Introduction to Immunology
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7/21/2019 Introduction to Immunology
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Immunology 101
Richard T Maziarz, MD
September 13, 2013
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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
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Self vs non-self admission isevolutionarily conserved
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&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
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M(& molecule
! M(& cla I
% ($,B,&
! , ., , ( % bi4uitou e5preion
! M(& cla II
% ($DR,D+,D6
! D7,D8
% imited e5preion
! ntigenic Di#erity
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&rytal tructure
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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:
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Immune Sytem
! dapti#e immune ytem # innate immune
ytem
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+athogen aociated molecular
pattern ;+M+<! Bacterial component
! =iral component
! ndogenou ource
% ric acid
% D*
% R*
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Toll li9e receptor acti#ation
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&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
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""ector cell
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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
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&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
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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
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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<$$/ &D2&D3&D or &D2&D3&DG
! T&R rearrangement accompanie poiti#e and
negati#e election
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&D and &DG &o$Receptor
! dheion molecule )
% &D)M(& II
% &DG) M(& I
! Recognition o" M(& $ coner#ed e4uence
! &o$timulatory "unction to augment T&R
ignalling ;aociated Fith lc9<! De"ine ubpopulation o" e""ector T cell
% (elper and cytoto5ic T cell
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T &ell in the thymu
! +oiti#e Selection
% oF a""inity T&R "or el" can mature and
migrate to periphery
! *egati#e Selection
% (igh a""inity T&R "or el" are deleted "olloFing
T&R ligation! ctual Mechanim remain unclear
% Signal intenity # De#elopmental tage
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ge Related &hange in Thymu
(ayne, nn Re# Imm, 2000
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ge Related &hange in Thymu
! ge KT pace Thymu out
! 0$1 L3 /10L
! 2$10 GG G'G 5 10G
! 11$2H E3 E'3 5 10G
! 2E$L H 'H 5 10G
! /H0 1G 1'G 5 10G
(ayne, nn Re# Imm, 2000
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&otimulation! T&R and &D2G imultaneou acti#ation lead to T cell proli"eration
and target cell death! T&R and &D1H2 ;&T< binding can limit a T cell proli"erati#e
repone
! The lac9 o" cell ur"ace &DG0 and &DGE can lead to T cell
programmed cell death or to induction o" peripheral tolerance ;e'g'
anergy<' % bence o" &DG0 on tumor can induce tolerance
% (eterotypic antibodie binding &D3 and &D2G can o#ercome
peripheral tolerance
% 7>T3 treatment in renal tranplant can render T cell re"ractory to
timulation
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! Immunologic Memory)
% ntigen e5poure$$/ 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
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&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
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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$&DE2lo
ubpopulation;:<
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*aN#e T cell) Molecular
Determination! &hromoome 1 i home o" alpha and delta
T&R
! Rearrangement o" T&R alpha locu duringthymic maturation plice out T&R delta locu
! T cell receptor e5ciion circle ;TR&<)
maintained epiomally and do not replicate! ntigen dri#en T cell e5panion doe not
e5pand TR&
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! TFo clae o" T&R
! T&R are polypeptide Fith tFo "unction$ 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<
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eneration o" TR&
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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 $Mar9ert, *PM, 1LLL
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Reco#ery o" &D and &DG T &ell
a"ter utoT5 "or MM
Doue9, ancet 2000
&DQ opa4ue
&DGQ open
&D3Qcircle
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T &ell Receptor nalyi
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*ormal =$O .amily 5preion
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&DR3 Size$+attern nalyi
*ormal (I=
In #itro
g timT cell line
Man"ra, P Imm Met, 1LLJ
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&DR3 Size$+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
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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
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Second Signal
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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'
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(elper T cell ubet
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CD4 T cell subsets
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*atural 9iller cell
! >iller inhibitory receptor ;>IR<
! Di#erity
! ( recognition
! May impact leu9emia outcome
! &linical rele#ance$ recognition o" herpe
#iru "amily member
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Impact o" tranplantation
conditioning on hot immunity! Myeloablati#e
! Immune upprei#e
! 6uantitati#e and 4ualitati#e de"icit
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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
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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
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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
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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
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(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$T cell
G ti f TIL (t
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Generation of TIL (tumorinltrating lympocytes!
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*o#el antibody therapy
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Hematologic RFS – MRD persistence or relapse of ALL (A) 20 evaluable patients (!) subset " allo HS#$ (#) subset %% c&emo onl'
$ cell engaging bispecific single c&ain (!i$) ab
$opp M S et al* !loo+ 20%2%20,-%.-/-%.
©2012 by American Society of Hematology
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&himeric antigen receptor$ T
;&R$T< cell
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C"#-T cell applications
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C"#-T$ mecanism of %illing
Clinical Response in the Patient
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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
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1pansion an+ ersistence of #&imeric Antigen Receptor $ #ells 3n 4ivo*
orter DL et al* 5 ngl 6 Me+ 20%%78-,2-/77*
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Than9 you "or litening
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