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
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 cytoki- nes (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
• 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”)