Introduction to Immunology

7/21/2019 Introduction to Immunology

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Immunology 101

Richard T Maziarz, MD

September 13, 2013



Baic concept

! Sel" # nonel" recognition

! Repone to danger ignal$ In"lammation

% terile # nonterile! &omponent o" the immune ytem

! Impact o" tranplantation on immune ytem'

! Immune recontitution'! (arneing the immune ytem



Self vs non-self admission isevolutionarily conserved





&haracteritic o" Mamnalian

Immune Repone! Sel") *onel" Recognition

% +rotection "rom "oreign pathogen

% limination o" malignant tran"ormed cell

% Re-ection o" "oreign allogra"t

% .ailure o" tolerance$$/ utoimmune diorder



M(& molecule

! M(& cla I

% ($,B,&

! , ., , ( % bi4uitou e5preion

! M(& cla II

% ($DR,D+,D6

! D7,D8

% imited e5preion

! ntigenic Di#erity



&rytal tructure



M(& Molecule ) Di#erity

! enetic tructure ) e5on croo#er e#ent

! Molecular tructure ) point mutation

! +eptide binding poc9et

! T+

! +rotein degradation and proceing! nd reult) Tiue peci"ic antigen

! .uture) +eptide peci"ic therapie, #accine:



Immune Sytem

! dapti#e immune ytem # innate immune

ytem





+athogen aociated molecular

pattern ;+M+<! Bacterial component

! =iral component

! ndogenou ource

% ric acid

% D*

% R*



Toll li9e receptor acti#ation



&omponent) Immune Sytem! ymphocyte ;Speci"icity< ) B cell, T cell, *>

cell

! *on$Speci"ic lement

% *> &ell % +&?) Monocyte@macrophageA endothelial cellA B

cellA Dendritic cellA 7ther$ microglia, angerhan?

cell, etc

% *eutrophil % Soluble mediator) cyto9ine, lympho9ine, chemo9ine





""ector cell



Immunologic peci"icity

! ntigen$peci"ic receptor on cell ur"ace

% T lymphocyte) antigen peci"ic T cell receptor

% B lymphocyte) ur"ace IgM or IgM IgD

! ntibodie in erum a"ter ecretion by

plama cell



&luter o" Di""erentiation ntigen

*omenclature! *omenclature de"ine the Cname o" the

antigen ) ;&D1 % &D32E<

! De#eloped to clari"y the biology o"repone aociated Fith antigen

! ll &D deignation are not necearily

independent molecule % 5ample ) &D3, &D11@&D1G are peptideA

&D1H de"ine &(7 idechain



CT cell and B cell clone are

actually indi#idual tiue' The

comle5ity o" the immune ytem

i impli"ied by the recognitionthat there are billion o" tiue in

circulation contributing toimmune ur#eillance



T cell

! Intrathymic # 5trathymic di""erentiation

! Thymu di""erentiation ) Fell ordered pathFay $

corte5$$/ medulla and out % &D3$$/ &D3 &DJ$$/ &D2&DJ;triple negati#e<$$

/ &D2&D3 ;double negati#e<$$/ &D2&D3&D&DG

;double poiti#e<$$/ &D2&D3&D or &D2&D3&DG

! T&R rearrangement accompanie poiti#e and

negati#e election



&D and &DG &o$Receptor

! dheion molecule )

% &D)M(& II

% &DG) M(& I

! Recognition o" M(& $ coner#ed e4uence

! &o$timulatory "unction to augment T&R

ignalling ;aociated Fith lc9<! De"ine ubpopulation o" e""ector T cell

% (elper and cytoto5ic T cell





T &ell in the thymu

! +oiti#e Selection

% oF a""inity T&R "or el" can mature and

migrate to periphery

! *egati#e Selection

% (igh a""inity T&R "or el" are deleted "olloFing

T&R ligation! ctual Mechanim remain unclear

% Signal intenity # De#elopmental tage



ge Related &hange in Thymu

(ayne, nn Re# Imm, 2000



ge Related &hange in Thymu

! ge KT pace Thymu out

! 0$1 L3 /10L

! 2$10 GG G'G 5 10G

! 11$2H E3 E'3 5 10G

! 2E$L H 'H 5 10G

! /H0 1G 1'G 5 10G

(ayne, nn Re# Imm, 2000





&otimulation! T&R and &D2G imultaneou acti#ation lead to T cell proli"eration

and target cell death! T&R and &D1H2 ;&T< binding can limit a T cell proli"erati#e

repone

! The lac9 o" cell ur"ace &DG0 and &DGE can lead to T cell

programmed cell death or to induction o" peripheral tolerance ;e'g'

anergy<' % bence o" &DG0 on tumor can induce tolerance

% (eterotypic antibodie binding &D3 and &D2G can o#ercome

peripheral tolerance

% 7>T3 treatment in renal tranplant can render T cell re"ractory to

timulation



! Immunologic Memory)

% ntigen e5poure$$/ proli"eration and di""erentiationA

mall o" cell may proceed to memory tate

% Secondary ntigenic &hallenge ) anamnetic

repone

! mpli"ication o" Immune Repone

% &ell) &ell interaction

% &ell) oluble mediator interaction



&yto9ine 5preion by T cell

population! *aN#e T cell

% I2, lo induction o" D& I12

! Memory T cell

% T$&M);&&RJB<)

! I2, induce D& I12

% T$M);&&RJ$<)! lo I2, I, IH, I.*$,

Salluto, *ature, 1LLL



Memory@""ector T cell

! ""ector T cell )

% &on#entional) +recuror o" memory cell:

% (ypothei) DoFntream cell a"terdi""erentiation o" T central memory cell:

! Supported by telomere hortening ober#ation

% +henotype) &DHR7B

&&RJB

and&DGB&DHRB&&RJ$&DE2lo

ubpopulation;:<





*aN#e T cell) Molecular

Determination! &hromoome 1 i home o" alpha and delta

T&R

! Rearrangement o" T&R alpha locu duringthymic maturation plice out T&R delta locu

! T cell receptor e5ciion circle ;TR&<)

maintained epiomally and do not replicate! ntigen dri#en T cell e5panion doe not

e5pand TR&



! TFo clae o" T&R

! T&R are polypeptide Fith tFo "unction$ e5ternal

antigen recognition and ignal tranduction

! T&R engage antigen on the cell ur"ace o" other cell

! T&R recognize antigen in conte5t o" M(&

! T&R "amilie can be aociated Fith dieae % =O2 in to5ic hoc9 ;uper antigen<

% =O12, 1J in multiple chleroi ;auto antigen<



eneration o" TR&



TR& ) &linical pplication

! Decreae Fith age, but perit into Jth decade $Doue9, *ature, 1LLL

! Decreaed in (I=$in"ected pt

! Increaed Fith aggrei#e anti#iral therapy in(I=

! Increaed in thymic tranplant "or Dieorge

yndrome, coincident Fith increae

&DHR, &DE2 $Mar9ert, *PM, 1LLL



Reco#ery o" &D and &DG T &ell

a"ter utoT5 "or MM

Doue9, ancet 2000

&DQ opa4ue

&DGQ open

&D3Qcircle



T &ell Receptor nalyi



*ormal =$O .amily 5preion



&DR3 Size$+attern nalyi

*ormal (I=

In #itro

g timT cell line

Man"ra, P Imm Met, 1LLJ



&DR3 Size$+attern nalyi in

Tranplantation! or9i, PI, 1LL)

% Repertoire tability

% Rate o" repertoire reco#ery

% Impact o" opportunitic in"ection

! Memon, I, 2000)

% &orrelated Fith &DB, &DHRB T cellreco#ery



T&R ignal tranduction

! cti#ation o" T cell

! Render T cell re"ractory to timulation

! &otimulation ;&D3 ) &D2G<

! Target "or therapy o" T cell dieae

! enetic de"ect ;S&IDS and other<

% ap J0 de"iciency

% &D3 gamma or epilon deletion



Second Signal



T cell ub$ubet! &D T cell di""erentiate into eparate

ubpopulation o" T cell

% Th1 are important "or cellular repone and reitance

to in"ectionA I$2, I.*$, T*.$alpha are produced

% Th2 are important "or humoral repone and canincreae uceptibility to in"ectionA I$, I$H, Il$E, I$

10, I$13, M$&S.A can doFnregulate Th1 repone

! &DG e""ector cell ubpopulation li9e &D cell

ha#e been identi"ied'



(elper T cell ubet



CD4 T cell subsets









*atural 9iller cell

! >iller inhibitory receptor ;>IR<

! Di#erity

! ( recognition

! May impact leu9emia outcome

! &linical rele#ance$ recognition o" herpe

#iru "amily member



Impact o" tranplantation

conditioning on hot immunity! Myeloablati#e

! Immune upprei#e

! 6uantitati#e and 4ualitati#e de"icit



Tumor &ell cape "rom T cell

Immunour#eillance! o o" e5preion o" M(& antigen

% Trancriptional repreion ;$< o" gene e5preion

% Intracellular competition Fith O2M % o o" tran acti#ating "actor "or e5preion

% ltered T+ tranporter

% &hromoomal Deletion! +roduction o" inhibitory cyto9ine e'g' I10,

T.$O



Tumor &ell cape "rom T cell

Immunour#eillance! Induction o" eta chain tranlocation and

anergy

! o o" adheion molecule! ac9 o" cotimulatory molecule ;&DG0,

&DGE, &D0<

! ac9 o" TST, T! Secretion o" oluble antigen to create tolerance



Immune recontitution

! +opulation K ymph &ount@ul K ymph count@ul

! Total T cell;&D3< HL'G 31E HH$G2K G00$3H00

! &D3 &D 23' 12 20$E0K H00$2000

! &D3 &DG 30'L 1E3 1H$30K 300$L00! &D3&D$&DG$;Doub'neg< 'G * EK

! &D3&DG;Doub' po< 0'0 * 2K

! &D&DHR7$ ;nai#e< 'E * G$H0K

! *>T E'L 3K

! *> cell ;&DHE&D3$< 3G' 203 H$20K JH$H00

! Total B$&ell ;&D1L< 0'0 0 H$1HK J0$H0

I i i



Immune recontitution

! K o" B$cell K o" B$cell

! IgD &D2J$ *ai#e B$cell 0'0 HG$G0K! IgD &D2J *on$Fitched memory B 0'0 J$21K

! Ig &D2J SFitched, memory B 0'0 L$1LK

! cti#ation Indicator +atient Reult

! Re"erence Range &D)&DG ratio 0'G 1'0$3'3

! Kymph Kymph

! &D3&D&DGbeta 0'0 1'HK

! &D3($DR G'J 10K

! &D&D2H 2'2 JK

! &DGbeta&DEL 1'L ( 1K

K o" &D T cell! &D&D2H bright;T reg< 12'0 ( 10K



(arneing the immune ytem

! ntibody therapy % I#Ig

% BIT

! &ellular therapie

% > *>$T! I2@ cyto9ine e5 #i#o e5panded cell population

% TI

% Treg

% Dendritic cell #accine$+ro#enge % &R$T cell

G ti f TIL (t



Generation of TIL (tumorinltrating lympocytes!





*o#el antibody therapy



Hematologic RFS – MRD persistence or relapse of ALL (A) 20 evaluable patients (!) subset " allo HS#$ (#) subset %% c&emo onl'

$ cell engaging bispecific single c&ain (!i$) ab

$opp M S et al* !loo+ 20%2%20,-%.-/-%.

©2012 by American Society of Hematology



&himeric antigen receptor$ T

;&R$T< cell



C"#-T cell applications



C"#-T$ mecanism of %illing

Clinical Response in the Patient



Clinical Response in the Patient.

Porter DL et al. N Engl J Med 2011;36!"2#"33.

1pansion an+ ersistence of #&imeric Antigen Receptor $ #ells 3n 4ivo



1pansion an+ ersistence of #&imeric Antigen Receptor $ #ells 3n 4ivo*

orter DL et al* 5 ngl 6 Me+ 20%%78-,2-/77*



Than9 you "or litening

Introduction to Immunology

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