Regulation of the immune response

Jan Żeromski2013/2014

POINTS TO BE DISCUSSED

Regulation by antigen and antigen-presenting cell

Regulation by antibodyThe role of T cells (Treg) and NK T cells The role of telomeres Idiotypes and idiotypic networkNeuroendocrine mechanismsGenetic 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• Interleukin-2 (IL-2)• IL-1• IL-4• IL-5• IL-6• IL-12• IL-18• Interferon gamma

(IFN- )

• 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 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 cellsprivate: 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 immunogenicAnti – idiotypic antibodies are formed

following formation anti - antigen antibodyAnti-idiotypic Ab induce anti-anti-idiotypic

responseThis 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”)

• 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

THIS IS ENOUGH! THANK YOU FOR ENDURANCE!

Next lecture:IMMUNOLOGY OF TRANSPLANTATION