Lec 5. 면역조절 II

미숙림프구

3. 면역 증진 건강기능식품 및 효능

1)고시형 건강기능식품

(1)인삼 : 강장, 면역 증강 기능,피로회복의 기능성

(2)홍삼 : 면역력 증진 및 피로 회복

(3)알로에 겔 : 면역력 증진, 피부 건강, 항염증 효능, 장건강

(4)알콕시글리세롤 함유 상어간유 : 면역 증강

2)개별인정형 건강기능식품

(1)금사상황버섯 : 인터페론 감마와 림프구 수 증가, 면역

기능 개선

(2)게란티 바이오-Ge 효모 : 면역글로블린, 항체 형성 효능

(3)L-글루타민 : 림프구 양 증가, 감염 발생 감소

(4)HemoHIM 당귀 등 혼합추출물 : 림프구의 활성 증가,

NK 세포활성, 사이토카인 증가

제2절 항염증 및 항알레르기 1. 염증 및 알레르기

1) 염증

① 외부 자극에 의해 손상된 생체조직을 복구하는 면역반응

히스타민 : 손상된 조직 부위에 혈액과 림프액 공급

킨니스 : 근수축 이완으로 혈액의 운반 원활

프로스타글란딘 : 백혈구에서 합성되어 통증과 열 발생

② 염증반응의 개요

염증 유도물질

세포 내 감지 센서

매개체

염증반응이 일어나는 조직

③백혈구의 작용

조직 손상부위로 이동하여 염증반응

식세포 작용 : 외부의 세균 및 박테리아 제거

염증성 매개체(inflammatory mediators) 분비

만성염증: 단핵세포(monocyte), 림프구

급성염증: 과립성 백혈구(granulocytes)

Cytokine, chemokine에 의해 백혈구와 내피세포간의 결합 활성화

최하부 막(basement membrane)을 뚫고 이동하여 염증조직으로의 침투

INITIATORS OF INFLAMMATION

Microbial • specific exotoxins – endotoxins (bacterial, viral, fungal, protozoan) Tissue injury/death • Lack of oxygen /nutrients (ischemia) • Trauma UV/ionizing radiation, burns Irritant/corrosive chemicals (acids, alkalis,oxidizers) Hypersensitivity… immunological responsiveness .. Auto-antibodies attack tissue… causes excessive reaction which damages tissues.

INFLAMMATION: Cellular elements

• Inflammatory process is largely

• defined by products released from

• local cells which are attracted to the

• area of inflammation and which

• become “activated”

• What/Which are these cells?

INFLAMMATION: Cellular elements

Mast cells.

• Innate immune cells,

• Tissue-resident

• Close contact with arterioles and venules.

• Degranulated by tissue damage, infections or crosslinked IgE

• Granules contain a variety of active factors

INFLAMMATION: Cellular elements

Monocytes: Macrophages (tissue specific) or dendritic cells (lymphoid tissue). Macrophages • Resident cells • Circulate as monocytes and reach site of injury within 24 - 48 hrs. • Activated by cytokines (TNFa), lipidic acids (prostaglandins / leukotrienes), endotoxins (TOL-r) , and other products of inflammation. • Dynamic properties..filpodia/active particle engulfment • Present though out body. Microglia, Kupffer cells, sinus histiocytes, alveolar macrophages, etc.

Lymphocytes.

• Antigen-experienced T cells travel efficiently to targets as they upregulate adhesion molecules and chemoattractant receptors. • T and B lymphocytes: Antigen-activated (via macrophages and dendritic cells) • Release macrophage activating cytokines (in turn macrophages release lymphocyte-activating cytokines until inflammatory stimulus is removed) • Plasma cells terminally differentiated B cells • Express MHC molecules enable recognition of epitopes of antigens that discriminate self from non-self.

Cell derived Histamine. (Mast cells, basophils, eosinophils. platelets) Stimulated by complement C3a and C5a, Iysosomal proteins Serotonin. Mast cells and platelets is vasoconstrictor. Lysosomal cmpds. (neutrophils) increases vascular permeability Prostaglandins. Inflammatory cells, increases vascular permeability Leukotrienes Lipidic acids also synthesized with vasoactive properties.

Mediators of Acute Inflammation

RESOLUTION OF INFLAMMATION.

Acute inflammation early characterized by extravascular

accumulation of neutrophils and edema formation.

Later mononuclear cells and macrophages accumulate.

Examination of the time course emphasizes that the

process is normally resolved over time… what processes

terminate/reverse the inflammatory cascades.. …?

• WHAT INITATES THE RESOLUTION OF ACUTE INFLAMMATION?

• REMOVAL OF STIMULUS

• Clearance of bacterial / viral components

• Clearance of injury products

MEDIATORS OF INFLAMMATION RESOLUTION.

• Early phase: inflammatory mediators initiate acute-phase.

• Counterbalanced by endogenous anti-inflammatory signals(corticosterone).

• As inflammation progresses, “stop signals” attenuate leukocyte traffic and

promote differentiation of monocyte to phagocytosing macrophage (lipoxins,

Resolvins, and PG-D)

• Fibroblasts evoke withdrawal of survival signals allowing leukocytes to

undergo apoptosis or be cleared by lymphatics.

INFLAMMATION

• “Inflammation in itself is not to be

• considered as a disease, but as a

• salutary operation consequent to

• some violence or some disease”.

John Hunter Scottish surgeon, 1794

BENEFITS OF INFLAMMATION

Dilution of toxins. carried away in lymphatics. Entry of antibodies. Increased vascular permeability. Fibrin formation. Fibrin formation from exuded fibrinogen impede movement of micro-organisms Delivery of nutrients and oxygen. Delivery of nutrients and oxygen for neutrophils Stimulation of immune response. Drainage into the lymphatics allows particulate and soluble antigens to reach Iymph nodes.

HARM OF INFLAMMATION

The release of by inflammatory cells may also have harmful effects:

Digestion of normal tissues: lysosomal enzymes

Swelling: obstruct airway, cranial cavity.

Inappropriate inflammatory response: (e.g. hay fever)

Progression to Chronic Inflammation

• Progression to chronic stage.

• Cellular exudate changes: macrophages,

lymphocytes and plasma cells replace

neutrophils.

• Tissue destruction (necrosis)

• Attempts at reconstructing the damaged tissue

(healing/ repair): granulomatous response

CHRONIC INFLAMMATORY STATES.

• Persistent Injury or inflammation

• Ulcer, TB, Ulcerative colitis, Inflammatory

• bowel disease, Atheroclerosis

• Prolonged toxic agent exposure

• Silicosis, foreign body

• Autoimmune disease states

• Rheumatoid arthritis, Multiple sclerosis

Important classes of agents used clinically

in modulating the inflammatory process

NSAIDS

Steroids

Cytokine blocking agents

TNFa

IL1ß

NSAID (Non Steroidal Anti-inflammatory

drug): Common properties of action • NSAIDs inhibit cyclooxygenase (COX) • COX forms PGs in periphery/ spinal cord • PGs’ sensitize sensory nerve terminal to enhance pain transmission(hyperalgesia). • Block COX→↓inflammation/hyperalgesia • COX1 constitutively expressed throughout (GI mucosa, Platelets, kidney, etc) • COX2. Expressed in brain and kidney and induced at site of injury • Classical agents block both, while recent agents are COX2-selective.

CYCLOOXYGENASE

• 2 distinct active catalytic sites on COX ⎯

• Cyclooxygenase active site (CAS) (AA → PGG2) and

• the peroxidase active site (PAS) (PGG2 → PGH2).

• PGH2 may then be acted upon by various enzymes

• to yield multiple prostanoids

CYCLOOXYGENASE 1 and 2 • COX 1 is stably expressed in brain and periphery

• COX2 is stably expressed in brain and but not periphery…upregulated by a variety of stimuli: Bacterial endotoxin, IL-1, and TNF-a Cytokines (IL1ß) stabilizes COX-2 transcripts. • Cortisol and dexamethasone NEGATIVELY controls COX2 transcription. • Distinct binding pocket permits synthesis of COX2 preferring molecules Ibuprofen: COX1 = COX2 Celebrex: COX2>>COX1 Thus COX 2 inhibitors will be effective where there is ongoing inflammation leading to upregualtion of COX2.

2)알레르기(allergy)

무해한 외래물질이나 자가물질을 외부 감염원으로 인식하여 일어나는 면역반응

산업화가 진행됨에 따라 환경오염 및 식습관의 변화 등에 의해 알레르기 환자의 증가

T 림프구에 의해 항원이 인식되면 기억 B 세포가 자극을 받고 항체를 생산

알레르기 증상 환자는 과잉 면역반응이 일어남

무해한 항원에 대한 반응성이 점점 커져 더 격렬한 면역반응이 일어남

Genes Identified to date in Atopy

Common allergens associated with type I hypersenstivity

Proteins

Foreign serum

Vaccines

Plant pollens

Rye grass

Ragweed

Timothy grass

Birch trees

Drugs

Penicillin

Sulfonamides

Local anethetics

Salicylates

Foods

Nuts

Seafood

Eggs

Peas, beans

Milk

Insect products

Bee venom

Wasp venom

Ant venom

Cockroach calyx

Dust mites

Mold spores

Animal hair and dander

Mast cell are abundant in the mucosa of the respiratory,

gastrointestinal tracts and in the skin, where atopic

reaction localize.

Mast cell release mediator cause the pathophysiology

of the immediate and late phases of atopic diseases.

Mast Cell

Mast Cell Activation

Mast cell

Classic Allergic Reaction

Flushing

Hypotension

Increased mucus production

Pruritus

Smooth muscle contraction

Vascular leakage

Late –phase Reaction

Eosinophil infiltration

Neutrophil infiltration

Fibrin deposition

Mononuclear infiltration

Tissue destruction

Minutes Hours

Performed Mediators/ Primary Mediators

Histamine: is one well-known mediator. This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause: contraction of smooth muscles of the airway and GI tract, increased vascular permeability and vasodilation, nasal mucus production, airway mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion. Serotonin: increased vascular permeability and contraction of smooth Muscles. Tryptase: is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a. Tryptase is found in all human mast cells but in few other cells and thus is a good marker of mast cell activation. Proteoglycans: include heparin and chondroitin sulfate. Chemotactic factors

http://drainameducci.blogspot.com/2011/08/hypersensitivity.html

Important Clinical Aspects of

Immediate Hypersensitivity

Main organ Disease Main sympto

ms

Typical allergen

s

Route of entery

Lung Asthma Wheezing, dys

pnea, tachypne

a

Pollens, house d

ust, animal dande

rs

Inhalation

Nose and Eyes Rhinitis, conjunctivitis

Hay fever

Runny nose, re

dness and itchi

ng of eyes

Pollens Contact with muc

ous membrane

Skin Eczema (atopic derm

atitis)

Urticaria

Pruritic, vesicul

ar lesions

Pruritic, bullous

lesions

Uncertain

Various foods

Drugs

Uncertain

Ingestion

Various

Intestinal tract Allergic gastroentero

pathy

Vomiting diarrh

ea

Various food Ingestion

Systemic Anaphylaxis Shock, hypoten

sion, wheezing

Insect venom;bee

Drugs; penicillin

Foods; Peanuts

Sting

Various

Ingestion

2. 기능성 평가 방법

1)시험관 내 실험 수준

① 히스타민 및 헥소사이니데이스

② T 세포 증식

③ 리폭시제네이즈 생성량

④ 사이토카인 생성량

2)동물 실험 수준

① 전신성 알레르기반응, 국소성 알레르기반응(PCA)

② 히스타민과 염증성 사이토카인 및 IgE 함량

③ 귀 부종법

④ 족척두께 증가

3)임상시험

① 단자 시험(prick test)

② 혈액 중 히스타민 함량

③ 혈액 중 IgE

④ 혈중 사이토카인 함량

3.항염증 및 항알레르기 건강기능식품

1)개별인정형 건강기능식품

(1)Enterococcus faecalis FK-23 효소 및 가열처리 분말

Th2 매개면역을 Th1 매개면역 방향으로 전환시키는 효능

코막힘 증상을 개선하는데 도움을 줄 수 있음

The cutaneous test

(prick test, puncture test epicutaneous test)

Routine diagnosis in diseases (atopic or anaphylactic).

A single drop of concentrated aqueous allergen extract

placed on the skin which is then pricked lightly with a

needle point at the center of the drop. After 20 minutes

the reaction is graded and recorded

Skin Tests

Reference

• Funtional food 이형주 외 수학사 • Allergic diseases: in Medical Immunology .eds ( Tristram G.Parslow, Daniel P. A Stites,

Abba I.Terr.and John B. Imboden), 814 pages • tenth edition. McGraw-Hill/Appleton & Lange; 10 edition 2001) • (March 23, ISBN-13: 978-0838563007 • ISBN-10: 0838563007 • Anaphylaxis and Urticaria: in Medical Immunology .eds ( Tristram G.Parslow, Daniel P. A

Stites, Abba I.Terr.and John B. Imboden), 814 pages • tenth edition. McGraw-Hill/Appleton & Lange; 10 edition 2001) • (March 23, ISBN-13: 978-0838563007 • ISBN-10: 0838563007 • Adkinson NF Jr. Middleton’s Allergy: Principles and Practice. 6th ed. Philadelphia, Pa:

Mosby; 2003. • Rakel RE. Textbook of Family Medicine. 7th ed. Philadelphia, Pa: WB Saunders; 2007. • Miriam K Anand, Michael A Kaliner, et al., Advances in Immunology. N Engl. J.Med,. vol.

344, No.1. January4, 2001. Available from. • http://emedicine.medscape.com/article/136217-overview#a0104 • Sell S, Rich RR, Fleisher TA, et al, eds. Clinical Immunology: Principles and Practice. ed. St.

Louis, Mo: Mosby-Year Book; 1996:449-77