2016.12.03

Kazuyoshi TakedaDivision of Cell Biology, Biomedical Research Center

and Department of Biofunctional Micribiota, Graduate School of Medicine,

Juntendo University, Tokyo, Japan

8th INDIA PROBIOTIC SYMPOSIUM“PROBITOTICS IN HEALTH-EMERGING OPPORTUNITIES”

Enhancement of Natural Killer Cell Activityby Probiotics

Session 1: Probiotics in Allergy and Immunity

＝ reactions to eliminate foreign material (non-self) from the body (self) by lymphoid cells

→ rejection in organ transplantation

virus, bacteria, parasites 　

cancer cells ＝ crazy non-stop growing cells out of controlThe crazy marks are expressed on cell surface.

Immune cells attack cancer cellsbasing on the recognition of these crazy marks.

Immunity ＝ mechanisms to avoid diseases

Not distinguish 　 an enemy from a friend

How about cancer cell? Cancer cells are originally derived from a self cell

≒ 　 pathogens

rough recognition strictly recognize one cell responses to many　　　　　　　　　　　　　　　　　　　　　　　　　（ handy man ）

one cell response to one 　　　　　　　　　　 　 (specialist ）

How much does it cost for activation?

Improved by habits and/or diet Activated by vaccination

instable(sensitive to many stimulants)

stable

so so

cheep

quick

skillful

high

slownot at the first encounterlearn and rememberquick response at the 2nd encounter

at the first encounterquick response

Natural Immue Res. Acquired Immune Res.

Immunity

Speed of start up

Recognition of enemy

＝ Natural immunity+ Acquired immunity

when memory is kept,never get same disease

resistant to diseases,but not completely

not completely prevent/cure completely prevent/cure

eat help kill makeantibodies

NK cellMacrophage B cell

4 8

T cell

kill

Front line Headquarters

Front line provides the information of the enemy.

At the second invasion of same enemy, headquarters promptly attack with more effective 　 ways based on the information provided by front line at first encounter.

1 ： natural immunity 2 ： acquired immunityquick, cheap, and so so slow, expensive, and skillful

HELP

information

natural immunity acquired immunity

4 8

4 8

4 8

foreign bodiesforeign bodies

attack

attac

k

attack

attack

attac

k

attack

foreign bodies

attack

attack

attack

information

Dendritic cells(DC)

information

dendritic cells (DC)

HELP

information

natural immunity acquire immunity

4 8

4 8

4 8att

ack

attackatt

ack

foreignbodyforeignbodyforeignbody

prompt and forceful attackby activated CD8T and B cells

attac

k

information

dendritic cells (DC)

prompt and 　 forceful attackby activated CD8T and B cells attack

information

dendritic cells (DC)

Cooperation of two kinds of immunity in self-defense

Bacteria Virus Tumor cells

NK cell: natural killer cell ： born killer cell　　　　　 one subset of lymphocytes killing the

cells that do not belong to self even at the first encounter

What is NK cell ？

NK cell activity (killing activity) = how many tumor cells NK cells can kill in 4 h (%)

100806040200NK cell activity （％）

Num

ber o

f per

sons

NK cell activity (killing activity) is various individually.

The patients genetically impaired in NK cell, but not T and B cells, suffer from severe infections with herpes virus.

What does happen in the human who has no NK cells or low NK cell activity ?

Elderly humans with low NK cell activity exhibit a higher mortality rate due to infectious diseases compared with their counterparts with high NK cell activity.

Epidemiological study revealed that the population with low NK cell activity has a significantly higher risk of cancer than the population with intermediate or high NK cell activity.

Decrease in NK cell number and/or activity

↓Higher risk of cancer development and

infectious diseases

↓Augmentation of NK cell activity

possibly reduces the risk of cancer development and infectious diseases

↓How augment NK cell activity in daily life?

Supplementation of live beneficial bacteriapromotes health and reduces the risk of various diseases.

Probiotics are live microorganisms which,when administered in adequate amounts,confer a health benefit on the host. (FAO/WHO 2001)

yoghurt, fermented foods, some mushrooms, etc

Improvement of the dietary habitstake good foods for health and reduce ill foods

Yakult ： Fermented milk drink containing Live Lactobacillus casei Shirota (LcS)

Do probiotics augment NK cell activity?

Augmentation of NK cell activity by LcS intake

%

%

(E/T =20)

LcS more effectively augments NK cell activity in the people who need NK cell activation.

NK cell activation by LcS is more effectivein the persons who have lower NK cell activity

To activate NK cells by the oral intake of LcS,LcS must go into the body through epithelium.

Such experiments do not sufficiently explainhow LcS augment NK cell activity in vivo.

M. Takahashi, et al.

LcS

Lactic acid bacteria phagocytized by M cells

LcS

M cell

Intestine

NK cell

　　Macrophageand/or

Dendriticcell

T cell

CBLcSCB

Enteric microbiota Commensal bacteria

Regulation

Mucosal ImmunityIntestinal Immunity

LcS

LcS enter into the body through M cell at intestine

Correlation between augmentation of cytotoxic activityand IL-12 production in LcS-induced NK cell activation

PBMC were co-cultured with freeze-dried LcS 　 in vitro

M cell

Intestine

CancerPathogens

LcS LcS

IL-12activation

activation by contact

IFN-g

NK cell

　　Macrophageand/or

Dendriticcell

Possible mechanisms of LcS-induced NK cell activation

activation

Probiotics augments NK cell activity via the enhancement of immune responses in intestine

1. Probiotics possibly enter into a body at intestine.

2. DC and Mf recognize probiotics and produce NK cell activating 　cytokines　　　 (e.g. IL-12, IFN-g).3. NK cells are activated and would prevent diseases.

4 8

4 8

4 8

LcS

LcS

LcS

LcS

LcS

LcS

LcS

LcS

LcS

Juntendo University, School of MedicineDepartment of Immunology

K. OkumuraF. Nagao

Yalult Central Institute for Microbiological ResearchM. NannoT. SuzukiK. ShidaS. -I. ShimadaY. MatsuokaY. Yamaoka

Takane HospitalH. Takane

Acknowledgements