Download REGULATION OF THE IMMUNE RESPONSE

Regulation of the immune response
Jan Żeromski
2013/2014
POINTS TO BE DISCUSSED
 Regulation by antigen and antigen-presenting
cell
 Regulation by antibody
 The role of T cells (Treg) and NK T cells
 The role of telomeres
 Idiotypes and idiotypic network
 Neuroendocrine mechanisms
 Genetic aspects in immune regulation
 Immune regulation vs immune modulation vaccines
REGULATION BY ANTIGEN
• Chemical nature of Ag-polysaccharides
vs.proteins
• Soluble vs.intracellular Ags
• Large doses vs. small doses of Ag
• Competition between antigens and
peptides
• The route of administration of Ag
• The role of adjuvants
THE SIGNIFICANCE OF
ANTIGEN-PRESENTING CELL
• Professional vs. non-professional APC
• CD40L on T cell- CD40 on APC interaction
• CD28 |CTLA4 | vs. CD80 and CD86
The level of expression of MHC on APC
THE SIGNIFICANCE OF
ANTIGEN-PRESENTING CELL 2
• The extent of cytokines secreted by
APC
• Cross-presentation (cross-priming) of
viral Ags by APC to Tc (CD8+) cells via
MHC-I
• APC killing by cytotoxic T cells
IMMUNE RESPONSE:
STIMULATORY AND INHIBITORY
CYTOKINES
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Interleukin-2 (IL-2)
IL-1
IL-4
IL-5
IL-6
IL-12
IL-18
Interferon gamma
(IFN- )
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IL-4
IL-10
IL-11
IL-13
Transforming growth
factor beta (TGF-)
• IFN-/
• IFN-
REGULATION BY T LYMPHOCYTES
• CTLA-4, instead of CD28, on T cells, binds
B7 (on APC) – inhibition of activation
• Fratricide – mutual killing of T cells by
Fas- FasL system
• T cell suicide – by the same token
• Prevention of induction of autoimmunity by
CD4+ CD25+Treg cells
FEATURES OF Treg CELLS
• Quantity: 5-10 % of CD4+ T cells in the blood
• Surface markers: CD25, CD103, Foxp3
GITR,(glucocorticoid-induced TNF receptor)
• Cytokine expression/secretion:IL-10,
IFN-, TGF-
• Suppression mechanism: contact with activated
target CD8+ / CD4+ T cells, secretion of cytokines (IL-10, TGF-) and non-specific inhibition
(„bystander effect”)
Regulation of cell senescence by telomere
shortening
• Telomeres – repeats of the DNA sequence
(GGGTTA) and protein located at the end of
chromosomes – up to 2000 copies per cell
• Provide stabilization and protect chromosomal
ends from damage; regulate cell replication
• At every cell division they shorten by 50-100 bp
Regulation of cell senescence by telomere
shortening -2
• When telomeres become too short, chromosome
gets unstable and DNA damage can occur. To
prevent damaged cells being replicated such cells:
- die by apoptosis,
- Enter cell arrest, known as cellular senescence.
• T cells in elderly people have significantly shorter
telomeres than young ones,
• People with some premature ageing syndromes
have short telomeres and usually have low life
expectancy
IDIOTYPIC REGULATION OF IMMUNE
RESPONSES (IR)
• Idiotype = the sum of idiotopes,
variable determinants in a given
antibody molecule or TCR
• There are public and private idiotopes: public: those found on other cells
private: unique for given cell or cell
clone
IDIOTYPIC REGULATION OF IMMUNE
RESPONSES (IR)
• Anti-idiotypic antibodies may block
antigen binding and thus regulate
immune response
• These antibodies are present in small
amounts within immunoglobulin pool of
all humans and participate in normal
both, humoral and cellular IR
JERNE’S IDIOTYPIC NETWORK
(NOBEL PRIZE IN 1984)
 Idiotypic determinants are immunogenic
 Anti – idiotypic antibodies are formed
following formation anti - antigen antibody
 Anti-idiotypic Ab induce anti-anti-idiotypic
response
 This leads to gradual fading of immune
response against given antigen
B cells, Tcells and NK cells
express receptors that
contain immuno-receptor
tyrosine based inhibitory
motifs (ITIMs), apart from
ITAMs (activating ones).
NEUROENDOCRINE MODULATION OF
IMMUNE RESPONSES
• Most lymphoid tissues possess
sympathetic innervation
• Lymphocytes express receptors for a
variety of hormones, neurotransmitters
and neuropeptides
NEUROENDOCRINE MODULATION OF
IMMUNE RESPONSES -2
• Examples include steroids,
catecholamines, enkephalins,
endorphins and others
• When released in vivo during stress,
most of them are immunosuppressive
NEUROENDOCRINE MODULATION OF
IMMUNE RESPONSES - 3
• On the other hand, IL-1 and IL-6
cytokines act as stimulants of adrenal
corticosteroid production
• Both IL-1 and IL-6 are synthesized by
neurons and glial cells and, in addition
by cells in pituitary and adrenal glands
GENETIC CONTROL OF IMMUNE
RESPONSES
• Strains of mice with different MHC haplotypes
vary in their ability to mount immune
response to given antigens
• Peptide-binding groove of APC is formed by
the most polymorphic residues in MHC
molecules (encoded by different alleles)
• Thus, MHC dependent aminoacid sequences
of the groove determine the accuracy of
peptide binding and in turn, antigen
presentation
CLINICAL IMPLICATIONS OF GENETIC
CONTROL OF IR
• MHC-linked genes control the response to
several infections
• Certain HLA haplotypes confer protection
from malaria (Plasmodium falciparum)
• Susceptibility to autoimmune diseases is
influenced by MHC-linked genes
CLINICAL IMPLICATIONS OF GENETIC
CONTROL OF IR (2)
• Linkage disequilibrium denotes grouping of
some genes that increase risk of particular
disease(example:HLA-DR3/DR4 -diabetes)
• Non-MHC-linked genes also affect
susceptibility to several diseases
IMMUNE MODULATION – MANIPULATION
OF THE IMMUNE RESPONSE
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Vaccination – passive and active
Application of cytokines
Application of monoclonal antibodies
Suppression by glucocorticoids and other
immunosuppressive drugs
• Infusion of immune cells
• Gene therapy related to the immune system
FEATURES OF GOOD VACCINE
1. Safe to use (live vaccines bear
potential risk)
1. Induce the right type of immunity
1. Is affordable by the population
concerned
1. Easy to produce and store
ADVANTAGES OF LIVE ATTENUATED
VACCINES
1. Preserve immunogenicity of virulent agent,
especially conformational antigens involved
in antibody production
1. Mimic natural infection better than inactive
vaccines
1. Usually stimulate multiple components of
the immune system including T cell and
mucosal immunity mediated by IgA
1. Herd immunity
DISADVANTAGES OF LIVE
ATTENUATED VACCINES
• May contain adventitious agents
• Can revert to virulence by mutation or
interserotypic recombination
• Can cause serious ilness in
immunosupressed individuals
• Stringent storage instructions for vaccine
efficacy and safety
THERAPEUTIC MODULATION OF
IMMUNE RESPONSES
• Non-specific immunization (BCG, bacterial
lysates, cytokines)
• Passive immunization: direct infusion of
antibodies
• Active immunization = vaccination:
– live attenuated organisms(measles,mumps)
– non-living organisms or subcellular
fragments(pertussis, polio)
– recombinant DNA-based (hepatitis B)
– Edible transgenic plants (HBs in lettuce)
NEW APPROACHES FOR BETTER
VACCINES
• Inactivated vaccines
• Recombinant proteins produced in yeast,
bacteria, cell culture or plants
• Synthetic peptides
• Anti-idiotypic vaccines
• Nucleic acid vaccines
• Novel adjuvants
• Novel carriers
ADJUVANTS, IMMUNOSTIMULANTS,
PROBIOTICS
• Adjuvants – organic and inorganic compounds
enhancing immune response while applied
together with an antigen (Freunds a. )
• Immunostimulants – microbial compounds that
enhance general immune response(ribomunyl)
• Probiotics – living microorganisms exerting
favourable effect on patient’s health
(Lactobacillus)
Immunomodulation by monoclonal
antibodies
• Advantages structural stability
unlimited supply of reagent,
high specificity
• Disadvantages: risk of sensitization for
foreign protein (murine or rat Ig),
potential hazard of anafilactic shock,
difficult accesibility, high cost
Modifications of monoclonal antibodies Mabs
• Chimeric Mabs –-Variable parts from mice, constant regions (C)
human (75% human sequences)
• Humanized Mabs – hypervariable regions from mice, C regions
from man (95% human sequences)
• Human Mabs – human Ig gene expresion in various biological
carriers (bacteriofages, transgenic animals, bacteria and even
plants – „plantibodies”)
• Minibodies – miniaturised Mabs (have better penetration)
• Bispecific Mabs – specificity for 2 antigens
Examples of Mabs currently used in
therapy
• Infliximab /anti TNF/ rheumatoid arthritis |RA|,
Crohn disease
• Rytuksymab /Anti CD20/ RA, B cell leukemias
/lymphomas
• Efalizumab /anti CD11a/ psoriasis
• Trastuzumab /HER 2/neu/ breast carcinoma
• Cetuksymab /EGFR/ large bowel carcinoma
Next lecture:
IMMUNOLOGY OF TRANSPLANTATION
THIS IS ENOUGH! THANK
YOU FOR ENDURANCE!