overview of the immune response and it’s …overview of the immune response and it’s relevance...
TRANSCRIPT
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Overview of the Immune Response and it’s Relevance to Vaccine
Efficacy
James A. Roth, DVM, PhDInstitute for International Cooperation in
Animal BiologicsIowa State University
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What is the basis for protective immunity for the disease in question
• Circulating antibody?– IgM, IgG?
• Mucosal antibody?– IgA, IgE?
• Cell-mediated immunity?- Cytokine secretion (TH1 vs TH2)?- Cytotoxic T cells?- Gamma Delta T cells?
• What are the important antigens?
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Pathogenic Mechanisms
• Adherence to Mucosa• Invasive parasite• Exotoxin/Endotoxin• Viremia• Septicemia• Intracytoplasmic Growth• Growth in phagosome• Infect epithelial cells
Defense Mechanisms
• Mucosal Antibody (IgA)• IgE• Neutralizing Antibody• Neutralizing Antibody• Opsonizing Antibody• Cytotoxic T cells• TH1 Cytokines• Gamma Delta T cells
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RoittRoitt, I., , I., BrostoffBrostoff, J., Male, D. 1998. , J., Male, D. 1998. ImmunologyImmunology. 5th Ed. . 5th Ed. MosbyMosby. Philadelphia. pg17. Philadelphia. pg17
Functional T-cell subsets
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Lymphocyte Type Antigen Recognition
B cells Intact, unprocessed molecules
TH1 and TH2 cells Exogenous peptides processed and presented on MHC II
Tc cells Endogenous peptides processed and presented on MHC I
Gamma Delta T cells Intact, unprocessed molecules
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Lymphocyte Type Response to Antigen
B cells Produce AntibodiesTH1 cells Secrete cytokines which
enhance phagocyte killingTH2 cells Secrete cytokines which
help antibody production (IgA and IgE)
Tc cells Cytotoxic for cells synthesizing foreign proteins
Gamma Delta T cells Secrete cytokines and/or cytotoxic for cells with abnormal surface antigens
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Parham, P., The Immune System. 2000, Garland
Publishing, Fig. 6.32
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Selection of effector mechanisms by TH1 and TH2 cells
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T Helper Cell T Cytotoxic Cell
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Exogenous Pathway of Antigen
PresentationAbbas, et al. Cellular and
Molecular Immunology, 1997
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Abbas, et al. Cellular and Molecular Immunology, 1997
Endogenous Pathway of Antigen
Presentation
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Parham, P., The Immune System. 2000, Garland Publishing, Fig 12.5
ISCOMs Carry Peptides into the Cytoplasm
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Roitt, I. et al. Immunology,
1996
Allele-specific motifs in peptides eluted from MHC class II molecules
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Roitt, I. et al. Immunology,
1996
Binding peptides from class I molecules
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Abbas, A.K., Lichtman, A.H., Pober, J.S. 1994. Cellular and Molecular Immunology. 2nd Ed. W.B. Saunders Co., Philadelphia.
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Bacterial Antigens
ExotoxinEndotoxin
Tizard, Ian R. Veterinary Immunology: An Introduction, 6th ed. ,2000
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Viral Antigens
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Roitt, I., Brostoff, J., Male, D. Immunology. 1985
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Roitt, I. et al, Immunology,
1996
Critical molecules involved in antigen presentation
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Detection of Antigen Specific T cell subset Activation
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(CD25)
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Flow Cytometer
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Flow Cytometer
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(% T cells stimulated)(MFI)
(% T cells unstimulated)(MFI)Expression Index =
UnstimulatedUnstimulated
T Cell
CD4
StimulatedStimulated
T Cell
CD4CD25
CD25
CD25
CD
25
CD25
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Methods
Modified live Modified live and inactivated and inactivated vaccinesvaccines
ImmunizeImmunize
Isolate PBMC from Isolate PBMC from immune & naïve calvesimmune & naïve calves
Stimulate with Ag: Stimulate with Ag: live, inactivated, live, inactivated,
recombinantrecombinant
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Two-color flow cytometry
Monoclonal Ab Monoclonal Ab stainingstaining
IL2R IL2R (CD25)(CD25)
CD4CD4 CD8CD8 γδγδ TCRTCR
1) Anti 1) Anti -- IL2RIL2R
2) Anti 2) Anti -- CD4, CD4, CD8 or CD8 or γδγδ TCRTCR
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Flow cytometry output
CD 4 CD 4
CD
25
CD
25
CD 4 CD 4 Negative ResponseNegative Response Positive ResponsePositive Response
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Induction of T Lymphocytes Specific for BVD Virus in Calves With
Maternal Antibody
Janice Endsley1, Julia Ridpath2, John Neill2, James Roth1
1Iowa State University2USDA ARS National Animal Disease Center
Endsley et. al., Viral Immunol, 17:13-23, 2004
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Objective
To determine if infection with virulent BVDV in the presence of maternal antibody will induce antigen specific T cells and protective immunity without inducing antibody
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Experimental Design
• Pooled colostrum from BVDV hyper-immunized cows fed to 12 calves.
• Six calves inoculated with BVDV 1373 at 6 to 20 days of age.
• All calves challenged with BVDV 1373 at 8 months of age.
• Monitor antibody and T cell subset responses
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0
0.5
1
1.5
2
2.5
3
3.5
4
1 2 3 4 5 6 7 8 9 10
Colostrum Colostrum, BVDV
Serum Neutralizing Antibody to Type 2 BVDV
Months after first BVDV challenge
SN T
iter (
log
10)
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Activation of CD4+ T cells by BVDV2 890
0
5
10
15
20
25
30
0-10 wks 11-20 wks 21-32 wks
Colostrum Colostrum, BVDV
Weeks after first BVDV challenge
Exp
ress
ion
Inde
x P = 0.07
P <0.05
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Activation of CD8+ T cells by BVDV2 890
0
5
10
15
20
25
30
0-10 wks 11-20 wks 21-32 wks
Colostrum Colostrum, BVDV
Weeks after first BVDV challenge
Exp
ress
ion
Inde
x
P < 0.01
P = 0.10
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Activation of γδ T cells by BVDV2 890
0
5
10
15
20
25
30
0-10 wks 11-20 wks 21-32 wks
Colostrum Colostrum, BVDV
Exp
ress
ion
Inde
x
Weeks after first BVDV challenge
P < 0.05 P < 0.01P < 0.05
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0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
1 4 0
C o lo s t ru m , n o B V D V C o lo s t ru m , B V D V W e e k s a f te r f i r s t B V D V c h a l le n g e
P < 0 .0 1
P < 0 .0 1
P < 0 .0 1
Interferon Gamma in Supernatants From Mononuclear Cells Stimulated with BVDV 890
IFNγ
ng/m
l
0-10 wks 11-20 wks 21-32 wks
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Rectal Temperature After BVDV 1373 Challenge at 8 Months of Age
99.0100.0101.0102.0103.0104.0105.0106.0
0 2 4 6 8 10 12 14Days After Infection
Deg
rees
Fah
renh
eit
PreviouslyChallenged
Not PreviouslyChallenged
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Total Leukocyte Counts After BVDV 1373 Challenge at 8 Months of Age
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
0 2 4 6 9 11 13Days After Infection
Plat
elet
s
PrevioslyChallenged
Not PreviouslyChallenged
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DAYS POST CHALLENGE
Previously Challenged
Not Previously Challenged
2 4 6 8 10 12
0/5 0/5 0/5 0/5 0/5 0/5
3/6 4/6 6/6 6/6 2/6 2/6
Isolation of BVD Virus from Buffy Coat After Second Challenge
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ConclusionsWhen challenged with virulent BVDV, calves with high maternal antibody titers to BVDV:
•Did not produce an antibody response to BVDV
•Did develop memory CD4+, CD8+, and γδ T cells
•Did produce an anamnestic antibody response upon subsequent challenge
•Are protected from BVDV challenge in the absence of detectable serum neutralizing antibody
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T Cell-Populations Responsive to Bovine Respiratory Syncytial Virus in
Seronegative Calves
Matt Sandbulte and James RothVet Immunol Immunopathol, 84:111-123, 2002
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Two-Fold Testing for BRSV Immunity in Beef Calves
Calves tested for virus-specific neutralizing antibody and T cells
16 identified as seronegative
Among these, T cell responses were detected in several.
#94
#95
#96
#97
#99
#100
#101
#132
#134
#135
#136
#138
#139
#141
0
5
10
15
20
25
30
35
CD
25 E
xpre
ssio
n In
dex
T Cell Responses to BRSV in Seronegative Calves
CD4CD8GD
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Why T Cells Without Antibody?
Hypothesis:Those calves were previously infected with BRSV in the presence of maternal antibody. The humoral response was blocked, but T cells were primed.
Test:Vaccinate naïve calves and T cell-positive calves with BRSV. Does the latter group have immunologic memory, i.e. develop superior antibody and T cell responses?
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CD4+ T Cell Responses
02468
101214161820
Week -4 Week -2 Week 0 Week 2 Week 4 Week 6
CD
25 E
xpre
ssio
n In
dex Group 1
Group 2Group 3 †‡
†‡
‡
†‡ †‡
*
*
†‡
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CD8+ T Cell Responses
05
101520253035404550
Week -4 Week -2 Week 0 Week 2 Week 4 Week 6
CD
25 E
xpre
ssio
n In
dex
Group 1Group 2Group 3
†‡
‡
† *
†‡
*
†‡ ‡
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Gamma delta T Cell Responses
0
20
40
60
80
100
120
Week -4 Week -2 Week 0 Week 2 Week 4 Week 6
CD
25 E
xpre
ssio
n In
dex Group 1
Group 2Group 3
†‡ †‡
†‡*
†‡
†‡
*
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Neutralizing Antibody Responses
* Group 2 > Group 1 † Group 3 > Group 1 ‡ Group 3 > Group 2
0
1
2
3
4
5
6
7
Week -8 Week -4 Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6
Log(
2) S
VN T
iter Naïve / No treatment
Naïve / Vaccine
CMI(+) / Vaccine† ‡
† ‡
† ‡ † ‡
**
†
†
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Limitations to Technology for DetectingLimitations to Technology for DetectingT Cell Subset ActivationT Cell Subset Activation
•• Day to day and animal to animal variability require Day to day and animal to animal variability require that large numbers of animals be used and that they that large numbers of animals be used and that they be sampled repeatedlybe sampled repeatedly
•• Expensive; labor and equipment intensiveExpensive; labor and equipment intensive
•• Lymphocytes should be set up the same day as Lymphocytes should be set up the same day as collected collected
•• Valid comparisons can only be made on lymphocytes Valid comparisons can only be made on lymphocytes assayed in parallelassayed in parallel