Lecture No. 2 February 5, 2004 Regulation and maintenance of the immune response during disease and

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Lecture No. 2 February 5, 2004Regulation and
maintenance of the immune response during disease
and vaccinationImmunological memoryLaurel J.
Gershwin
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Principles of Vaccination

• Exposure to a pathogen or antigens from a
  pathogen in an inactivated form stimulates an
  acquired immune response.
  
• Immunologic memory is developed by stimulation of
  T and B lymphocytes specific for the pathogens
  antigenic epitopes.
  
• Some of these cells become long living memory
  cells, capable of responding to the viable
  pathogen upon encounter.

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Thucidides observation on immunological memory

(Athens 430 BC)
Only those who have recovered from the Plague
could nurse the sick because they could not catch
the disease a second time... This altered
state is specific.
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Empirical Observation
E. Jenner, 1778.
There is a disease to which the horse,
from his state of domestication, is
frequently subject... it commonly happens
that it is communicated to the cows, and
from the cows to the dairy-maids... this
disease has obtained the name of Cow
Pox.... Morbid matters of various kinds, when
absorbed into the system, may produce
effects in some degree similar, but what
renders the Cow Pox so extremely singular
is that the person who has been affected
is for ever after secure from the disease
of the Small Pox.
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Successful Vaccination Depends On

• Specificity of the immune response
• Immunological Memory

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Specificity of the Immune Response

• Receptor based
• T cell receptor
• B cell receptor

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Determinants of Specificity
Ag
Ag
a
b
b
b
a
a
BCR
TCR
Antigen Specific Receptors
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Immunogenic Epitopes on Virus
External epitope
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Bacterial Pathogens
Streptococcus bacteria
Salmonella bacteria
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Bacterial Antigens
capsule (polysaccharide)
Bacterium
flagellum (protein)
cell membrane (protein)
lipopolysaccharide
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ANTIGEN PRESENTING CELLS

• APCs are cells that can present peptides to T
  lymphocytes to initiate an acquired immune
  response .
  
• These cells include
• macrophage
• B lymphocyte
• dendritic cell
• Langerhans cell

Dendritic Cell
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Late Cytokines
B cell
HSA
CD40L
CD40
ICAM-1/ICAM-2
LFA-1
VCAM-1
VLA-4
CD4/CD8
APC
MHC
Ag
TCR
CD28 CTLA4
B7
Early Cytokines
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Lymphocyte Activation
Stimulus
Resting lymphocyte
Short-lived effectors T cells Short and/or long l
ived Plasma cells
G1
24 hrs.
M
S
G2
Cell division
Long-lived memory cells
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Immunological Memory
Immunological memory is the ability of the immune
system to respond more rapidly and effectively to
pathogens that have been encountered previously
either by previous infection or by vaccination
This reflects the pre-existence of clonally
expanded lymphocytes with specificity for the
antigen.
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B Cell Development
ANTIGEN
Bone Marrow
Lymphoid Tissue
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Plasma Cell and Memory Cell Generation
Antigen
Antigen
Antigen
Memory Cells
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Kinetics of T and B Cells Responses
PHASE
Primary response
Secondary response
Immediate ( 12-24 hr)
Amplification
Induction
Early ( 24 - 96 hr)
Amplification, differentiation
effector
effector
Amplification, differentiation and effector.
Late ( 96 hr)
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Primary Antibody Response
Lag
Log
Plateau
IgM
Antigen
IgG
14
Days
7
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Secondary Immune Response
IgG
IgM
Days
7
14
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Generation of Antibody Response from Memory B
Cells Differs from Primary Response
From Janeway, Immunobiology 5, Garland Publishing
Company
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Affinity Maturation

• After vaccination not only is there an increase
  in the number of antigen reactive B cells, but
  the affinity of the antigen receptor is
  increased. This is referred to as affinity
  maturation.

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Maintenance of Memory

• Persistence of long-lived memory cells in the
  absence of antigen
  
• Versus
• Lymphocytes under perpetual stimulation by
  residual antigen
  

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L. Panum observation on immunological memory
during measles epidemic in the Faroe Islands
(1846)
65 years disease free
1781
1846
Second epidemic
First epidemic
Of the many aged people that still living
on the Faroes who had had measles in 1781,
not one was attacked a second time..all the
old people who had not gone through with
measles in earlier life were attacked when they
were exposed to infection
Property of Manuel Campos
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Maintenance of Memory

• Persistence of long-lived memory cells in the
  absence of antigen
  
• NOT
• Lymphocytes under perpetual stimulation by
  residual antigen
  

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Memory T cells are distinct from effector T cells
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Memory Subsets of CD4T cells

• Effector memory cells
• Secrete large amounts of IFN?, IL-4, IL-5 after
  restimulation.
  
• Lack CCR7, but have ß1 and ß2 integrins, to move
  into inflammatory tissue.
  
• Central memory cells
• Express CCR7 and recirculate into lymphoid tissue
  T cell zones.
  
• Sensitive to TCR crosslinking and readily
  upregulate CD40L after restimulation.
  

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Temporal relationship between primary immune
response and clearance of infection during
acute infections
100
Antibody
50
Intensity of response
CMI effectors
Infection level
5
10
0
Time after infection (days)
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Temporal relationship between secondary immune
response and control of replication during
acute infections
100
Antibody
50
Intensity of response
CMI effectors
Infection level
5
10
0
Time after infection (days)
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Effectiveness of memory
More responder cells More effective recognition
More effective migration
More effective function
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Original Antigenic Sin

• Example
• Host infected with influenza virus in early life
  when re-infected with another variant that has
  both new and old epitopes will preferentially
  make antibodies to the epitopes shared with the
  original virus.
• A subnormal immune response is made to the new
  epitopes.

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Memory T cells and Antibody Regulate Immune
Responses to Subsequent Antigen Exposure.

• Suppression of naïve lymphocyte activation is
  demonstrated by
  
• Effects of maternal antibody on vaccination.
• Passive transfer experiments with Ab or T cells
  in mice.
  
• Use of Rhogam to prevent anti-Rh response in an
  Rh negative mother.
  
• Inhibits naïve B cells, but not memory B cells

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Disease Pathogenesis in the Immune versus the
Naive Host
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Pathogen vs. Immune System
Clinical disease is a race between the pathogens
ability to replicate and/or cause disease(
) and the speed with which the body can mount a
protective immune response ( ).
Highly Virulent
Mildly Virulent
Max

N a i v e

Replication/Pathogenicity Rate
Immune Response
Replication/ Pathogenicity Rate
Immune Response
Min

• Examples of virulence determinants
• Challenge dose
• Virulence (i.e. tropisms, replication rate)

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Pathogen vs. Immune System
Immunologic memory ( ) from prior
vaccination results in a faster, stronger and
more relevant immune response to infection.
Mildly Virulent
Highly Virulent
V a c c i n a t e
Max
Immune Response
Immune Response
Replication/Pathogenicity Rate
Replication/ Pathogenicity Rate
Min
Time
Time
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How often should we vaccinate?
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Longevity of Immunity and Protection
Protective levels
Intensity of immunity
Non- protective levels
Time (months or years)
Response after Vaccination
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Antibody half life in serum
100
IgG
Serum concentration ()
IgE
IgA
IgM
50
0
20
10
Time (days)
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Duration of Immunity Vs Duration of Protection
Protective memory effectors level
Protective active effectors level
Relative levels
non protective levels
Time
Vaccination or primary infection
Re-infection
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T Cell Education During Primary Responses
Do polarized effectors give rise to polarized
memory? If so, it is important that a vaccine in
duces the appropriate polarization
to elicit a protective not pathological response
to infection.
Secondary Effectors
Primary Effector
Memory
IFNg IL-12
Th1
Th1
?
Naive
Th0
Th0
?
IL-4 IL-13?
Th2
Th2
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Vaccination may set the tone for future immune
responses

• Vaccination with formalin-inactivated RSV
  (FI-RSV) prior to infection resulted both in
  human and in the mouse model in extensive lung
  pathology. In the mouse model, it has been shown
  that this aggravation of disease was associated
  with a shift in the balance between Th1 and Th2
  cytokines towards a Th2-type response. Boelen et
  al. Vaccine. 2000 Nov 2219(7-8)982-91.

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Expectations from Vaccines
Safe Stable Inexpensive High response rate Pre
vention of disease Prevention of infection Long
lasting protection
Prevention of transmission