Insulin Proinsulin B cell encounters antigen BCR Antigen is B cell T cell Cytokine secretion Shortlong lived p lasma cell Ab binds antigen Memory B cell IgM IgG Class switch Tcr MHC II CD28 CD8086 ID: 825078
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InsulinProinsulinB cellencountersant
InsulinProinsulinB cellencountersantig
enBCRAntigen isinternalizedB cellT
enBCRAntigen isinternalizedB cellTce
llCytokinesecretionShort/longlivedp
llCytokinesecretionShort/longlivedpl
asma cellAb binds antigenMemoryB cell
asma cellAb binds antigenMemoryB cellI
gMIgGClass switchTcrMHC IICD28CD8
gMIgGClass switchTcrMHC IICD28CD80/
86CD40CD40LLegend:A)B)C)D)Antige
86CD40CD40LLegend:A)B)C)D)Antigen
-bindingsiteAntigen-bindingsiteH
-bindingsiteAntigen-bindingsiteH2
NH2NLight chainLight chainHeavy
NH2NLight chainLight chainHeavy c
hainHeavy chainFabFabNH2NH2COOH
hainHeavy chainFabFabNH2NH2COOHC
OOHHOOCHOOCHingeregionsIgG1IgG2Ig
OOHHOOCHOOCHingeregionsIgG1IgG2IgG3
IgG4Disulfidebondsin hin
IgG4Disulfidebondsin hinge
region24112GAD65Secretorymicrov
region24112GAD65Secretorymicroves
icleZnT8IA2β-cellplasmamembrane
icleZnT8IA2β-cellplasmamembraneIn
sulinInsulinsecretorygranuleDay 0
sulinInsulinsecretorygranuleDay 0
1 3 9
1 3 9
15 21
15 21
30 48month
30 48monthm
onthsmonthsmonthsmonthsmonthsmonths
onthsmonthsmonthsmonthsmonthsmonthsP
haseIIDay 0 1 3
haseIIDay 0 1 3
9 15
9 15
21 30 month
21 30 monthmo
nthsmonthsmonthsmonthsmonthsPhaseI
nthsmonthsmonthsmonthsmonthsPhaseIII
010002000300040000139152130
010002000300040000139152130Mo
nthGADA titers (U/ml)n.sn.sp=0.001
nthGADA titers (U/ml)n.sn.sp=0.001p
=0.01p=0.04p=0.01p=0.03Responders
=0.01p=0.04p=0.01p=0.03RespondersI
ntermediatesNon-responders01000200
ntermediatesNon-responders010002000
300040005000115000125000135000GADA
300040005000115000125000135000GADA t
iters (U/ml)p0.05n.sp=0.0701000200
iters (U/ml)p0.05n.sp=0.07010002000
30004000013915213048n.sn.sp
30004000013915213048n.sn.sp0.
001p=0.009p=0.030p=0.013p=0.030
001p=0.009p=0.030p=0.013p=0.030p
=0.034MonthGADA titers (U/ml)4D vs 2D
=0.034MonthGADA titers (U/ml)4D vs 2Dn
.sn.sn.sn.sp=0.024n.s4D vs Placeb
.sn.sn.sn.sp=0.024n.s4D vs Placebo
n.sp=0.024p.001p.001p.001p.0012D
n.sp=0.024p.001p.001p.001p.0012D vs
Placebon.sp=0.007p.001p.001p.001p
Placebon.sp=0.007p.001p.001p.001p.0
014D vs 2Dn.sn.sn.sp=0.007p=0.012
014D vs 2Dn.sn.sn.sp=0.007p=0.0124D
vs Placebop.001p.001p.001p.001p.0
vs Placebop.001p.001p.001p.001p.001
2D vs Placebop.001p.001p.001p.001
2D vs Placebop.001p.001p.001p.001p.
001Baseline1 m3 m9 m15 m21 m1010
001Baseline1 m3 m9 m15 m21 m10100
100010000GADA median titers (U/ml)1 m
100010000GADA median titers (U/ml)1 m3
m9 m15 m21 m0246810124 D2 D
m9 m15 m21 m0246810124 D2 DP
laceboGADA median fold-changeABp=
laceboGADA median fold-changeABp=0.
0461 m3 m9 m15 m21 m02468102
0461 m3 m9 m15 m21 m02468102D
phaseIII2D phaseIIGADA median fold
phaseIII2D phaseIIGADA median fold-
change% of total IgGGADABaseline3
change% of total IgGGADABaseline3m
15mIgG180859095100p= 0.005n.s
15mIgG180859095100p= 0.005n.sn.
sIgG201234n.sn.sn.s0246Ig
sIgG201234n.sn.sn.s0246IgG
3p= 0.01n.sn.s0IgG41234p= 0.0
3p= 0.01n.sn.s0IgG41234p= 0.048
n.sn.sBaseline3m15mBaseline3m
n.sn.sBaseline3m15mBaseline3m15
mBaseline3m15mTime-point024
mBaseline3m15mTime-point0246
81080859095100Baseline1m3m9
81080859095100Baseline1m3m9m
15m21mIgG1IgG2IgG 3IgG 4% of t
15m21mIgG1IgG2IgG 3IgG 4% of tot
al IgGGADAIgG4, p0.001IgG3, p=0.001
al IgGGADAIgG4, p0.001IgG3, p=0.001Ig
G1, p=0.003Baseline3 months9 months
G1, p=0.003Baseline3 months9 months1
10100100010000IA-2A titer (U/ml)p
10100100010000IA-2A titer (U/ml)p0.
05p0.05p0.05ABBaseline3 m15 m02
05p0.05p0.05ABBaseline3 m15 m0200
400600800IA-2A titers (U/ml)p=0.0
400600800IA-2A titers (U/ml)p=0.01
p=0.001p=0.001GAD-alumPlaceboBasel
p=0.001p=0.001GAD-alumPlaceboBaselin
e14 %0%43 %0%ZnT8W(Trp)6 %Zn
e14 %0%43 %0%ZnT8W(Trp)6 %ZnT8
R(Arg)11 %ZnT8Q (Gln)0%Neg: 2
R(Arg)11 %ZnT8Q (Gln)0%Neg: 26
%3%0%59 %0%ZnT8W(Trp)6 %Zn
%3%0%59 %0%ZnT8W(Trp)6 %ZnT8
R(Arg)15 %ZnT8Q (Gln)0%Neg:
R(Arg)15 %ZnT8Q (Gln)0%Neg: 18
%15 months9%0%40 %0%ZnT8W(
%15 months9%0%40 %0%ZnT8W(Tr
p)6 %ZnT8R(Arg)14 %ZnT8Q (Gln
p)6 %ZnT8R(Arg)14 %ZnT8Q (Gln)
0%Neg: 31 %6 %0%53 %0%ZnT8W
0%Neg: 31 %6 %0%53 %0%ZnT8W(
Trp)3 %ZnT8R(Arg)18 %ZnT8Q (G
Trp)3 %ZnT8R(Arg)18 %ZnT8Q (Gln
)0%Neg: 21 %110100100010000Z
)0%Neg: 21 %110100100010000ZnT
8A (U/ml)ZnT8(Arg)AZnT8(Gln)AZnT8
8A (U/ml)ZnT8(Arg)AZnT8(Gln)AZnT8(
Trp)AnsnsnsABBaseline3 months9
Trp)AnsnsnsABBaseline3 months9
months0.00.51.01.52.0Tetanus ab (I
months0.00.51.01.52.0Tetanus ab (IU/
ml)Baseline21 months110100100010
ml)Baseline21 months11010010001000
0IgE (kU/l)ABn.sn.sBaseline3 m
0IgE (kU/l)ABn.sn.sBaseline3 mon
ths15 monthsSPS02000400060008000
ths15 monthsSPS0200040006000800010
000cpmn.sn.sn.sp=0.001p=0.001p=0.
000cpmn.sn.sn.sp=0.001p=0.001p=0.00
1Baseline3 months15 monthsSPS02000
1Baseline3 months15 monthsSPS020004
0006000800010000cpmn.sn.sn.sAB
0006000800010000cpmn.sn.sn.sAB48
months48 monthsSPS 020004000600
months48 monthsSPS 0200040006000
800010000cpmCn.sp=0.001p=0.001p=0
800010000cpmCn.sp=0.001p=0.001p=0.0
01p=0.001p=0.001SPST1DGAD-alumHi
01p=0.001p=0.001SPST1DGAD-alumHigh
risk0102030405060708090100%
risk0102030405060708090100% o
f maximum rh-GAD65enzymeactivityS
f maximum rh-GAD65enzymeactivitySPS
T1DGAD-alumHigh risk010203040
T1DGAD-alumHigh risk01020304050
60708090100% of competedb78p=0.
60708090100% of competedb78p=0.03
2p=0.010p0.001p=0.042p=0.028p=0.001
2p=0.010p0.001p=0.042p=0.028p=0.001A