptibility of target cells to
lysis, J. Exp. Med. 147 (1978) 1314-1333.
[2] F.P. Siegal, The Nature of the Principal Type 1 Interferon-Producing Cells in
Human Blood, Science 284 (1999) 1835-1837.
[3] M. Gilliet, W. Cao, Y.J. Liu, Plasmacytoid dendritic cells: sensing nucleic acids in
viral infection and autoimmune diseases, Nature Reviews Immunology 8 (2008) 594606.
[4] J.M. Lund, L. Alexopoulou, A. Sato, M. Karow, N.C. Adams, N.W. Gale, A. Iwasaki,
R.A. Flavell, Recognition of single-stranded RNA viruses by Toll-like receptor 7, Proc.
Natl. Acad. Sci. U. S. A. 101 (2004) 5598-5603.
[5] S.S. Diebold, T. Kaisho, H. Hemmi, S. Akira, C. Reis e Sousa, Innate antiviral
responses by means of TLR7-mediated recognition of single-stranded RNA, Science
303 (2004) 1529-1531.
[6] H.K. Lee, J.M. Lund, B. Ramanathan, N. Mizushima, A. Iwasaki, Autophagydependent viral recognition by plasmacytoid dendritic cells, Science 315 (2007) 13981401.
[7] H. Hemmi, O. Takeuchi, T. Kawai, T. Kaisho, S. Sato, H. Sanjo, M. Matsumoto, K.
Hoshino, H. Wagner, K. Takeda, S. Akira, A Toll-like receptor recognizes bacterial
DNA, Nature 408 (2000) 740-745.
[8] S. Bauer, C.J. Kirschning, H. Hacker, V. Redecke, S. Hausmann, S. Akira, H.
Wagner, G.B. Lipford, Human TLR9 confers responsiveness to bacterial DNA via
species-specific CpG motif recognition, Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 92379242.
[9] E. Latz, A. Verma, A. Visintin, M. Gong, C.M. Sirois, D.C. Klein, B.G. Monks, C.J.
McKnight, M.S. Lamphier, W.P. Duprex, T. Espevik, D.T. Golenbock, Ligand-induced
conformational changes allosterically activate Toll-like receptor 9, Nat. Immunol. 8
(2007) 772-779.
103
[10] K. Honda, H. Yanai, T. Mizutani, H. Negishi, N. Shimada, N. Suzuki, Y. Ohba, A.
Takaoka, W.C. Yeh, T. Taniguchi, Role of a transductional-transcriptional processor
complex involving MyD88 and IRF-7 in Toll-like receptor signaling, Proc. Natl. Acad.
Sci. U. S. A. 101 (2004) 15416-15421.
[11] T. Kawai, S. Sato, K.J. Ishii, C. Coban, H. Hemmi, M. Yamamoto, K. Terai, M.
Matsuda, J. Inoue, S. Uematsu, O. Takeuchi, S. Akira, Interferon-alpha induction
through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and
TRAF6, Nat. Immunol. 5 (2004) 1061-1068.
[12] T. Ito, H. Kanzler, O. Duramad, W. Cao, Y.J. Liu, Specialization, kinetics, and
repertoire of type 1 interferon responses by human plasmacytoid predendritic cells,
Blood 107 (2006) 2423-2431.
[13] K. Honda, Y. Ohba, H. Yanai, H. Negishi, T. Mizutani, A. Takaoka, C. Taya, T.
Taniguchi, Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I
interferon induction, Nature 434 (2005) 1035-1040.
[14] A.N. Theofilopoulos, R. Baccala, B. Beutler, D.H. Kono, Type I interferons
(alpha/beta) in immunity and autoimmunity, Annu. Rev. Immunol. 23 (2005) 307-336.
[15] A.J. Sadler, B.R. Williams, Interferon-inducible antiviral effectors. Nat Rev
Immunol. 8 (2008) 559-568.
[16] D.J. Lenschow, C. Lai, N. Frias-Staheli, et al. IFN-stimulated gene 15 functions
as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proc
Natl. Acad. Sci. U. S. A. 104 (2007) 1371-1376.
[17] T.Y. Hsiang, C. Zhao, R.M. Krug, Interferon-induced ISG15 conjugation inhibits
influenza A virus gene expression and replication in human cells. J. Virol. 83 (2009)
5971-5977.
[18] C. Zhao, T.Y. Hsiang, R.L. Kuo, et al. ISG15 conjugation system targets the viral
NS1 protein in influenza A virus-infected cells. Proc. Natl. Acad. Sci. U. S. A. 107
(2010) 2253-2258.
[19] Y. Tang, G. Zhong, L. Zhu, et al. Herc5 attenuates influenza A virus by catalyzing
ISGylation of viral NS1 protein. J. Immunol. 184 (2010) 5779-5790.
104
[20] C. Zhao, C. Denison, J.M. Huibregtse, et al. Human ISG15 conjugation targets
both IFN-induced and constitutively expressed proteins functioning in diverse cellular
pathways. Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 10200-10205
[21] Bogunovic D, Boisson-Dupuis S, Casanova JL. ISG15: leading a double life as a
secreted molecule. Exp. Mol. Med. 45 (2013), e18
[22] Okumura F, Okumura AJ, Uematsu K, et al. Activation of double-stranded RNAactivated protein kinase (PKR) by interferon-stimulated gene 15 (ISG15) modification
down-regulates protein translation. J. Biol. Chem. 288 (2013), 2839-2847.
[23] T. Luft, K.C. Pang, E. Thomas, P. Hertzog, D.N. Hart, J. Trapani, J. Cebon, Type I
IFNs enhance the terminal differentiation of dendritic cells, J. Immunol. 161 (1998)
1947-1953.
[24] P. Blanco, A.K. Palucka, M. Gill, V. Pascual, J. Banchereau, Induction of dendritic
cell differentiation by IFN-alpha in systemic lupus erythematosus, Science 294 (2001)
1540-1543.
[25] A. Le Bon, N. Etchart, C. Rossmann, M. Ashton, S. Hou, D. Gewert, P. Borrow,
D.F. Tough, Cross-priming of CD8+ T cells stimulated by virus-induced type I
interferon, Nat. Immunol. 4 (2003) 1009-1015.
[26] P. Marrack, J. Kappler, T. Mitchell, Type I interferons keep activated T cells alive,
J. Exp. Med. 189 (1999) 521-530.
[27] A. Le Bon, D.F. Tough, Links between innate and adaptive immunity via type I
interferon, Curr. Opin. Immunol. 14 (2002) 432-436.
[28] M.F. Mescher, J.M. Curtsinger, P. Agarwal, K.A. Casey, M. Gerner, C.D.
Hammerbeck, F. Popescu, Z. Xiao, Signals required for programming effector and
memory development by CD8+ T cells, Immunol. Review 211 (2006) 81-92.
[29] H. Takagi, T. Fukaya, K. Eizumi, Y. Sato, K. Sato, A. Shibazaki, H. Otsuka, A.
Hijikata, T. Watanabe, O. Ohara, T. Kaisho, B. Malissen, K. Sato, Plasmacytoid
dendritic cells are crucial for the initiation of inflammation and T cell immunity in
vivo, Immunity 35 (2011) 958-971.
[30] A. Krug, R. Uppaluri, F. Facchetti, B.G. Dorner, K.C. Sheehan, R.D. Schreiber, M.
Cella, M. Colonna, IFN-producing cells respond to CXCR3 ligands in the presence of
105
CXCL12 and secrete inflammatory chemokines upon activation, J. Immunol. 169
(2002) 6079-6083.
[31] B. Vanbervliet, N. Bendriss-Vermare, C. Massacrier, B. Homey, O. de Bouteiller, F.
Briere, G. Trinchieri, C. Caux, The inducible CXCR3 ligands control plasmacytoid
dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor
1 (SDF-1)/CXCL12, J. Exp. Med. 198 (2003) 823-830.
[32] F. Gerosa, A. Gobbi, P. Zorzi, S. Burg, F. Briere, G. Carra, G. Trinchieri, The
reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells
profoundly affects innate resistance functions, J. Immunol. 174 (2005) 727-734.
[33] G. Jego, A.K. Palucka, J.-P. Blanck, C. Chalouni, V. Pascual, J. Banchereau,
Plasmacytoid Dendritic Cells Induce Plasma Cell Differentiation through Type I
Interferon and Interleukin 6, Immunity 19 (2003) 225-234.
[34] H. Poeck, M. Wagner, J. Battiany, S. Rothenfusser, D. Wellisch, V. Hornung, B.
Jahrsdorfer, T. Giese, S. Endres, G. Hartmann, Plasmacytoid dendritic cells, antigen,
and CpG-C license human B cells for plasma cell differentiation and immunoglobulin
production in the absence of T-cell help, Blood 103 (2004) 3058-3064.
[35] H. Tezuka, Y. Abe, J. Asano, T. Sato, J. Liu, M. Iwata, T. Ohteki, Prominent role
for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction,
Immunity 34 (2011) 247-257.
[36] A. Sato, M. Hashiguchi, E. Toda, A. Iwasaki, S. Hachimura, S. Kaminogawa,
CD11b+ Peyer's patch dendritic cells secrete IL-6 and induce IgA secretion from naive
B cells. J Immunol. 171 (2003) 3684-3690.
[37] Y. Jin, Y. Hu, D. Han, M. Wang, Chronic heat stress weakened the innate
immunity and increased the virulence of highly pathogenic avian influenza virus
H5N1 in mice, J. Biomed. Biotechnol. 2011 (2011) 367846.
[38] Grolleau-Julius A, Harning EK, Abernathy LM, Yung RL. Impaired dendritic cell
function in ageing. Cancer Res. 68 (2008) 6341-6349.
[39] H.W. Stout-Delgado, X. Yang, W.E. Walker, B.M. Tesar, D.R. Goldstein, Aging
impairs IFN regulatory factor 7 up-regulation in plasmacytoid dendritic cells during
TLR9 activation, J. Immunol. 181 (2008) 6747-6756.
106
[40] D. Fujiwara, S. Inoue, H. Wakabayashi, T. Fujii, The anti-allergic effects of lactic
acid bacteria are strain dependent and mediated by effects on both Th1/Th2 cytokine
expression and balance, Int. Arch. Allergy Immunol. 135 (2004) 205-215.
[41] H. Wakabayashi, C. Nariai, F. Takemura, W. Nakao, D. Fujiwara, Dietary
supplementation with lactic acid bacteria attenuates the development of atopicdermatitis-like skin lesions in NC/Nga mice in a strain-dependent manner, Int. Arch.
Allergy Immunol. 145 (2008) 141-151.
[42] D. Fujiwara, H. Watanabe, S. Nishida, H. Iino, A. double-blind trial of
Lactobacillus paracasei strain KW3110 administration for immunomodulation in
patients with pollen allergy, Allergol. Int. 54 (2005) 143-149.
[43] M. Kawase, F. He, A. Kubota, K. Yoda, K. Miyazawa, M. Hiramatsu, Heat-killed
Lactobacillus gasseri TMC0356 protects mice against influenza virus infection by
stimulating gut and respiratory immune responses. FEMS Immunol. Med. Microbiol.
64 (2012) 280-288.
[44] T. Nagai, S. Makino, S. Ikegami, H. Itoh, H. Yamada, Effects of oral
administration of yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus
OLL1073R-1 and its exopolysaccharides against influenza virus infection in mice, Int.
Immunopharmacol. 11 (2011) 2246-2250.
[45] T. Izumo, T. Maekawa, M. Ida, A. Noguchi, Y. Kitagawa, H. Shibata, H. Yasui, Y.
Kiso, Effect of intranasal administration of Lactobacillus pentosus S-PT84 on
influenza virus infection in mice, Int. Immunopharmacol. 10 (2010) 1101-1106.
[46] S. Makino, S. Ikegami, A. Kume, H. Horiuchi, H. Sasaki, N. Orii, Reducing the
risk of infection in the elderly by dietary intake of yoghurt fermented with
Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1, Br. J. Nutr. 104 (2010) 9981006.
[47] K. Namba, M. Hatano, T. Yaeshima, M. Takase, K. Suzuki, Effects of
Bifidobacterium longum BB536 Administration on Influenza Infection, Influenza
Vaccine Antibody Titer, and Cell-Mediated Immunity in the Elderly, Biosci.
Biotechnol. Biochem. 74 (2010) 939-945.
107
[48] M. Gleeson, N.C. Bishop, M. Oliveira, P. Tauler, Daily probiotic's (Lactobacillus
casei Shirota) reduction of infection incidence in athletes, Int. J. Sport. Nutr. Exerc.
Metab. 21 (2001) 55-64.
[49] D. Piccioli, C. Sammicheli, S. Tavarini, et al. Human plasmacytoid dendritic cells
are unresponsive to bacterial stimulation and require a novel type of cooperation with
myeloid dendritic cells for maturation. Blood 113 (2009) 4232-4239.
[50] K. Jounai, K. Ikado, T. Sugimura, Y. Ano, J. Braun, D. Fujiwara, Spherical lactic
acid bacteria activate plasmacytoid dendritic cells immunomodulatory function via
TLR9-dependent crosstalk with myeloid dendritic cells, PloS One 7 (2012) e32588.
[51] K. Jounai, T. Sugimura, K. Ohshio, D. Fujiwara, Oral administration of
Lactococcus lactis subsp. lactis L. JCM 5805 enhances lung immune response
resulting in protection from murine parainfluenza virus infection, PLoS One 10 (2015)
e0119055.
[52] K. Jounai, T. Sugimura, Y. Morita, K. Ohshio, D. Fujiwara, Administration of
Lactococcus lactis strain Plasma induces maturation of plasmacytoid dendritic cells
and protection from rotavirus infection in suckling mice, Int. Immunopharmacol. 56
(2018) 205-211.
[53] M. Parcina, C. Wendt, F. Goetz, R. Zawatzky, U. Zahringer, K. Heeg, I.
Bekeredjian-Ding, Staphylococcus aureus-induced plasmacytoid dendritic cell
activation is based on an IgG-mediated memory response, J. Immunol. 181 (2008)
3823-3833.
[54] A.N. Morrow, H. Schmeisser, T. Tsuno, K.C. Zoon, A Novel Role for IFNStimulated Gene Factor 3II in IFN-γ Signaling and Induction of Antiviral Activity in
Human Cells, J. Immunol. 186 (2011) 1685-1693.
[55] A. Komatsuda, H. Wakui, K. Iwamoto, M. Ozawa, M. Togashi, R. Masai, N. Maki,
T. Hatakeyama, K. Sawada, Up-regulated expression of Toll-like receptors mRNAs in
peripheral blood mononuclear cells from patients with systemic lupus erythematosus,
Clin. Exp. Immunol. 152 (2008) 482-487.
[56] J.A. Villadangos, L. Young, Antigen-presentation properties of plasmacytoid
dendritic cells, Immunity 29 (2008) 352-361.
108
[57] M. de Verse, P. Winkler, P. Rautenberg, T. Harder, C. Noah, C. Laue, S. Ott, J.
Hampe, S. Schreiber, K. Heller, J. Schrezenmeir, Effect of Lactobacillus gasseri PA
16/8, Bifidobacterium longum SP 07/3, B. bifidum MF 20/5 on common cold episodes: a
double blind, randomized, controlled trial, Clin. Nutr. 24 (2005) 481-491.
[58] F. Luis, B.B. Miriam, P.D. Julio, et al. Sources, isolation, characterization and
evaluation of probiotics. Br. J. Nutr. 109 (2013) S35-S50.
[59] S. Yamamoto, M. Ando, E. Suzuki, High-temperature effects on antibody response
to viral antigen in mice, Exp. Anim. 48 (1999) 9-14.
[60] Y. Hu, H. Jin, X. Du, C. Xiao, D. Luo, B. Wang, R. She, Effects of chronic heat
stress on immune responses of the foot-and-mouth disease DNA vaccination, DNA Cell
Biol. 26 (2007) 619-626.
[61] Fujiwara D, Wei B, Presley LL, Brewer S, McPherson M, Lewinski MA,
Borneman J, Braun J.. Systemic control of plasmacytoid dendritic cells by CD8+ T
cells and commensal microbiota. J. Immunol. 180 (2008) 5843–5852.
[62] D.H. Canaday, N.A. Amponsah, L. Jones, D.J. Tisch, T.R. Hornick, L.
Ramachandra, Influenza-induced production of interferon-alpha is defective in
geriatric individuals, J. Clin. Immunol. 30 (2010) 373-383.
[63] A. Panda, F. Qian, S. Mohanty, D. van Duin, F.K. Newman, L. Zhang, S. Chen, V.
Towle, R.B. Belshe, E. Fikrig, H.G. Allore, R.R. Montgomery, A.C. Shaw, Ageassociated decrease in TLR function in primary human dendritic cells predicts
influenza vaccine response, J. Immunol. 184 (2010) 2518-2527.
[64] P. Konieczna, D. Groeger, M. Ziegler, R. Frei, R. Ferstl, F. Shanahan, E.M.
Quigley, B. Kiely, C.A. Akdis, L. O'Mahony, Bifidobacterium infantis 35624
administration induces Foxp3 T regulatory cells in human peripheral blood: potential
role for myeloid and plasmacytoid dendritic cells, Gut 61 (2012) 354-366.
[65] W.M. Schneider, M.D. Chevillotte, C.M. Rice, Interferon-stimulated genes: a
complex web of host defenses. Annu. Rev. Immunol. 32 (2014) 513-545.
[66] C. Zhao, M.N. Collins, T.Y. Hsiang, et al. Interferon-induced ISG15 pathway: an
ongoing virus-host battle. Trends in Microbiol. 21 (2013) 181-186.
109
[67] T. Sugimura, K. Jounai, K. Oshio, et al. Immunomodulatory effect of Lactococcus
lactis JCM5805 on human plasmacytoid dendritic cells. Clinical. Immunol. 149, (2013)
509-518.
[68] H.X. Shi, K. Yang, X. Liu, et al. Positive regulation of interferon regulatory factor
3 activation by Herc5 via ISG15 modification. Mol. Cell. Biol. 30 (2010) 2424-2436.
[69] Sugimura T, Takahashi H, Jounai K, Ohshio K, Kanayama M, Tazumi K,
Tanihata Y, Miura Y, Fujiwara D, Yamamoto N, Effects of oral intake of pDCstimulative lactic acid bacterial strain on pathogenesis of influenza-like illness and
immunological response to influenza virus, Br. J. Nutr. 114 (2015) 727–733.
[70] Wallin RP, Lundqvist A, Moré SH, von Bonin A, Kiessling R, Ljunggren HG, Heatshock proteins as activators of the innate immune system. Trends in Immunol. 23
(2002) 130-135.
[71] Gigley JP, Khan IA, Plasmacytoid DC from aged mice down-regulate CD8 T cell
responses by inhibiting cDC maturation after Encephalitozoon cuniculi infection,
PLoS One 6 e20838 (2011).
[72] Gupta S, Role of dendritic cells in innate and adaptive immune response in
human aging, Exp. Gerontol. 54 (2014) 47–52.
[73] Sugimura T, Jounai K, Ohshio K, Suzuki H, Kirisako T, Sugihara Y, Fujiwara D,
Long-term administration of pDC-Stimulative Lactococcus lactis strain decelerates
senescence and prolongs the lifespan of mice, Int. Immunopharmacol. 58 (2018) 166172.
[74] Nguyen KD, Qiu Y, Cui X, Goh YP, Mwangi J, David T, Mukundan L, Brombacher
F, Locksley RM, Chawla A., Brombacher F, Locksley RM, Chawla A, Alternatively
activated macrophages produce catecholamines to sustain adaptive thermogenesis,
Nature. 480 (2011) 104-108.
[75] Gavazzi G, Krause KH. Ageing and infection. Lancet Infect Dis. 2002; 2: 659-666.
[76] Finkel T, Serrano M, Blasco MA. The common biology of cancer and ageing.
Nature. 448 (2007) 767-774.
[77] Pawelec G, Goldeck D, Derhovanessian E. Inflammation, ageing and chronic
disease. Curr. Opin. Immunol. 29 (2014) 23-28.
110
[78] Maue AC, Yager EJ, Swain SL, Woodland DL, Blackman MA, Haynes L. T-cell
immunosenescence: lessons learned from mouse models of aging. Trends Immunol. 30
(2009) 301-305.
[79] Goronzy JJ, Fang F, Cavanagh MM, Qi Q, Weyand CM. Naive T cell maintenance
and function in human aging. J. Immunol. 194 (2015) 4073-4080.
[80] Miller JP, Allman D. The decline in B lymphopoiesis in aged mice reflects loss of
very early B-lineage precursors. J. Immunol. 171 (2003) 2326-2330.
[81] Frasca D, Riley RL, Blomberg BB. Effect of age on the immunoglobulin class
switch. Crit. Rev. Immunol. 24 (2004) 297-320.
[82] Frasca D, Blomberg BB. Aging affects human B cell responses. J. Clin. Immunol.
31 (2011) 430-435.
[83] Kovacs EJ, Palmer JL, Fortin CF, Fülöp T Jr, Goldstein DR, Linton PJ. Aging and
innate immunity in the mouse: impact of intrinsic and extrinsic factors. Trends
Immunol. 30 (2009) 319-324.
[84] Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM. Aging of the innate immune
system. Curr. Opin. Immunol. 22 (2010) 507-513.
[85] Grolleau-Julius A, Harning EK, Abernathy LM, Yung RL. Impaired dendritic cell
function in ageing. Cancer Res. 68 (2008) 6341-6349.
[86] Takeda T, Hosokawa M, Takeshita S, Irino M, Higuchi K, Matsushita T, et al. A
new murine model of accelerated senescence. Mech. Ageing Dev. 17 (1981) 183-94.
[87] Hosokawa M, Kasai R, Higuchi K, Takeshita S, Shimizu K, Hamamoto H, et al.
Grading score system: a method for evaluation of the degree of senescence in
senescence accelerated mouse (SAM). Mech. Ageing Dev. 26 (1984) 91-102.
[88] Takeda T, Matsushita T, Kurozumi M, Takemura K, Higuchi K, Hosokawa M.
Pathobiology of the senescence-accelerated mouse (SAM). Exp. Gerontol. 32 (1997)
117-127.
[89] Kimoto-Nira H, Suzuki C, Kobayashi M, Sasaki K, Kurisaki J, Mizumachi K.
Anti-ageing effect of a lactococcal strain: analysis using senescence-accelerated mice.
Br. J. Nutr. 98 (2007) 1178-1186.
111
[90] Kawase M, He F, Miyazawa K, Kubota A, Yoda K, Hiramatsu M. Orally
administered heat-killed Lactobacillus gasseri TMC0356 can upregulate cell-mediated
immunity in senescence-accelerated mice. FEMS Microbiol. Lett. 326 (2012) 125-130.
[91] Matsumoto S, Watanabe N, Imaoka A, Okabe Y. Preventive effects of
Bifidobacterium- and Lactobacillus-fermented milk on the development of
inflammatory bowel disease in senescence-accelerated mouse P1/Yit strain mice.
Digestion 64 (2001) 92-99.
[92] Reeves PG, Nielsen FH, Fahey GC Jr. AIN-93 purified diets for laboratory
rodents: final report of the American Institute of Nutrition ad hoc writing committee
on the reformulation of the AIN-76A rodent diet. J. Nutr. 123 (1993) 1939-51.
[93] Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the
future. Immunity 39 (2013) 1003-1018.
[94] Bhattacharyya TK, Thomas JR. Histomorphologic changes in aging skin:
observations in the CBA mouse model. Arch Facial Plast Surg. 2004; 6: 21-25.
[95] Wulf HC, Sandby-Møller J, Kobayasi T, Gniadecki R. Skin aging and natural
photoprotection. Micron. 35 (2004) 185-191.
[96] Ruggiero C, Cherubini A, Ble A, Bos AJ, Maggio M, Dixit VD, et al. Uric acid and
inflammatory markers. Eur. Heart J. 27 (2006) 1174–1181.
[97] Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, et al.
Involvement of oxidative stressinduced abnormalities in ceramide and cholesterol
metabolism in brain aging and Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S. A. 101
(2004) 2070–2075.
[98] Zhang, N., Ahsan, M. H., Purchio, A. F. & West, D. B. Serum amyloid A-luciferase
transgenic mice: response to sepsis, acute arthritis, and contact hypersensitivity and
the effects of proteasome inhibition. J. Immunol. 174 (2005) 8125-8134.
[99] Gregorio J, Meller S, Conrad C, Di Nardo A, Homey B, Lauerma A, et al.
Plasmacytoid dendritic cells sense skin injury and promote wound healing through
type I interferons. J. Exp. Med. 207 (2010) 2921-2930.
112
[100] Sakata K, Sasaki Y, Jounai K, Fujii T, Fujiwara D. Preventive effect of
Lactococcus lactis subsp.lactis JCM 5805 yogurt intake on influenza infection among
schoolchildren. Health 9 (2017) 756-762.
[101] 鈴木 弘章、金山 雅也、藤井 敏雄、藤原 大介、杉村 春日 乳酸菌 Lactococcus
lactis subsp. lactis JCM 5805 含有飲料の摂取による抗ウイルス免疫応答および体調の維
持に対する効果-プラセボ対照ランダム化二重盲検並行群間比較試験- 薬理と治療
（JPT）Vol.43 No.10 (2015)
[102] Shibata T, Kanayama M, Haida M, Fujimoto S, Oroguchi T, Sata K, Mita N,
Kutsuzawa T, Ikeuchi M, Kondo M, Naito K, Tsuda M, Nishizaki Y, Ishii N.
Lactococcus lactis JCM 5805 activates anti-viral immunity and reduces symptoms of
common cold and influenza in healthy adults in a randomized controlled trial. J. Func.
Food. 24 (2016) 492-500.
[103] Fujii T,Jounai K, Horie A, Takahashi H, Suzuki H, Ohshio K, Fujiwara D,
Yamamoto N. Effects of heat-killed Lactococcus lactis subsp. lactis JCM 5805 on
mucosal and systemic immune parameters, and antiviral reactions to influenza virus
in healthy adults; a randomized controlled double-blind study. J. Func. Food. 35 (2017)
513-521.
[104] Fujii T, Tomita Y, Ikushima S, Horie A, Fujiwara D. Draft genome sequence of
Lactococcus lactis subsp. lactis JCM 5805T, a strain that induces plasmacytoid
dendritic cell activation. Genome Announc. 3 (2015) e00113-15.
[105] Horie A, Tomita Y, Oshio K, Fujiwara D, Fujii T. Characterization of genomic
DNA of lactic acid bacteria for activation of plasmacytoid dendritic cells. BMC
Microbiol. 19 (2019) 88.
[106] Sugimura T, Jounai K, Ohshio K, Fujiwara D. Plasmacytoid dendritic cell
dysfunction caused by heat stress is improved by administration of Lactococcus lactis
strain plasma in mice. Biosci. Biotechnol. Biochem. 83 (2019) 2140-2143.
[107] Tsuji R, Yamamoto N, Yamada S, Fujii T, Yamamoto N, Kanauchi O. Induction of
anti-viral genes mediated by humoral factors upon stimulation with Lactococcus lactis
strain Plasma results in repression of dengue virus replication in vitro. Antiviral Res.
160 (2018) 101-108.
113
[108] Suzuki H, Tsuji R, Sugamata M, Yamamoto N, Yamamoto N, Kanauchi O.
Administration of plasmacytoid dendritic cell-stimulative lactic acid bacteria is
effective against dengue virus infection in mice. Int. J. Mol. Med. 43 (2019) 426-434.
[109] Suzuki H, Ohshio K, Fujiwara D. Lactococcus lactis subsp. lactis JCM 5805
activates natural killer cells via dendritic cells. Biosci. Biotec. Biochem. 80 (2016) 798800.
[110] Suzuki H, Jounai K, Ohshio K, Fujii T, Fujiwara D. Administration of
plasmacytoid dendritic cell-stimulative lactic acid bacteria enhances antigen-specific
immune responses. Biochem. Biophys. Res. Commun. 503 (2018) 1315-1321.
[111] Kokubo T, Komano Y, Tsuji R, Fujiwara D, Fujii T, Kanauchi O. The effects of
plasmacytoid dendritic cell-stimulative lactic acid bacteria, Lactococcus lactis strain
Plasma, on exercise-induced fatigue and recovery via immunomodulatory action. Int.
J. Sport Nutr. Exerc. Metab. 5 (2019) 1-5.
[112] Komano Y, Shimada K, Naito H, Fukao K, Ishihara Y, Fujii T, Kokubo T, Daida
H. Efficacy of heat-killed Lactococcus lactis JCM 5805 on immunity and fatigue
during consecutive high intensity exercise in male athletes: a randomized, placebocontrolled, double-blinded trial. J. Int. Soc. Sports Nutr. 15 (2018) 39.
[113] Tsuji R, Komano Y, Ohshio K, Ishii N, Kanauchi O. Long-term administration of
pDC stimulative lactic acid bacteria, Lactococcus lactis strain Plasma, prevents
immune-senescence and decelerates individual senescence. Exp. Gerontol. 30 (2018)
10-16.
[114] Tsuji R, Fujii T, Nakamura Y, Yazawa K, Kanauchi O. Staphylococcus aureus
epicutaneous infection is suppressed by Lactococcus lactis strain Plasma via
interleukin 17A elicitation. J. Infect. Dis. 24 (2019).
[115] Arunachalam PS, Wimmers F, Mok CKP, Perera RAPM, Scott M, et al. Systems
biological assessment of immunity to mild versus severe COVID-19 infection in
humans. Science. 369 (2020) 1210-1220.
[116] 田中 健太郎、鈴木 弘章、金山 雅也、藤井 敏雄、藤原 大介、野澤 元、杉村 春
日 乳酸菌 Lactococcus lactis subsp. lactis JCM 5805 および難消化性デキストリン含有
114
飲料の長期摂取時および過剰摂取時における安全性の検討-プラセボ対照ランダム化二重
盲検並行群間比較試験- 薬理と治療（JPT）Vol.43 (2015) No.12
[117] Kato Y, Kanayama M, Yanai S, Nozawa H, Kanauchi O, Suzuki S. Safety
evaluation of excessive Intake of Lactococcus lactis subsp. lactis JCM 5805: a
randomized, double-blind, placebo-controlled, parallel-group trial. Food Nutr Sci. 9
(2018) 403-419.
115
＜謝辞＞
本論文は筆者がキリン株式会社 R&D 本部基盤技術研究所に在籍中の研究成果をまとめ
たものです。本論文をまとめるにあたり、論文の構成や内容について数多くのご助言をい
ただき、さらに論文審査委員主査をお引き受けいただいた東京大学大学院農学生命科学研
究科・食の安全研究センター・免疫制御研究室准教授 八村敏志先生に対し、深謝の意を表
します。
ヒトインフルエンザウイルスに関する研究の実行にあたり、多くのご指導と有益なご助
言をいただきました国立感染症研究所・インフルエンザウイルス研究センター（当時）山
本典生先生、高橋仁先生に対し、心より御礼申し上げます。
本研究の実行および本論文の執筆にあたり、研究の機会を与えていただき、多大なるご
理解とご支援をいただいたキリン株式会社 基盤技術研究所（当時）水谷悟氏、吉田有人
氏、藤原大介氏、及び、キリンホールディングス株式会社 飲料未来研究所の永嶋一史
氏、片山貴仁氏、蒲生徹氏、村上敦司氏に感謝いたします。特に、藤原大介氏には、研究
内容全般に対して多くのご助言とご指導を賜り、研究者として多くのことを学ばせていた
だき、貴重な財産となりました。
また、本研究を遂行する上で、多くのご協力をいただいたキリン株式会社 基盤技術研
究所（当時）の城内健太氏、大塩木乃実氏、井門久美子氏、阿野泰久氏、鈴木弘章氏、桐
浴隆嘉氏、杉原圭彦氏、森田悠治氏、藤井敏雄氏、健康技術研究所（当時）の金山雅也
氏、田墨恭子氏、谷畑葉子氏、三浦裕氏、及び、小岩井乳業株式会社の諏訪昌宏氏、田中
貴章氏をはじめ、多くの関係者の皆様に厚く御礼申し上げます。特に、本研究の推進にあ
たり、実験計画の策定、実行、考察などへの多大なるご協力をいただき、互いに切磋琢磨
しながら研究者として共に成長させていただいた城内健太氏と大塩木乃実氏に深く感謝申
し上げます。
最後に、
本論文をまとめるにあたり、
常に温かく支えてくれた家族に心から感謝します。
116
＜発表論文・業績＞
1. 原著論文
Immunomodulatory effect of Lactococcus lactis JCM5805 on human plasmacytoid
dendritic cells.
Sugimura T, Jounai K, Ohshio K, Tanaka T, Suwa M, Fujiwara D.
Clin Immunol. 2013 Dec;149(3):509-18. DOI: 10.1016/j.clim.2013.10.007
（第 2 章）
Effects of oral intake of plasmacytoid dendritic cells-stimulative lactic acid bacterial
strain on pathogenesis of influenza-like illness and immunological response to influenza
virus.
Sugimura T, Takahashi H, Jounai K, Ohshio K, Kanayama M, Tazumi K, Tanihata Y,
Miura Y, Fujiwara D, Yamamoto N.
Br J Nutr. 2015 Sep 14;114(5):727-33. DOI: 10.1017/S0007114515002408
（第 3 章）
Plasmacytoid dendritic cell dysfunction caused by heat stress is improved by
administration of Lactococcus lactis strain plasma in mice.
Sugimura T, Jounai K, Ohshio K, Fujiwara D.
Biosci Biotechnol Biochem. 2019 Nov;83(11):2140-2143.
DOI: 10.1080/09168451.2019.1642098
（第 4 章）
Long-term administration of pDC-Stimulative Lactococcus lactis strain decelerates
senescence and prolongs the lifespan of mice.
Sugimura T, Jounai K, Ohshio K, Suzuki H, Kirisako T, Sugihara Y, Fujiwara D.
Int Immunopharmacol. 2018 May;58:166-172. DOI: 10.1016/j.intimp.2018.03.024
（第 5 章）
原著論文を掲載いただいた各出版社・各誌にお礼申し上げます。
117
2. その他関連論文
Spherical lactic acid bacteria activate plasmacytoid dendritic cells immunomodulatory
function via TLR9-dependent crosstalk with myeloid dendritic cells.
Jounai K, Ikado K, Sugimura T, Ano Y, Braun J, Fujiwara D.
PLoS One. 2012;7(4):e32588.
Oral administration of Lactococcus lactis subsp. lactis JCM5805 enhances lung immune
response resulting in protection from murine parainfluenza virus infection.
Jounai K, Sugimura T, Ohshio K, Fujiwara D.
PLoS One. 2015 Mar 6;10(3):e0119055.
Administration of Lactococcus lactis strain Plasma induces maturation of plasmacytoid
dendritic cells and protection from rotavirus infection in suckling mice.
Jounai K, Sugimura T, Morita Y, Ohshio K, Fujiwara D.
Int Immunopharmacol. 2018 Mar;56:205-211.
ウイルス感染防御を統括するプラズマサイトイド樹状細胞を活性化する乳酸菌の開発
化学と生物 Vol.53 No.9 Page. 626 - 632
藤原大介、城内健太、杉村哲
3. 業績
【受賞】
平成 28 年農芸化学技術賞
ウイルス感染防御機能を持つ Lactococcus lactis JCM5805 の発見と事業応用
藤原大介、城内健太、杉村哲、藤井敏雄
118
...
論文の公開元へ
