Summary cellular therapies
Module 1: Blood transfusion, alloimmunity and transplantation
Introduction innate immunity
There are three basic defense mechanisms of the human body:
1. Physical barrier → mechanical and chemical
2. Innate immunity
3. Adaptive immunity
Characteristics of innate and adaptive:
Innate: Rapid response (hours), fixed, limited number of specificities, constant during response and
no immune memory.
Adaptive: Slow response (days to weeks), variable, numerous highly selective specificities, improve
during response, immune memory.
Innate immunity:
Phase 1 (immediate innate immune response) 0-4 hours: aim at local elimination of pathogens
without collateral damage.
→ The pathogen invades the tissue and proliferates. It is recognized by preformed soluble
effector molecules and resident effector cells in the infected tissue. It is eliminated and very
minor tissue damage is repaired.
Phase 2 (induced innate immune response) 4 hours to 4 days: local reinforcement by new recruits.
→ When the pathogen is not eliminated right away, this phase is induced. There is activation
of cells resident in the infected tissue and recruitment of effector cells to the infected tissue.
Inflammation, fever and the acute-phase response occurs. Soluble effector molecules and
effector cells recruited to the infected tissue recognize and attack the pathon. It’s eliminated
and minor tissue damage is soon repaired.
When the pathogen is still not eliminated the adaptive immunity is induced.
Cells of the innate immunity: dendritic cells, mast cells, macrophages, NK-cells, complement protein
and granulocytes (neutrophils, basophils and eosinophils).
NK-cells, macrophages and neutrophils are dedicated killer cells. Mast cells, basophils and
eosinophils are involved in responses against parasites and allergic substances.
Key steps in innate responses:
1. Recruitment to infection site
Epithelial cells become ‘activated’ upon contact with a microorganism and they produce
chemokines and cytokines. Phagocytic neutrophils respond to these chemokines and
migrate from the blood into the tissue. Extravasation? → weak selectin-mediated adhesion
allows neutrophils to roll along the endothelium (rolling adhesion). A tight binding occurs,
which allows diapedesis and migration.
, 2. Recognition of the pathogen
Pattern recognition receptors (PRR) are activated by pathogen-associated molecular patterns
(PAMPS). They can lead to direct pathogen recognition and uptake by phagocytosis. An
alternative way of pathogen recognition is by opsonization of pathogens by antibodies (Fc-
mediated killing). Activated complement proteins can ‘tag’ and destroy pathogens as well.
C3a and C5a induce inflammation. This leads to local reinforcement of the response.
3. Phagocytosis and killing of pathogen
The intracellular killing of pathogens: Acidification of the phagolysosome, formation of
reactive oxygen metabolites and antimicrobial proteins. NK-cells kill virus-infected cells in
which expression of MIC ligands for NKG2D has been induced.
Activated tissue-resident innate cells create the right environment to locally fight invading
pathogens, but also to start wound healing.
Introduction adaptive immunity
Only animals possess the adaptive immunity. One cell = one specificity. The cells that belong to the
adaptive immunity are the B-cells and T-cells.
Where are these cells?
~ 150 × 109 in the lymph nodes
~ 31 × 109 in the spleen
~ 95 × 109 in extra-lymphoid organs
~ 25 × 109 in the bone marrow
~ 7 × 109 in the blood
Antigen = any structural substance that serves as a target for the receptors of an adaptive immune
response.
Immune response
, Lymphocyte Maturation Recognition of antigen Antigen receptor
Humoral immune B cell Bone marrow Intact antigen Surface
response immunoglobulin
Cellular immune T cell Thymus Fragment of antigens on T cell receptor
response other cells (TCR)
Both antibodies and T cell receptors consist of a constant region and a variable region containing the
antigen-binding site. There is a preformed pool of lymphocytes with unique antigen specificity due
to VDJ recombination. → 300.000.000.000 different specificities possible!
Antibodies/BCRs recognize protein antigens, while TCRs need MHC to present fragments of antigens.
When an antigen is recognised, there is clonal expansion of antigen specific cells.
Dendritic cells are the bridge between the innate and adaptive immune responses. They take up
antigens and then move to enter a draining lymphatic vessel. DCs bearing antigens enter the
draining lymph nodes, where they settle in the T cell area. There are 2 signals required for T cell
activation:
1. Antigen presentation (TCR + MHC)
2. Costimulation (CD28 + B7)
When there is only a specific signal, this induces T cell anergy. When there is only a co-stimulatory
signal, there is no response of the T cell.
MHC class 1 vs MHC class 2
Expression Role
MHC class 1 All nucleated cells - Role in presentation of intracellular
antigens on “self” cells
- Recognition by CD8+ cytotoxic T cells
MHC class 2 Antigen-presenting cells - Presentation of extracellular antigens
- Recognition by CD4+ T helper cells
There are a lot of different specialized T helper cell subsets against different pathogen classes. They
secrete different effector molecules onto the surface of the target cells.
- TH1 cell → IFN-γ, intracellular bacteria
- TH22 cell → Il-4, Il-5, Il-13, Helminths
- TH17 cell → IL-17, extracellular bacteria, funghi
- TREG cell → IL-10, regulatory function
- TFH cell → IL-21, IL-4, B cell help
Regulatory T cells can prevent auto-immune responses by suppression of autoreactive T cells. It
requires them to interact with the same APC. This mechanism can also be used to prevent/reduce
, excessive inflammation, resolve after infection/prevent tissue damage and prevent allergic immune
responses.
B cell interaction with T helper cells results in the production of antibodies. There are 3 signals
required for B cell activation:
1. TCR-MHC-2 peptide
2. CD40L-CD40
3. IL-2,3 and 4 → ILR
There are multiple processes involved in B cell proliferation and differentiation (not all B cells
undergo these processes). First of all, clonal expansion takes place. This results in the formation of 3
types of cells: plasma cells, IgG-expressing B cells and high-affinity IgG-expressing B cells. The plasma
cells are responsible for the antibody secretion. The high-affinity IgG-expressing B cells take care of
affinity maturation or can become memory B cells. The IgG-expressing B cells can undergo isotype
switching.
Affinity maturation is the outcome of somatic hypermutation.
Isotype switching occurs through recombination within the C genes encoding the constant part of
the heavy chain and depends on T cell cytokines. Each human immunoglobulin isotype has
specialized functions.
Effector functions of antibodies: immunomodulation, opsonization, activation of complement,
generation of oxidants, reduced damage to host from inflammatory response, direct antimicrobial
activity, virus and toxin neutralization and antibody-dependent cell cytotoxicity.
Immunological memory is the basis for protection following earlier infection or vaccination. The first
response is slower, at a lower level and with a lower affinity of IgM and IgG. Memory cells live longer
than the short-lived effector cells. A second infection leads to a higher frequency of antigen-specific t
cells and a higher affinity of antibodies.
Module 1: Blood transfusion, alloimmunity and transplantation
Introduction innate immunity
There are three basic defense mechanisms of the human body:
1. Physical barrier → mechanical and chemical
2. Innate immunity
3. Adaptive immunity
Characteristics of innate and adaptive:
Innate: Rapid response (hours), fixed, limited number of specificities, constant during response and
no immune memory.
Adaptive: Slow response (days to weeks), variable, numerous highly selective specificities, improve
during response, immune memory.
Innate immunity:
Phase 1 (immediate innate immune response) 0-4 hours: aim at local elimination of pathogens
without collateral damage.
→ The pathogen invades the tissue and proliferates. It is recognized by preformed soluble
effector molecules and resident effector cells in the infected tissue. It is eliminated and very
minor tissue damage is repaired.
Phase 2 (induced innate immune response) 4 hours to 4 days: local reinforcement by new recruits.
→ When the pathogen is not eliminated right away, this phase is induced. There is activation
of cells resident in the infected tissue and recruitment of effector cells to the infected tissue.
Inflammation, fever and the acute-phase response occurs. Soluble effector molecules and
effector cells recruited to the infected tissue recognize and attack the pathon. It’s eliminated
and minor tissue damage is soon repaired.
When the pathogen is still not eliminated the adaptive immunity is induced.
Cells of the innate immunity: dendritic cells, mast cells, macrophages, NK-cells, complement protein
and granulocytes (neutrophils, basophils and eosinophils).
NK-cells, macrophages and neutrophils are dedicated killer cells. Mast cells, basophils and
eosinophils are involved in responses against parasites and allergic substances.
Key steps in innate responses:
1. Recruitment to infection site
Epithelial cells become ‘activated’ upon contact with a microorganism and they produce
chemokines and cytokines. Phagocytic neutrophils respond to these chemokines and
migrate from the blood into the tissue. Extravasation? → weak selectin-mediated adhesion
allows neutrophils to roll along the endothelium (rolling adhesion). A tight binding occurs,
which allows diapedesis and migration.
, 2. Recognition of the pathogen
Pattern recognition receptors (PRR) are activated by pathogen-associated molecular patterns
(PAMPS). They can lead to direct pathogen recognition and uptake by phagocytosis. An
alternative way of pathogen recognition is by opsonization of pathogens by antibodies (Fc-
mediated killing). Activated complement proteins can ‘tag’ and destroy pathogens as well.
C3a and C5a induce inflammation. This leads to local reinforcement of the response.
3. Phagocytosis and killing of pathogen
The intracellular killing of pathogens: Acidification of the phagolysosome, formation of
reactive oxygen metabolites and antimicrobial proteins. NK-cells kill virus-infected cells in
which expression of MIC ligands for NKG2D has been induced.
Activated tissue-resident innate cells create the right environment to locally fight invading
pathogens, but also to start wound healing.
Introduction adaptive immunity
Only animals possess the adaptive immunity. One cell = one specificity. The cells that belong to the
adaptive immunity are the B-cells and T-cells.
Where are these cells?
~ 150 × 109 in the lymph nodes
~ 31 × 109 in the spleen
~ 95 × 109 in extra-lymphoid organs
~ 25 × 109 in the bone marrow
~ 7 × 109 in the blood
Antigen = any structural substance that serves as a target for the receptors of an adaptive immune
response.
Immune response
, Lymphocyte Maturation Recognition of antigen Antigen receptor
Humoral immune B cell Bone marrow Intact antigen Surface
response immunoglobulin
Cellular immune T cell Thymus Fragment of antigens on T cell receptor
response other cells (TCR)
Both antibodies and T cell receptors consist of a constant region and a variable region containing the
antigen-binding site. There is a preformed pool of lymphocytes with unique antigen specificity due
to VDJ recombination. → 300.000.000.000 different specificities possible!
Antibodies/BCRs recognize protein antigens, while TCRs need MHC to present fragments of antigens.
When an antigen is recognised, there is clonal expansion of antigen specific cells.
Dendritic cells are the bridge between the innate and adaptive immune responses. They take up
antigens and then move to enter a draining lymphatic vessel. DCs bearing antigens enter the
draining lymph nodes, where they settle in the T cell area. There are 2 signals required for T cell
activation:
1. Antigen presentation (TCR + MHC)
2. Costimulation (CD28 + B7)
When there is only a specific signal, this induces T cell anergy. When there is only a co-stimulatory
signal, there is no response of the T cell.
MHC class 1 vs MHC class 2
Expression Role
MHC class 1 All nucleated cells - Role in presentation of intracellular
antigens on “self” cells
- Recognition by CD8+ cytotoxic T cells
MHC class 2 Antigen-presenting cells - Presentation of extracellular antigens
- Recognition by CD4+ T helper cells
There are a lot of different specialized T helper cell subsets against different pathogen classes. They
secrete different effector molecules onto the surface of the target cells.
- TH1 cell → IFN-γ, intracellular bacteria
- TH22 cell → Il-4, Il-5, Il-13, Helminths
- TH17 cell → IL-17, extracellular bacteria, funghi
- TREG cell → IL-10, regulatory function
- TFH cell → IL-21, IL-4, B cell help
Regulatory T cells can prevent auto-immune responses by suppression of autoreactive T cells. It
requires them to interact with the same APC. This mechanism can also be used to prevent/reduce
, excessive inflammation, resolve after infection/prevent tissue damage and prevent allergic immune
responses.
B cell interaction with T helper cells results in the production of antibodies. There are 3 signals
required for B cell activation:
1. TCR-MHC-2 peptide
2. CD40L-CD40
3. IL-2,3 and 4 → ILR
There are multiple processes involved in B cell proliferation and differentiation (not all B cells
undergo these processes). First of all, clonal expansion takes place. This results in the formation of 3
types of cells: plasma cells, IgG-expressing B cells and high-affinity IgG-expressing B cells. The plasma
cells are responsible for the antibody secretion. The high-affinity IgG-expressing B cells take care of
affinity maturation or can become memory B cells. The IgG-expressing B cells can undergo isotype
switching.
Affinity maturation is the outcome of somatic hypermutation.
Isotype switching occurs through recombination within the C genes encoding the constant part of
the heavy chain and depends on T cell cytokines. Each human immunoglobulin isotype has
specialized functions.
Effector functions of antibodies: immunomodulation, opsonization, activation of complement,
generation of oxidants, reduced damage to host from inflammatory response, direct antimicrobial
activity, virus and toxin neutralization and antibody-dependent cell cytotoxicity.
Immunological memory is the basis for protection following earlier infection or vaccination. The first
response is slower, at a lower level and with a lower affinity of IgM and IgG. Memory cells live longer
than the short-lived effector cells. A second infection leads to a higher frequency of antigen-specific t
cells and a higher affinity of antibodies.
