Ch 19: Inflammation & the Immune ResponseI. Introduction

protection from harmful microorganisms and cellsrecovery after injury/ tissue damagecritical to maintaining health/preventing diseaseimmunocompetent: when all different parts of in‡ammation & immunity are working wellfunction of immunity reduced by disease, injury, medical therapy

temporary or permanent reductionendangers person÷s healthloss of protection r/ t poor function of any or all parts of in‡ammation & immunityoverfunctions/ inappropriate time functioning

II. Overviewcomposed of cell functions that protect people against invasion or effects of injurydefenses to prevent organisms from getting into internal environment

intact skinmucous membranesskin surface ‡oranatural chemicals (inhibit bacterial growth)

invasions occur often, more often than disease (due to proper immune function)Purpose of Inflammation & Immunity

meet human need for protection by neutralizing, eliminating, & destroying organisms that invade the internal environmentmeet protection needs without harming the body by only

attacking non-self proteins & cellsSelf vs. Non-Self

non-self proteins & cells include infected body cells, cancer cells & all invading cells & organismsself-tolerance: the ability to recognize self vs non self

immune system cells are only cell capable of thisp o s s ib le b e c a u s e o f p ro t e in o n c e ll m e m b ra n e s

each cell is surrounded by a plasma membraneproteins protrude through the membranethe AA sequence of each protein differs from all othersproteins are unique to the person

o n ly s h a re d w it h id e n t ic a l t w ins e rve a s UPC o r ”c e llu la r fln g e rp rin t ‘re c o g n iz e d a s fo re ig n o r n o n -s e lf t o a n o t h e r p e rs o n ÷s im m u n e s ys t e m

t h e r e f o r e t h e y a r e a n t ig e n s ( p r o t e in s c a p a b le o f s t im u la t in g a n im m u n e r e s p o n s e )

human leukocyte antigens (HLAs): the unique UPC for each personalso present on the surface of nearly all body cells (not just leukocytes)

d e t e rm in e t is s u e t yp e s o f a p e rs o nthey are antigens only if they enter another person÷s body40 major HLAs, unknown # of minor HLAs

m a jo r HLAs d e t e rm in e d b y s e t o f g e n e s c a lle d t h e m ajo r h is t o c o m p at ab ilit y c o m p le x ( s p e c iflc a n t ig e n s d e t e rm in e d b y g e n e t ic s )

key for recognition & self confldenceat each encounter immune system cells compare the surface protein HLAs to determine if cell is self or non-self

s e lf = n o t a t t a c ke dn o n s e lf = n e u t ra liz e , d e s t ro y , e lim in a t e fo re ig n in va d e r

immune function changes during life according to:nutritional statusenvironmental conditiondrugsdiseaseage (most efflcient in 20÷s & 30÷s then declines, older adults

not in any one organ/ body areain‡uenced by many body systems, especially:

n e rvo u se n d o c rin eGI

most immune system cells come from bone marrowsome mature in bone marrowothers leave bone marrow in mature elsewherewhen mature they are released into the blood where they circulate & have speciflc effects

bone marrow is a source of all blood cells (even immune cells)produces stem cells (immature, undifferentiated cells)

p lu rip o t e n t : e a c h c e ll h a s m o re t h a n o n e p o s s ib le o u t c o m ewh e n 1 s t c re a t e d it is u n d if f e re n t iat e d ( n o t ye t c o m m it t e d t o m a t u rin g in t o a s p e c iflc b lo o d c e ll t yp e ) t h e re fo re it is ‡ e xib le ( c o u ld b e c o m e a n y o n e o f m a n y m a t u re b lo o d c e lls o r p lu rip o t e n t )

t y p e o f m a t u r e s t e m c e ll it b e c o m e s d e p e n d s o n t h e p a t h w a y it f o llo w s

m a t u r a t io n a l p a t h w a y d e p e n d s o n :b o d y n e e d s a t t im ep r e s e n c e o f s p e c ifl c c h e m ic a ls ( g r o w t h f a c t o r s )

WBCs/ leukocytes protect the body from invasion effectsaka immune system cellsprovide protection through defensive actions

re c o g n it io n o f s e lf vs . n o n -s e lfd e s t ru c t io n o f fo re ig n in va d e rs , c e llu la r d e b ris & u n h e a lt h y o r a b n o rm a l s e lf c e llsp ro d u c t io n o f a n t ib o d ie s d ire c t e d a g a in s t in va d e rsc o m p le m e n t a c t iva t io np ro d u c t io n o f c y t o kin e s t h a t s t im u la t e in c re a s e d fo rm a t io n o f le u ko c y t e s in b o n e m a rro w & in c re a s e s p e c iflc le u ko c y t e a c t iv it y

3 processes needed for human protection through immunity1. in‡ammation2. antibody mediated immunity (AMI) ”humoral immunity‘3. cell mediated immunity (CMI) ”cellular immunity‘each process uses different defensive actions but also requires assistance from the other twofull immunity (immunocompetence) requires the function and

III. Inflammation “natural immunity”immediate protection against effects of tissue injury & invading foreign proteinsin‡ammatory response critical to health & well-beingdiffers from immunity (AMI & CMI) in 2 ways

immediate but short term, no ”true immunity‘ on repeated exposurenon-speciflc defense to invasion or injury & can be started quickly by almost anything regardless of where it occurs & what causes it

how widespread in‡ammation is depends on:1. intensity of exposure2. severity of exposure3. duration of exposure

Purpose start tissue actions that cause visible & uncomfortable symptoms

rid body of organismsin‡ammation in excess = tissue damagestart AMI & CMI actions to activate full immune response

Infectionin‡ammation occurs in response to tissue injury or invasion by microorganisms

in‡ammation does not mean that an infection is present!infection is usually accompanied by in‡ammationin‡ammation can occur without infection

s p ra in s , MI, s u rg ic a l in c is io n s , b lis t e rs , t h ro m b o p h le b it isin‡ammation with invasion of noninfectious foreign objects

a lle rg ic rh in it is , c o n t a c t d e rm a t it is , o t h e r a lle rg ic re a c t io n sin‡ammation with infection

o t it is m e d ia , a p p e n d ic it is , p e rit o n it is , v ira l h e p a t it is e t c .

Cell types involved in inflammationNeutrophils - use phagocytosis to destroy & eliminate invaders

Description & Origin5 5 -7 0 % o f t o t a l n o rm a l WBCc o m e fro m s t e m c e lls , m a t u re in b o n e m a rro w

a ka ”g ra n u lo c y t e s ‘ , ”s e g s ‘ , ”s e g m e n t e d n e u t ro p h ils ‘ , o r ”p o lym o rp h o n u c le a r c e lls ‘ , ”p o lys ‘ , & le s s m a t u re n e u t ro p h ils a re kn o wn a s ”b a n d s ‘1 2 -1 4 d a ys t o m a t u re n o rm a lly

s h o r t e n e d b y c o n d it io n s t h a t t r ig g e r g r o w t h f a c t o r p r o d u c t io n ( c y t o k in e s )

i. e . g r a n u lo c y t e - m a c r o p h a g e c o lo n y s t im u la t in g f a c t o r ( G M - C S F )

1 0 0 b illio n n e w, m a t u re n e u t ro p h ils re le a s e d fro m b o n e m a rro w t o c irc u la t io n d a ily

lif e s p a n = 1 2 - 1 8 h o u r sFunction

la rg e s t g ro u p o f c irc u la t in g le u ko c y t e s b u t e a c h c e ll is s m a llp ro t e c t io n a ft e r in va d e rs e n t e r b o d yd e s t ro y b y p h a g o c y t o s is o r e n z ym a t ic d ig e s t io ns m a ll e n e rg y s u p p ly ( c a n t re p le n is h ) & n o wa y t o re p le n is h e n z ym e s u s e d in p h a g o c y t o s is

1 e p is o d e o f p h a g o c y t o s is p e r n e u t r o p h ilm a t u re n e u t ro p h ils a re t h e o n ly o n e s t h a t c a n p e rfo rm p h a g o c y t o s is

% & # o f a c t u a l m a t u r e c ir c u la t in g n e u t r o p h ils = A N C ( a b s o lu t e n e u t r o p h il c o u n t ) / a b s o lu t e o r t o t a l g r a n u lo c y t e c o u n t

in c r e a s e d A N C = g r e a t e r r is k f o r in f e c t io nWBC d iffe re n t ia l s h o ws t h e # & % o f d iffe re n t t yp e s o f c irc u la t in g le u ko c y t e s

m o s t a r e s e g s , s m a ll p e r c e n t a r e b a n d sb a n d s s h o u ld n o t b e in b lo o d

c a u s e s s e p s iss e g s c h a n g e t o b a n d s ( ” le f t s h if t ‘ / b a n d e m ia )

p a t ie n t ÷s b o n e m a r r o w c a n n o t m a k e e n o u g h m a t u r e n e u t r o p h ils t o k e e p p a c e w it h c o n t in u in g in f e c t io n a n d is r e le a s in g im m a t u r e n e u t r o p h ils in t o t h e b lo o d

Macrophages - use phagocytosis to destroy & eliminate invadersDescription & Origin

o rig in a t e in m ye lo id s t e m c e lls in b o n e m a rro wfo rm t h e m o n o n u c le a r p h a g o c y t e s ys t e ms t e m c e lls t u rn t o m o n o c y t e s 1 s t ( re le a s e d in t o b lo o d )

lim it e d a c t iv it y - m o v e f r o m b lo o d in t o t is s u e s & m a t u r e t o m a c r o p h a g e s” fl x e d ‘ w it h in t is s u e s o r m o v e b e t w e e n / w it h in t is s u e sin d if f e r e n t t is s u e s t h e y ÷r e c a lle d d if f e r e n t t h in g sin la r g e # s in liv e r , s p le e n & in t e s t in a l t r a c t

Functionim p o rt a n t in im m e d ia t e in ‡ a m m a t o ry re s p o n s e s , a n d s t im u la t e AMI/ CMI im m u n it y

Description & Origino rig in a t e in m ye lo id s t e m c e lls1 % WBC c o u n tc a u s e m a n ife s t a t io n s o f in ‡ a m m a t io n

Functionh a ve g ra n u le s w it h m a n y c h e m ic a ls ( va s o a c t ive a m in e s ) t h a t a c t o n b lo o d ve s s e ls

h e p a r in , h is t a m in e , s e r o t o n in , k in in , le u k o c t r ie n e sa c t o n s m o o t h m u s c le & b lo o d v e s s e l w a llsh e p a r in : in h ib it s b lo o d & p r o t e in c lo t t in gh is t a m in e : c o n s t r ic t s s m a ll v e in s & r e s p ir a t o r y s m o o t h m u s c le

n a r r o w s a ir w a y & r e s t r ic t s b r e a t h in gin h ib it s b lo o d ‡ o w ( v e in c o n s t r ic t io n )

d e c r e a s e d v e n o u s r e t u r nb lo o d c o lle c t s in c a p illa r ie s / a r t e r io le s a n d in c r e a s e d c a p illa r y p e r m e a b ilit y & t h is c a n le a d t o v a s c u la r le a k s y n d r o m e ( w h e r e b lo o d le a k s in t o in t e r s t it ia l s p a c e )

Eosinophils - release chemicals that act on blood vessels to cause tissue-level responses

Description & Originm ye lo id o rig inm a n y va s o a c t ive c h e m ic a ls1 -2 % WBC c o u n t

Functiona c t a g a in s t in fe c t io n s o f p a ra s it ic la rva eg ra n u le s c o n t a in m a n y d iffe re n t s u b s t a n c e s

s o m e in d u c e in ‡ a m m a t io ne n z ym e s re le a s e d b y e o s in o p h ils d e g ra d e t h e va s o a c t ive c h e m ic a ls re le a s e d b y o t h e r le u ko c y t e s & c a n lim it t h e in ‡ a m m a t o ry re a c t io n s

e o s in o p h ils in c r e a s e d u r in g a lle r g ic r e s p o n s e

Phagocytosisengulflng/ destructing of invadersalso rids the body of debris after tissue injurymost efflcient: neutrophils & macrophages

1. exposure & invasion: must be exposed to organism in blood & ECF (foreign protein, debris, damage tissue), phagocytosis is triggered

2. attraction: second step, substances attract neutrophils and macrophages (chemotaxins) which are create/ secreted by damaged tissues & blood vessels

coating cell (antigen or organism) - many cells can act as opsonins (particles from dead neutrophils, antibodies, activated/ flxated complement components)

3. recognition: phagocytic cell sticks to surface of target cell and recognizes it as non-selfm a d e e a s ie r b y o p s o n in sn o n s e lf = p h a g o c y t o s is b e g in s

4. cellular ingestion: target cell brought inside the phagocytic cell by phagocytosis (engulfment) by bending membrane around target cell and form a vacuole

5. phagosome formation: occurs when granules are inside vacuole (break & release enzymes that attack the ingested target)

6. degradation: flnal step, enzymes digest engulfed target, broken to smaller pieces, only small particle of debris remain

Sequence of Inflammatory Response3 stages regardless of trigger, timing of stages may overlapresponses @ tissue level cause 5 cardinal manifestations of in‡ammation

1. warmth2. redness3. swelling4. pain5. decreased function

Stage 1: vascularchanges in blood vesselsinjured tissues and leukocytes secrete histamine, serotonin, kinins

c o n s t ric t s m a ll ve in s , d ila t e a rt e rio le sr e d n e s s & w a r m t h o f t is s u e s ( in c r e a s e d b lo o d ‡ o w o r h y p e r e m ia , in c r e a s e d d e liv e r y o f n u t r ie n t s ) c a u s e s e d e m a ( p r o t e c t s & d ilu t e s ) , le a d s t o c a p illa r y le a k s y n d r o m e ( b lo o d p la s m a m o v e s in t o t is s u e s a n d is a c c o m p a n ie d b y s w e llin g & p a in [ o c c u r s in 2 4 t o 7 2 h o u r s ]

macrophage is major cellra p id a c t io n ( a lre a d y in p la c e a t s it e o f in ju ry o r in va s io n )lim it e d b e c a u s e n u m b e r o f m a c ro p h a g e s is s m a ll

t o e n h a n c e in ‡ a m m a t o r y r e s p o n s e t h e o t h e r t is s u e

p r o d u c e W B C s ( u s u a lly 1 4 d a y s t o h o u r s )s o m e c y t o k in e s in c r e a s e r e le a s e o f n e u t r o p h ils f r o m t h e b o n e m a r r o w a n d a t t r a c t t h e m t o t h e s it e o f in ju r y o r in v a s io n w h ic h le a d s t o t h e n e x t s t a g e o f in ‡ a m m a t io n

Stage 2: cellular exudateneutrophilia (an increased # of circulating neutrophils occurs)

e xu d a t e / p u s fo rm sc o n t a in s d e a d W B C s , n e c r o t ic t is s u e a n d ‡ u id s t h a t c a n e s c a p e f r o m d a m a g e d c e lls

neutrophil is main cellu n d e r in ‡ u e n c e o f c y t o kin e s t h e n e u t ro p h il c o u n t c a n in c re a s e u p t o flve t im e s w it h in t we lve h o u rs o f o n s e t o f in ‡ a m m a t io n

n e u t r o p h ils a t t a c k a n d d e s t r o y o r g a n is m s a n d r e m o v e d e a d t is s u e t h r o u g h p h a g o c y t o s is

acute in‡ammation - healthy person produces enough mature neutrophils to keep pace with invasion and prevent the organism from growing

b e g in s s lo wly b u t is lo n g -la s t in gWBCs a n d in ‡ a m e d t is s u e s e c re t e c y t o kin e s

c y t o k in e s a llo w t is s u e m a c r o p h a g e s t o in c r e a s e a n d t r ig g e r b o n e m a r r o w p r o d u c t io n o f m o n o c y t e s

arachidonic acid (AA) cascade increases in‡ammatory responsec o n ve rs io n o f fa t t y a c id s in p la s m a m e m b ra n e s in t o AA

e n z y m e s ( c y c lo o x y g e n a s e ) c o n v e r t A A in t o c h e m ic a lsc h e m ic a ls f u r t h e r p r o c e s s e d in t o s u b s t a n c e s t h a t c o n t in u e in ‡ a m m a t o r y r e s p o n s e in t h e t is s u e s ( h is t a m in e s , le u k o t r ie n e s , p r o s t a g la n d in s , s e r o t o n in , k in in s )

a n t i-in ‡ a m m a t o ry d ru g s c a n s t o p t h is c a s c a d e b y p re ve n t in g a n e n z ym e fro m c o n ve rt in g AA in t o c h e m ic a ls m e n t io n e d

when an infection stimulating in‡ammation lasts longer than a few days, bone marrow cannot produce and release enough mature neutrophils (decreased number of circulating mature neutrophils)

b o n e m a rro w re le a s e s im m a t u re n e u t ro p h ilslim it s h e lp f u l e f f e c t s o f in ‡ a m m a t io nin c r e a s e d r is k o f s e p s is

Stage 3: tissue repair & replacementlast completed stage but begins at the time of injurycritical

s o m e WBCs in d u c e h e a lt h y c e lls t o d iv id et rig g e rs n e w b lo o d ve s s e l g ro wt h ( a n g io g e n e s is ) a n d s c a r t is s u e fo rm a t io n

s c a r t is s u e d o e s n o t b e h a v e lik e n o r m a l t is s u e

im m u n it ylo n g la s t in g im m u n e a c t io n s d e v e lo p t h r o u g h A M I & C M I

IV. Antibody-Mediated Immunity (AMI) “humoral immunity”

antigen-antibody interactions neutralize, eliminate & destroy foreign proteins Purpose

main purposes of B cells are to become sensitized to a speciflc foreign protein (antigen) and to produce antibodies directed speciflcally against that protein

the antibody (not the actual T-cell) causes one of several actions to neutralize, eliminate & destroy

B cells have the most direct role in AMImacrophages & T-lymphocytes work with B cells to start and complete antigen-antibody interactionsoptimal AMI - entire immune system must function adequatelyoriginate in bone marrow (primary lymphoid tissue) then commit to lymphocyte pathway and are then restricted in development

re le a s e d in t o b lo o dm ig ra t e in t o s e c o n d a ry lym p h t is s u e s ( m a t u ra t io n is c o m p le t e ) - s p le e n , p a rt s o f lym p h n o d e s , t o n s ils , in t e s t in a l m u c o s a

Antigen-Antibody Interactionsbody learns to make enough of any speciflc antibody to provide long lasting immunity and protection7 steps to produce a speciflc antibody directed at a speciflc antigen (whenever exposed)

1.) exposure or invasion:a n t ig e n m u s t e n t e r b o d ym u s t o c c u r in la rg e n u m b e rs t h a t s o m e o f t h e a n t ig e n is n o t d e t e c t e d b y b o d y÷s d e fe n s e s o r o ve rwh e lm s t h e in ‡ a m m a t o ry re s p o n s ea s a v iru s g ro ws , WBCs t a ke p a rt in a n t ib o d y-a n t ig e n re a c t io n s t o p re ve n t h im / h e r fro m h a vin g a d is e a s e m o re t h a n o n c e

r e c o g n it io n s t a r t e d b y m a c r o p h a g e sa lt e r e d s u r f a c e b y o p s o n iz a t io n ( r e c o g n iz e d a s n o n s e lf t h e n p h y s ic a lly a t t a c h e s it s e lfp r e s e n t s a n t ig e n t o h e lp e r T c e llb o t h m a c r o & T c e ll p r o c e s s a n t ig e n t o e x p o s e r e c o g n it io n s it e s ( U P C )T c e ll b r in g s a n t ig e n t o B c e llB c e ll r e c o g n iz e s a s n o n s e lf

3.) lymphocyte sensitization:B c e ll re c o g n iz e s a n t ig e n a s n o n s e lf & n o w is ”s e n s it iz e d ‘

c a n o n ly b e s e n s it iz e d o n e t im e ( s o c a n o n ly b e s e n s it iz e d t o o n e t y p e o f a n t ig e n )w ill r e s p o n d t o a n y s u b s t a n c e t h a t c a r r ie s t h e s a m e a n t ig e na lw a y s r e m a in s s e n s it iz e da ll c e lls p r o d u c e d b y t h a t B c e ll a r e a ls o s e n s it iz e d t o t h a t a n t ig e nim m e d ia t e ly f o r m s 2 c e lls b y d iv is io n

1. p la s m a c e ll: s t a r t s im m e d ia t e ly t o p r o d u c e a n t ib o d ie s a g a in s t s p e c ifl c a n t ig e n - s h o r t lif e s p a n

2. m e m o r y c e ll: s e n s it iz e d b u t d o e s n o t s t a r t f u n c t io n u n t il t h e n e x t e x p o s u r e t o t h e s a m e a n t ig e n

4.) antibody production & release:a llo w t h e a n t ib o d ie s t o s e a rc h o u t s p e c iflc a n t ig e n s

a n t ib o d ie s p r o d u c e d b y p la s m a c e llsw it h f u ll s t im u la t io n , e a c h p la s m a c e ll c a n m a k e 3 0 0 m o le c u le s o f a n t ib o d y / s e c o n de a c h p la s m a c e ll p r o d u c e s a n t ib o d y - s p e c ifl c o n ly t o t h e a n t ig e n t h a t o r ig in a lly s e n s it iz e dt h e a n t ib o d y c la s s ( Ig G , Ig M , e t c ) m a y v a r y b u t a n t ib o d y c a n o n ly b e d ir e c t e d a g a in s t t h a t s p e c ifl c a n t ig e nm a d e b y p la s m a a n d t h e n r e le a s e d in t o b lo o d a n d o t h e r ‡ u id s a s a f r e e a n t ib o d y ( r e m a in in b lo o d 3 - 3 0 d a y s )b e c a u s e it is s e p a r a t e f r o m B - c e lls a n d f o u n d in b o d y ‡ u id s s o m e t im e s c a lle d ” h u m o r a l im m u n it y

c irc u la t in g a n t ib o d ie s c a n b e t ra n s fe rre d fro m p e rs o n t o p e rs o n t o p ro vid e t h e re c e iv in g p e rs o n w it h im m e d ia t e im m u n it y o f s h o rt d u ra t io n

5.) antibody-antigen binding:n e e d e d fo r a n t i a n t ig e n a c t io n sa n t ib o d ie s a re y s h a p e d m o le c u le s

t ip s o f s h o r t a r m s o f t h e Y r e c o g n iz e t h e s p e c ifl c a n t ig e n & b in d t o itt h e r e f o r e e a c h a n t ib o d y c a n b in d t o t w o a n t ig e n s o r t o t w o a r e a s o f t h e s a m e a n t ig e ns t e m o f Y is t h e ” F c f r a g m e n t ‘ a n d c a n b in d t o F c r e c e p t o r s it e s o n W B C s

t h e W B C c a n t h e n a t t a c k a n t ig e n s a n d a ls o a d d s u r f a c e a n t ib o d ie s t h a t s t ic k t o t h e a n t ig e n

n o t n e c e s s a r ily le t h a l b u t b e g in s t h e o t h e r s t e p s t h a t n e u t r a liz e , e lim in a t e a n d d e s t r o y t h e a n t ig e n

6.) antibody-binding actions:

im m u n e c o m p le xu s u a lly b a c t e r ia a n d v ir u s e s a r e t h e n o n s e lf c e lls t h a t a r e d a m a g e d t h r o u g h m o s t t h r u ly s is

c . ) c o m p le m e n t a c t iv a t io n & fl x a t io na c t io n s t r ig g e r e d b y s o m e c la s s e s o f a n t ib o d ie s t h a t c a n r e m o v e o r d e s t r o y a n t ig e nt h e t w o c la s s e s o f a n t ib o d y t h a t c a n a c t iv a t e t h e c o m p le m e n t s y s t e m a r e Ig G & Ig Mb in d in g o f a n t ib o d y f r o m e it h e r o f t h e s e c la s s e s t o a n t ig e n p r o v id e s a b in d in g s it e f o r t h e 1 s t c o m p o n e n t o f c o m p le m e n to n c e t h e 1 s t c o m p le m e n t m o le c u le is a c t iv a t e d , o t h e r p r o t e in s o f t h e c o m p le m e n t s y s t e m a r e a c t iv a t e d in a c a s c a d e

d . ) p r e c ip it a t io ns im ila r t o a g g lu t in a t io n w it h a la r g e r r e s p o n s ea n t ib o d y m o le c u le s b in d s o m u c h a n t ig e n , t h a t la r g e , in s o lu b le , a n t ig e n - a n t ib o d y c o m p le x e s a r e f o r m e dc a n ÷t s t a y s u s p e n d e d in t h e b lo o d in s t e a d t h e y f o r m a la r g e p r e c ip it a t e w h ic h c a n b e a c t e d o n a n d r e m o v e d b y n e u t r o p h ils & m a c r o p h a g e s

e . ) in a c t iv a t io n ( n e u t r a liz a t io n )t h e p r o c e s s o f m a k in g a n a n t ig e n h a r m le s s w it h o u t d e s t r o y in g itu s u a lly a s m a ll a r e a o f t h e a n t ig e n ” t h e a c t iv e s it e ‘ c a u s e s t h e h a r m f u l e f f e c t s , r e s t o f t h e a n t ig e n n o t h a r m f u lw h e n a n a n t ib o d y b in d s t o t h e a n t ig e n a n d c o v e r s u p t h e a n t ig e n ÷s a c t iv e s it e , t h e a n t ig e n is m a d e u n h a r m f u l w it h o u t d e s t r o y in g it

7.) sustained immunity (memory):lo n g la s t in g im m u n it y t o a s p e c iflc a n t ig e nre s u lt s fro m m e m o ry B c e lls m a d e d u rin g t h e lym p h o c y t e s e n s it iz a t io n s t a g ere m a in s e n s it iz e d t o t h e s p e c iflc a n t ig e n t h e y we re o rig in a lly e xp o s e d t oo n re -e xp o s u re , t h e y ra p id ly re s p o n dflrs t m e m o ry c e lls d iv id e a n d fo rm n e w s e n s it iz e d b la s t c e lls a n d n e w s e n s it iz e d p la s m a c e llsb la s t c e lls c o n t in u e t o d iv id e p ro d u c in g m a n y m o re s e n s it iz e d p la s m a c e llst h e s e n e w p la s m a c e lls ra p id ly m a ke la rg e a m o u n t s o f t h e a n t ib o fy , s p e c iflc fo r t h e s e n s it iz in g a n t ig e nt h is a llo ws a ra p id a n d la rg e im m u n e ( a n a m n e s t ic ) re s p o n s e t o t h e a n t ig e nb e c a u s e s o m u c h a n t ib o d y is m a d e , u s u a lly t h e in va d in g o rg a n is m s a re c o m p le t e ly re m o ve d a n d t h e p e rs o n d o e s n o t b e c o m e s ic kb e c a u s e o f t h is , m o s t p e o p le d o n o t b e c o m e ill w it h c h ic ke n p o x o r o t h e r in fe c t io u s d is e a s e s m o re t h a n o n c e e ve n t h o u g h

in the gamma fraction of plasma proteins during electrophoresis5 antibody types classifled by differences in size and timingon 1st exposure to an antigen, the newly sensitized B-cell produces the IgM antibody against the antigenIgM forms itself in a 5 member group

each IgM group then has 10 antigen binding siteseven though slow at flrst exposure, antibody production produces very efflcient antibody type at antigen bindingensures initial illness lasts only 5-10 dayson reesposure the already sensitized B cell makes large amounts of IgG type of antibody against that antigen

IgG does not form groups of 5 but enormous amount produced efflcient at clearing the antigen and protecting the person from becoming ill with the disease again

Acquiring Antibody-Mediated Immunityinnate native immunity/ ”natural immunity‘ & adaptive acquired immunity

natural protective featurebarrier to prevent organisms from entering the body or can be an attacking force that eliminates organisms that have already entered the bodycannot be developed or transferred from one person to another and is not an adaptive response to exposure or invasion by foreign proteinsin‡ammatory response is a partother parts = skin, mucosa, antimicrobial chemicals on the skin, complement and natural killer cells

adaptive immunity - immunity that a person÷s body learns to make (or can receive) as an adaptive response to invasion to organism or foreign particle

i.e. antibody mediated immunityoccurs naturally or artiflcially through lymphocyte responses and can be active or passive

n a t u ra l - m o s t e ffe c t ive & lo n g la s t in ga rt iflc ia l - va c c in a t io n / im m u n iz a t io n

a c t ive - a n t ig e n s e n t e r t h e b o d y a n d re s p o n d s b y m a kin g s p e c iflc a n t ib o d ie s a g a in s t t h e a n t ig e n

a c t iv e b e c a u s e t h e b o d y t a k e s a n a c t iv e p a r t in m a k in g t h e a n t ib o d ie sn a t u r a l a c t iv e - o c c u r s w h e n t h e a n t ig e n e n t e r s t h e b o d y a n d t h e b o d y r e s p o n d s b y a c t iv e ly m a k in g a n t ig e n s

u s u a lly t h e in v a s io n t h a t t r ig g e r s a n t ib o d y p r o d u c t io n , a ls o c a u s e s t h e d is e a s ep r o c e s s e s o c c u r in g in t h e b o d y a t t h e s a m e t im e a s in f e c t io n c r e a t e im m u n it y t o t h a t a n t ig e n ( w ill n o t b e c o m e ill a f t e r a 2 n d e x p o s u r e t o s a m m e a n t ig e n )m o s t e f f e c t iv e , lo n g e s t la s t in g

a r t ifl c ia l a c t iv e im m u n it y is p r o t e c t io n d e v e lo p e d b y v a c c in a t io n o r im m u n iz a t io n

u s e d t o p r e v e n t in f e c t io n s o r illn e s s e s ( t e t a n u s , d ip t h e r ia , p o lio ) t h a t h a v e s u c h s e r io u s c o n s e q u e n c e s t h a t a v o id in g t h e d is e a s e a lt o g e t h e r is t h e m o s t d e s ir a b les m a ll a m o u n t s o f a s p e c ifl c a n t ig e n a r e p la c e d a s a v a c c in a t io n in t o t h a t p e r s o nim m u n e r e s p o n s e a c t iv e ly m a k e s a n t ib o d ie se x p o s u r e d o e s n o t c a u s e d is e a s e b e c a u s e t h e a n t ig e n s h a v e b e e n a t t e n u a t e d ( s p e c ifl c a lly p r o c e s s t h e m t o b e le s s lik e ly t o g r o w in t h e b o d y )la s t s m a n y y e a r s a lt h o u g h r e p e a t e d b y s m a lle r d o s e s o f o r ig in a l a n t ig e n r e q u ir e d a s a ” b o o s t e r ‘ t o r e t a in t h e p r o t e c t io n

p a s s ive im m u n it y o c c u rs wh e n n t ib o d ie s a g a in s t a n a n t ig e n a re in a p e rs o n ÷s b o d y b u t we re n o t c re a t e d t h e re

a n t ib o d ie s t r a n s f e r r e d t o t h e p e r s o n ÷s b o d y a f t e r b e in g m a d e in t h e b o d y o f a n o t h e r p e r s o n o r a n im a lb e c a u s e t h e y ÷r e f o r e ig n , t h e y ÷r e r e c o g n iz e d a s n o n s e lf a n d a r e e lim in a t e d q u ic k lyp r o v id e s o n ly im m e d ia t e , s h o r t t e r m p r o t e c t io n a g a in s t a s p e c ifl c a n t ig e nn a t u r a l p a s s iv e im m u n it y - a n t ib o d ie s a r e p a s s e d f r o m m o t h e r t o f e t u s v ia p la c e n t a o r t h r o u g h c o lo s t r u m / b r e a s t m ilka r t ifl c ia l p a s s iv e - in v o lv e s in je c t in g a p e r s o n w it h a n t ib o d ie s t h a t w e r e p r o d u c e d in a n o t h e r p e r s o n o r a n im a l

u s e d w h e n a p e r s o n is e x p o s e d t o a s e r io u s d is e a s e f o r w h ic h t h e y h a v e lit t le / n o a c t iv e ly a c q u ir e d im m u n it ya c t iv e a n t ib o d ie s e x p e c t e d t o in a c t iv a t e a n t ig e nt e m p o r a r y ( f e w d a y s t o w e e k s )c a n b e u s e d t o p r e v e n t d is e a s e o r d e a t h f o r p a t ie n t s e x p o s e d t o r a b ie s , t e t a n u s , s n a k e b it e s

AMI works with in‡ammation to protect against infectionAMI can provide the most effective, long lasting immunity when combined with CMI

V. Cell-Mediated Immunity (CMI) “cellular immunity”

producing and releasing cytokinesfor total immunocompetence CMI must function optimallyCell types involved in CMI

the WBCs with the most important roles in CMI include several speciflc T-lymphocytes (T-cells) along with a special population of cells known as natural killer (NK) cells

T cells have a variety of subsets each of which has a speciflc function

ID T-c e ll s u b s t s is t o e xa m in e ”m a rke r p ro t e in s ‘ ( a n t ig e n s ) o n t h e c e ll m e m b ra n e ÷s s u rfa c e> 2 0 0 d iffe re n t T c e ll p ro t e in s h a ve b e e n IDe d o n c e ll m e m b ra n e s a n d 1 1 o f t h e s e ( T1 -T1 1 ) a re u s e d t o c lin ic a lly ID c e llsAn t ib o d ie s h a ve b e e n m a d e a g a in s t e a c h o f t h e s et h e re fo re e a c h T c e ll s u b s e t c a n b e IDe d b y it s re a c t io n t o c o m m e rc ia l a n t ib o d ie s

m o s t T c e lls h a v e m o r e t h a n o n e a n t ig e n o n t h e ir c e ll m e m b r a n ei. e . a ll m a t u r e T c e lls c o n t a in T 1 , T 3 , T 1 0 , T 1 1 c e r t a in T c e lls a ls o c o n t a in o t h e r s p e c ifl c T c e ll m e m b r a n e a n t ig e n s

n a m e s u s e d t o id e n t ify s p e c iflc T c e ll s u b s e t s in c lu d e t h e s p e c iflc m e m b ra n e a n t ig e n a n d t h e o ve ra ll a c t io n s o f t h e c e lls in a s u b s e t3 T-c e ll s u b s e t s c rit ic a lly im p o rt a n t fo r t h e d e ve lo p m e n t a n d c o n t in u a t io n o f CMI a re :

1 . ) h e lp e r / in d u c e r T c e llsh a v e T 4 p r o t e in s o n t h e ir m e m b r a n e t h e s e c e lls a r e u s u a lly c a lle d T 4 + c e lls o r T h c e lls - m o s t c o r r e c t n a m e is C D 4 + ( c lu s t e r o f d if f e r e n t ia t io n 4 ) - a ls o r e f e r r e d t o a s O K T 4 p o s it iv e o r L e u - 3 p o s it iv e b e c a u s e o f t h e s p e c ifl c a n t ig e n s o n t h e m e m b r a n e s u r g a c ee a s ily r e c o g n iz e a s s e lf o r n o n s e lf c e llsin r e s p o n s e t o r e c o g n it io n o f n o n s e lf ( a n t ig e n ) , h e lp e r / in d u c e r T c e lls s e c r e t e ly m p h o k in e s t h a t c a n e n h a n c e a c t iv it y o f o t h e r W B C sm o s t ly m p h o k in e s s e c r e t e d in c r e a s e im m u n e f u n c t io n , in c r e a s e b o n e m a r r o w p r o d u c t io n o f s t e m c e lls a n d s p e e d u p t h e ir m a t u r a t io n

t h u s h e lp e r / in d u c e r T c e lls a c t a s o r g a n iz e r s in ” c a llin g t o a r m s ‘ v a r io u s s q u a d s o f W B C s in v o lv e d in in ‡ a m m a t o r y , a n t ib o d y a n d c e llu la r p r o t e c t iv e a c t io n s t o d e s t r o y o r n e u t r a liz e a n t ig e n s

2 . ) s u p p r e s s o r T c e llsc a n h e lp r e g u la t e C M Ih a v e t h e T 8 ly m p h o c y t e a n t ig e n o n t h e ir m e m b r a n e

b a la n c e is 2 :1 r a t io o f h e lp e r / in d u c e r s u p p r e s s o r c e llsw h e n r a t io in c r e a s e s ( h e lp e r v a s t ly o u t # s u p p r e s s o r ) o v e r r e a c t io n s c a n o c c u r ( s o m e a r e t is s u e d a m a g in g a s w e ll a s u n p le a s a n t )w h e n r a t io d e c r e a s e s ( f e w e r t h a n n o r m a l h e lp e r / in d u c e r T c e lls ) im m u n e f u n c t io n is s u p p r e s s e d a n d t h e p e r s o n ÷s r is k f o r in f e c t io n s in c r e a s e s

3 . ) c y t o x ic / c y t o ly t ic T c e lls a k a ” T c c e lls ‘s u b s e t o f s u p p r e s s o r c e lls b e c a u s e t h e y h a v e t h e T 8 p r o t e in p r e s e n t o n t h e ir s u r f a c e sd e s t r o y c e lls t h a t c o n t a in a p r o c e s s e d a n t ig e n s m a jo r h is t o c o m p a t a b ilit y c o m p le x ( M H C )

m o s t e f f e c t iv e a g a in s t s e lf c e lls in f e c t e d b y p a r a s it e s , s u c h a s v ir u s e s o r p r o t o z o

p a r a s it e in f e c t e d c e lls h a v e b o t h s e lf M H C p r o t e in s ( U P C ) a n d t h e p a r a s it e ÷s a n t ig e n s o n t h e c e ll s u r f a c e

t h is a llo w s t h e p e r s o n ÷s im m m u n e s y s t e m c e lls t o r e c o g n iz e t h e in f e c t e d s e lf c e lls a s a b n o r m a l a n d t h e c y t o x ic / c y t o ly t ic T c e ll c a n b in d t o itw h e n t h e c y t o x ic / c y t o ly t ic T c e ll b in d s t o t h e in f e c t e d c e lls M H C , t h e c y t o x ic / c y t o ly t ic T c e ll m a k e s h o le s in t h e m e m b r a n e o f t h e in f e c t e d c e ll, c a u s in g it t o ly s e a n d d ie

o n c e t h e le t h a l h it h a s b e e n d e liv e r e d , t h e c y t o x ic / c y t o ly t ic T c e ll r e le a s e s t h e d y in g , in f e c t e d c e ll a n d c a n t h e n d e s t r o y a n d a t t a c k o t h e r in f e c t e d c e lls c a r r y in g t h e s a m e a n t ig e n M H C c o m p le x

+ n a t u r a l k ille r c e ll - n o t a t r u e T c e ll b u t c o n t r ib u t e s t o C M I ( a k a ” C D 1 6 + ‘ )

v e r y im p o r t a n t in p r o v id in g C M Ia c t u a l s it e o f d if f e r e n t ia t io n a n d m a t u r a t io n u n k n o w nh a s s o m e T c e ll f e a t u r e s , b u t n o t a t r u e T c e ll s u b s e td ir e c t c y t o x ic e f f e c t s o n s o m e n o n s e lf c e lls w it h o u t b e in g s e n s it iz e dt h e c e ll k illin g a c t io n s a r e in d e p e n d e n t o f t h e in t e r a c t io n o f o t h e r W B C s” s e e k & d e s t r o y ‘ m is s io n s in t h e b o d y t o e lim in a t e n o n s e lf c e llsm o s t e f f e c t iv e in d e s t r o y in g u n h e a lt h y o r a b n o r m a l s e lf c e llsm o s t o f t e n c a n c e r c e lls a n d v ir a lly in f e c t e d b o d y c e lls

CytokinesCMI regulates the immune system by production & activation of cytokines (small protein hormones produced by many WBCs and some other tissues)cytokines made by the macrophages, neutrophils, eosinophils and monocytes = monokinescytokines produced by T-cells are lymphokinesworks like other types of hormones

one cell produces a cytokinewhich in turn exerts its effects on other cells of the immune

c y t o kin e s c o n t ro l m a n y in ‡ a m m a t o ry a n d im m u n e re s p o n s e s a n d a re c o n t ro lle d b y in t e ra c t io n s w it h o t h e r s ys t e m s ( e s p . t h e n e rvo u s s ys t e m )s o m e c y t o kin e s a re p le io t o p ic ( e ffe c t s a re w id e s p re a d w it h in t h e im m u n e s ys t e m ) a n d s e n t in t o m o t io n m a n y d iffe re n t im m u n e a c t io n so t h e r c y t o kin e s h a ve s p e c iflc a c t io n s lim it e d t o o n ly o n e t yp e o f c e llc y t o kin e s in c lu d e in t e rle u kin s ( la rg e s t g ro u p ) , in t e rfe ro n s , c o lo n y s t im u la t in g fa c t o rs a n d t u m o r n e c ro s is fa c t o

Protection provided by CMICMI helps protect the body through the ability to differentiate self vs. non selfthe non self cells most easily recognized by CMI are cancer cells and those infected by organisms that live within host cellswatches for and rids body of self cells that might potentially harm the bodyimportant in preventing the development of cancer and metastasis after exposure to carcinogens

Transplant rejectionNK cells and cytoxic/ cytolytic T cells also destroy cells from other people or animalsusually helpful but responsible for rejection of tissue grafts and transplanted organs

because seldom protect identical match of human leukocyte antigens the immune system recognize organ as non-self and starts in‡ammatory and immunologic actions to destroy or eliminate these non self cells

t h is c a u s e s o rg a n re je c t io nr e s u lt o f a c o m p le x s e r ie s o f r e s p o n s e s t h a t c h a n g e o v e r t im e a n d in v o lv e d if f e r e n t c o m p o n e n t s o f t h e im m u n e s y s t e m

3 types of rejection1.) Hyperacute rejection

b e g in s im m e d ia t e ly o n t ra n s p la n t a t io na n t ib o d y-m e d ia t e d re s p o n s ea n t ig e n -a n t ib o d y c o m p le xe s fo rm in t h e b lo o d ve s s e ls o f t h e t ra n s p la n t e d o rg a nt h e h o s t ÷s b lo o d h a s p re -e xis t in g a n t ib o d ie s t o o n e o r m o re

fo rm t h ro u g h o u t t h e o rg a no c c lu d e s b lo o d v e s s e ls a n d le a d s t o is c h e m ic n e c r o s is , in ‡ a m m a t io n w it h p h a g o c y t o s is o f t h e n e c r o t ic b lo o d v e s s e ls a n d r e le a s e o f ly t ic e n z y m e s in t o t h e n e w o r g a n

t h e s e e n z y m e s c a u s e m a s s iv e c e llu la r d e s t r u c t io n a n d g r a f t lo s s

o c c u r s m o s t ly in t r a n s p la n t e d k id n e y s b u t le s s c o m m o n r e la t e d t o g r e a t e r e f f o r t s in H L A m a t c h in gt h o s e a t g r e a t e s t r is k a r e t h o s e w h o h a v e r e c e iv e d d o n a t e d o r g a n s o f a n A B O b lo o d t y p e d if f e r e n t t h a n t h e ir o w n , h a v e r e c e iv e d m u lt ip le b lo o d t r a n s f u s io n s a t a n y t im e in lif e b e f o r e t r a n s p la n t a t io n , h a v e a h is t o r y o f m u lt ip le p r e g n a n c ie s o r h a v e r e c e iv e d a p r e v io u s t r a n s p la n t

m a n ife s t a t io n s a re a p p a re n t in m in u t e s o f a t t a c h m e n t o f d o n a t e d o rg a n t o t h e h o s t s b lo o d s u p p lyp ro c e s s c a n n o t b e s t o p p e d o n c e it h a s b e e n s t a rt e d a n d t h e re je c t e d o rg a n is re m o ve d a s s o o n a s t h e h yp e ra c u t e re je c t io n is d ia g n o s e d

2.) Acute rejectiono c c u rs 1 we e k t o 3 m o n t h s a ft e r t ra n s p la n t a t io n2 m e c h a n is m s re s p o n s ib le

1 . ) a n t ib o d y m e d ia t e d a n d r e s u lt s in v a s c u lit is in t r a n s p la n t e d o r g a n ( b lo o d v e s s e l n e c r o s is le a d s t o t h e o r g a n ÷s d e s t r u c t io n )2 . ) c e llu la r h o s t c y t o x ic / c y t o ly t ic T c e lls a n d N K c e lls e n t e r t h e t r a n s p la n t e d o r g a n t h r o u g h t h e b lo o d , p e n e t r a t e t h e o r g a n c e lls , s t a r t a n in ‡ a m m a t o r y r e s p o n s e a n d c a u s e t h e ly s is o f t h e o r g a n c e lls

d ia g n o s e d w it h la b t e s t s t h a t s h o w t h e im p a ire d fu n c t io n o f t h e d o n a t e d o rg a n a n d b y a b io p s y o f t h e d o n a t e d o rg a ns ym p t o m s va ry w it h e a c h p a t ie n t a n d t h e s p e c iflc o rg a n t ra n s p la n t e d

i. e . k id n e y - s o m e t e n d e r n e s s in k id n e y a r e a a n d g e n e r a l s y m p t o m s o f in ‡ a m m a t io n

a n e p is o d e d o e s n o t a u t o m a t ic a lly m e a n t h e p a t ie n t w ill lo s e t h e n e w o rg a nd ru g m a n a g e m e n t o f h o s t im m u n e re s p o n s e s a t t h is t im e m a y lim it t h e d a m a g e t o t h e o rg a n a n d a llo w t h e g ra ft t o b e m a in t a in e d

3.) Chronic rejectionu n c le a r o rig ins im ila r t o c h ro n ic in ‡ a m m a t io n & s c a rrin gs m o o t h m u s c le s o f b lo o d ve s s e ls o ve rg ro w a n d o c c lu d e t h e ve s s e lst h e d o n a t e d o rg a n t is s u e s a re re p la c e d w it h flb ro t ic , s c a r like t is s u e

fl b r o t ic t is s u e is n o t o r g a n t is s u e - t r a n s p la n t e d o r g a n s f u n c t io n is r e d u c e d in p r o p o r t io n t o t h e a m o u n t o f n o r m a l

wh e n flb ro s is in c re a s e s t o t h e e xt e n t t h a t t h e t ra n s p la n t e d o rg a n c a n n o lo n g e r fu n c t io n , t h e o n ly c o u rs e is re t ra n s p la n t a t io n

Treatment of transplant rejectionre je c t io n in vo lve s a ll 3 c o m p o n e n t s o f im m u n it y a lt h o u g h CMI c o n t rib u t e s t h e m o s tm a in t e n a n c e t h e ra p y : c o n t in u o u s im m u n e s u p re s s io n

c o m b o o f s p e c ifl c im m u n e s u p p r e s a n t sc y c lo s p o r in e ( s a n d im u n e , N e o r a l, G e n g r a f )

in c lu d e s s p e c ifl c a n d e f f e c t iv e s u p p r e s s io n b u t w it h m a jo r lo n g t e r m s id e e f f e c t s , & e x p e n s iv e

le s s s p e c ifl c im m u n o s u p p r e s s io n sa z a t h io p r in e ( Im u r a n )m y c o p h e n o la t e ( C e ll- c e p t , M y f o r t ic )

a n d o n e o f t h e c o r t ic o s t e r o id sp r e d n is o n e ( D e lt a - c o r t e f )

n e w d r u g - g u s p e r im u s ( S p a n d in )d o s a g e o f a ll is a d ju s t e d t o t h e im m u n e re s p o n s e o f e a c h p a t ie n tt re a t m e n t w it h t h e s e a g e n t s in c re a s e ris k fo r b a c t e ria l a n d fu n g a l in fe c t io n s a n d fo r c a n c e r d e ve lo p m e n tT c e ll s u p p re s s io n : t a c ro lim u s ( Pro g ra t ) is s im ila r t o e ry t h ro m yc in a n d s p e c iflc a lly s u p p re s s e s T c e ll a c t io n s in c lu d in g IL-2 p ro d u c t io n

w it h o u t IL - 2 , h e lp e r T c e lls a n d c y t o x ic a n d c y t o ly t ic T c e lls a r e s lo w t o r e p r o d u c e a n d d o n o t p e r f o r m t h e ir u s u a l f u n c t io n ss u p p r e s s io n a llo w s d o n a t e d o r g a n t o n o t b e d e s t r o y e dg e n e r a l im m u n o s u p p r e s s io n is n o t a s p r o f o u n d a n d t h e h o s t ÷s r is k f o r in f e c t io n is n o t g r e a t ly in c r e a s e da ls o p r e v e n t s a c t iv a t io n o f u n s e n s it iz e d c y t o x ic / c y t o ly t ic T c e llso t h e r d r u g s w it h s im ila r a c t io n s in c lu d e s ir o lim u s ( Ra p a m u n e ) a n d e v e r o lim u s ( C e r t ic a n )

u s e o f m o n o c lo n a l a n t ib o d ie s d ire c t e d a t IL-2 re c e p t o r s it e s o n a c t iva t e d T-c e lls ( e s p e c ia lly h e lp e r/ in d u c e r)

t h e s e a n t ib o d ie sb a s ilix im a b ( S im u le c t )d a c liz u m a b ( Z e n a p a x )

a r e g iv e n w it h in 2 h o u r s IV b e f o r e t h e t r a n s p la n t s u r g e r y

r e d u c e s T c e ll g r o w t h a n d a c t iv a t io n f o r m o n t h sre s c u e t h e ra p y : u s e d t o t re a t a c u t e re je c t io n e p is o d e s

m a y b e u s e d in a d d it io n t o o r in p la c e o f t h e m a in t e n a n c e d r u g s in t h e h o s t s n o r m a l t r e a t m e n t r e g im e n

a n t ilym p h o c y t e g lo b u lin ( ALG) is a n a n t ib o d y p ro d u c e d a ft e r t h e a n im a l h a s b e e n e xp o s e d t o h u m a n lym p h o c y t e s

c a n b e m a d e m o r e s p e c ifl c b y e x p o s in g t h e a n im a l t o h u m a n T - c e llsw h e n t h e s e a n t ih u m a n ly m p h o c y t e s a r e g iv e n t o h u m a n s

e f f e c t iv e n e s s in c o m b a t t in g g r a f t r e je c t io n d e c r e a s e w it h e a c h u s e

o n ly g iv e n f o r s h o r t t im e t o c o m b a t a c u t e r e je c t io n e p is o d e b e c a u s e o f im m u n o lo g ic s id e e f f e c t s w h ic h in c r e a s e in in t e n s it y o n r e p e a t e d e x p o s u r ea n t ib o d ie s m a d e in o t h e r a n im a ls ( e s p . m ic e ) c a u s e s / e in h u m a n s b e c a u s e a n im a l p r o t e in s a r e r e c o g n iz e d a s f o r e ig n b y h u m a n im m u n e s y s t e m

in c id e n c e o f s id e e f f e c t s is d e c r e a s e d b e c a u s e a n t ib o d ie s h a v e b e e n ” h u m a n iz e d ‘

r e m o v e s m o u s e s p e c ifl c p r o t e in s a n d r e p la c e s w it h h u m a n s p e c ifl c p r o t e in s