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12. MUCOSAL IMMUNITY

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1 2 . MUCOSAL IMMUNITY. 1 3 . TRANSPLANTA TION. 1 4 . ANTI-TUMOUR IM M UNIT Y. 1 5 . REGULA TION OF IM MUNE RESPONSES. MECHANISM S OF Treg. DEVELOPMENT AND SELECTION IN THYMUS – ALSO Treg !!!. - PowerPoint PPT Presentation

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12. MUCOSAL IMMUNITY

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MUCOSAL IMMUNE SYSTEM

Protect mucous membranes from pathogens

Prevent the development of self-damaging inflammatory immune responses against harmless environmental antigens

Transport of antigens across mucosal surface - M-cells

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HUMORAL MUCOSAL RESPONSES

Massive production of IgA (under the influence of TGF-, IL-10, IL-4 in mucosal lymphoid tissues)

Transport of IgA across epithelial cells on the

mucosal surface: Transcytosis; poly-Ig-receptor; secretory component

IgA in mother milk (newborn human does not

have own antibodies; serum contains only small amounts of antibodies obtained transplacentary from the mother)

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CELL MEDIATED MUCOSAL RESPONSES

Intraepithelial T-lymphocytes

T-lymphocytes in lamina propria,

Peyer’s plaques CHARACTERISTIC FEATURE:

Mucosal immunization usually results in induction of

„tolerance“ (suppression of TH1, TC; stimulation of TH2 resp.

TH3 - IgA)

Suppressive (anti-inflammatory) cytokines

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13. TRANSPLANTATION

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TRANSPLANTATION OF TISSUES AND ORGANS

BASIC TERMS

Donor, recipient, “graft“, rejection

Grafts genetically identical with the recipient are syngeneic

Grafts from genetically non-identical donor of the same species are allogeneic

Grafts from a different species donor are xenogeneic

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SUPPRESSION OF TRANSPLANTATION

REJECTION REACTION

- Choice of genetically related donors (best - relatives)

- Immunosupression (cyclosporin A; corticosteroids;

antibodies to T-lymphocytes; irradiation)

- Ideal: induction of tolerance

- Xenotransplantation – possibly real; genetically modified

animals (baboons, pigs)

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IMMUNE “PRIVILEGED“ ORGANS, TISSUES

Isolated from cells of immune system

- Anterior eye chamber

- Central nervovous system

- (Developing foetus)

Defense system of brain – microglial cells (a form of tissue macrophages)

- Active mechanisms – FasL (destruction of activated T-cells attacking a privileged tissue)

- Privileged sites vs. tissues

- Th2 x Th1. PREVENTION OF INFLAMMATION

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BONE MARROW TRANSPLANTATION

- Inborn defects of hematopoiesis, immunodeficiencies

- Radiation, chemical damage

- Leukaemia, lymphoma

PROBLEM:

- Attack “graft vs. host“ (GvHD)

- Necessity of best possible genetic similarity and strong immunosuppression

- Ideal – transplantation of pure stem cells

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ALLOREACTIVITY IN VITRO

- Mixed lymphocyte reaction (MLR)

Mutual stimulation of allogeneic lymphocytes (mainly

proliferation of TH, also TC): measurement of the rate of

incorporation of radioactive nucleotides

- Use – selection of potential donors

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RATE OF TRANSPLANTATE REJECTION DEPENDS ON:

- Genetic difference between donor and recipient

- Type of tissue

- Activity of recipient immune system

Hyperacute rejection - during minutes to hours

Cause: antibodies (e.g. xeno-);

complement

Acute rejection– during several days

Cause: alloreactive T-lymphocytes (TH1, TC)

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ALLOREACTIVITY

Genetic difference in MHC (extremely polymorphic): the cells of

the graft carry complexes MHC-peptide completely different

from the recipient cells. Many T-lymphocytes therefore recognize

graft cells as foreign (as if infected).

Genetic differences in v non-MHC: a similar situation; the

number of the “foreign“ complexes is however much lower

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XENOREACTIVITY

Similar to alloreactivity; paradoxically even smaller

(partial inter-species incompatibility of adhesive and

signaling molecules).

Big problem – “natural“ xenoantibodies

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MOST COMMON TRANSPLANTATIONS

- Blood transfusion

- Kidney (> 30 000 per year)

- Heart (3 000)

- Liver (5 000)

- Cornea – mostly no imunological problems;

a “privileged“ site

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14. ANTI-TUMOUR IMMUNITY

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ANTI-TUMOUR IMMUNITY - Tumour-specific antigens (TSA)

- Tumour-associated antigens (TAA)

TSA:

- Complexes of MHC gp with abnormal protein fragments (mutants; abnormal cleavage). (Chemically induced tumors)

- Complexes of MHC gp with fragments of oncogenic viruses (polyoma, SV40, EBV)

- Abnormal forms of glycoproteins

- Idiotopes of myelomas

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TUMOUR ASSOCIATED ANTIGENS (TAA)

ONCOFETAL ANTIGENS:

-fetoprotein (AFP)

carcinoembryonal antigen (CEA)

OTHERS

melanoma antigens (MAGE-1, Melan-A)

HER-2/neu (growth factor receptor, epithelial cells) Amplification in breast cancer cells

EPCAM (epithelial cells; metastases of carcinomas)

“Differentiation antigens“ in leukaemia (CALLA - CD10)

Diagnostic, partially therapeutic importance

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ANTITUMOUR IMMUNE MECHANISMS

- HYPOTHESIS OF “IMMUNOLOGICAL

SURVEILLANCE” (?)

- Inflammation; macrophages (possible stimulation by BCG

injection, Corynebacterium)

- NK (anomalous expression of MHC I)

- Antibodies, TC

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MECHANISMS OF TUMOUR RESISTANCE

- Do not act as APC (absence of costimulatory surface molecules)

- Variability (loss of tumour antigen, immunoselection)

- Paradoxical stimulatory effect of antibodies (“enhancement”)

- Production of factors inactivating generally T-lymphocytes

- “Blocking factors“ (soluble forms of tumour antigens shedded from the cell surface)

(privileged tissue!)

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TUMOUR IMMUNOTERAPIES BASED ON ANTIBODIES

- Monoclonal antibodies, resp. immunotoxins against tumour antigens

Problems:

Damage of normal tissue

Immunoselection of the antigen-loss variants

Accessibility (best after surgery; micrometastases);

EPCAM; HER-2/neu; myelomy

- Bispecific antibodies (against tumour antigen x against T, NK)

- Autologous bone marrow transplantation (leukaemia); “purging“ of

leukaemic cells by means of monoclonal antibodies

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IMMUNOTHERAPY OF TUMOURS – CELLULAR MECHANISMS

- “Non-specific“ stimulation of inflammation (BCG; bladder

carcinomas)

- Stimulation of LAK, TIL

- Improvement of APC-function (transfection of CD80, cytokines; APC fusion)

- “Tumour vaccines“ (identification of peptides recognized by TIL on melanomas and other tumours, optimal stimulation of TC, TH1)

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15. REGULATION OF IMMUNE

RESPONSES

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REGULATION OF IMMUNE RESPONSE

Regulation by antigen

- Primary regulator (eliciting, finishing of response, affinity maturation; memory)

- Antigenic competition (for MHCgp) Surface density of the MHC-peptide complexes on APC decisive for TH1 x TH2. Necessity to achieve a threshold density

- Agonistic, semi-agonistic, antagonistic peptides

- Automatic mechanisms of finishing of the response (apoptosis of activated T-cells, short life time of most plasma cells)

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REGULATION BY CYTOKINES AND INTERCELLULAR CONTACT

PROBABLY THE MOST IMPORTANT MECHANISM OF REGULATION!

APC – T TH1- M TH1 x TH2

FDC – B TH2 – B

(TH – TC)

Development of various leukocyte subpopulations

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REGULATION BY ANTIBODIES

- Competition for antigen between BCR and soluble antibodies

- Crosslinking of BCR and FcR on B-cells by immunocomplexes – negative signal

- Idiotypic network

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NEGATIVE REGULATION (SUPRESSION)

1) TH1 x TH2 (cytokines)

2) TREG, TS

Possible mechanisms:

- effect on DC (tolerogenic)

- inhibition of TH

- creation of “cytokine environment“ prefering TH2

- anergic cells competing for IL-2

3) Anergization; clonal elimination (non-professional APC)

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ESSENTIAL IMPORTANCE OF

Treg

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MECHANISMS OF Treg

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DEVELOPMENT AND SELECTION IN THYMUS – ALSO Treg!!!

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REGULATORY IMPORTANCE OF DC

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NEUROENDOCRINE REGULATION - Neurotransmitters (noradrenaline…) act on leukocytes

- Direct contact of nerve endings and mastocytes

- Many endocrine hormones affect markedly leukocytes (corticosteroids, growth hormone, thyroxine, endorfins)

- Leukocytes produce hormones (endorfins, ACTH, TSH, growth hormone etc.)

- Many cytokines act on neuronal system (IL-1, IL-6, LIF, TNF)

- Clear negative effect of stress on immune system (wound healing, anti-infection immunity, alergy). Activity of fagocytes, NK. Mainly the effects of the released corticosteroids?

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IMMUNOLOGIC TOLERANCE

Immunity x tolerance

Inability to react to a certain antigen

Physiologically – tolerance to autoantigens

Experimentally – tolerance induction (instead of immunity) to foreign antigens

Importance – transplantation; autoimmune diseases

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FACTORS AFFECTING EXPERIMENTAL TOLEROGENIC RESPONSE

- State of the immune system (immature; weakened by irradiation, immunosupresive drugs)

- Properties of antigen (size of the molecule; monomer x polymer, aggregate)

- Antigen dose (very low and very high doses tend to be tolerogenic)

- Way of application (injection to blood, subcutaneous; adjuvans; peroral)

- Genetic effects (allelic forms of MHC)

EXPLANATION:

Mainly presentation of antigen (type of APC; density of the MHC-peptide complexes; TH1 x TH2; activation of TREG)

Immune paralysis, exhaustion (high antigen doses – saturation of binding sites, activation of all antigen-specific cells at the same time, no memory cells).

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MECHANISMS OF SELF-TOLERANCE

- Elimination of autoreactive clones (negative selection)

- Anergization of immature B-cells

- Ignoring of autoantigens present in small amounts or isolated from immune system (“invisible“)

- Anergization of T-cells by contact with non-professional APC (missing costimulatory signal)

- Activity of various types of TREG, TS

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BASIC DOGMA OF THE ADAPTIVE RESPONSE:

ANTIBODY RESPONSES (B, Th2) – EFFECTIVE AGAINST EXTRACELLULAR PARASITES

INFLAMMATORY RESPONSES (Th1, Tc) – EFFECTIVE AGAINST INTRACELLULAR PARASITES

MUTUAL COMPETITION Th1 vs. Th2 (REGULATION BY POSITIVE FEEDBACK)

WRONG CHOICE OF THE Th1 vs. Th2 RESPONSE

CAN BE FATAL (LEPROSY…)

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Th1 x Th2 („they don’t like each other …“)

IFN vs. IL-4

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16. IMMUNOPATOLOGIC

REACTIONS - ALLERGIES

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ALERGIES AND OTHER HYPERSENSITIVITIES

Hypersensitivity to harmless antigens; reaction damages the organism

Type I – Alergy, atopy (IgE)

Type II – Hemolytic reactions (complement)

against alloantigens (transfusion reaction;

hemolytic disease of the newborn – Rh)

Type III – Caused by immunocomplexes

Type IV – Delayed type (DTH) and contact hypersensitivity

(TH1 reaction)

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MECHANISMS OF ALERGIES (TYPE I)

- Completely analogous to defense IgE reactions against parasites: IgE; Ig-receptors on mastocytes, basophils and eosinophils

- Sensitisation; production of IgE; binding to IgE-R

- After next encounter of allergen - binding to mastocytes coated by IgE – receptor cross-linking

- Consequences:

“degranulation” – release of primary mediators (histamine, enzymes)

stimulation of secondary mediators production (prostanglandins, leukotrienes – arachidonate derivatives)

local inflammation (1. a 2. phase); swelling of mucosa, secretions, itching, pain, smooth muscle contraction; 2nd phase – also other cells participate (typical inflammation)

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FACTORS AFFECTING ALLERGIES

- Nature of aergens: unclear why just certain antigens of pollen, house mites, foods, etc. elicit IgE responses

- Genetic predispositions (polymorphism of MHC genes, IL-4, IgE-R)

- Environment (exposition to the allergen; climatic conditions)

- Diet in early childhood (breast feeding?)

- Infections in early childhood (some respiratory viral infections: bronchial hyperreactivity; absence of intestinal parasites in childhood? low exposition to antigens in general? „hygienic hypothesis“)

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Incidence of prototypical infectious diseases and immune disorders 1950 to 2000

N Engl J Med, Vol 347, No. 12, 09/2002

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HUGE INCREASE OF ALLERGIES AS „CIVILIZATION DISEASES“

Epidemiological studies - hygienic hypothesis:

Early childhood on a (primitive) farm (mycobacteria, LPS?)Intestinal parasitesBreast feedingNon/pasteurized milk “Good” intestinal floraHepatitis ADiesel exhaust particles?

Life style in general (DDR vs. FRG, Turkish immigrants, anthroposophy..)

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Allergens that get to blood circulation may cause systemic anaphylaxis (anaphylactic shock)

- insect venoms

- penicillin (alergens are penicilloylated proteins)

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TREATMENT OF ALLERGIES

- Profylaxis

- Antialergics (blocking of histamine receptors; corticoids inhibit histamine synthesis; effects on membrane composition – inhibition of degranulation)

- Desensitisation, hyposensitisation (empiric efforts to enhance competing IgG responses instead of IgE). Reliable rational procedures (TH1 x TH2?) do not exist yet.

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TYPE II HYPERSENSITIVITY

Transfusion reaction

(A, B, 0; “isohemagglutinins”)

Minor blood groups

Hemolytic disease of newborn:

85% individuals - RhD+

RhD- mother – immunization by RhD+ foetus (delivery)

Next pregnancy – foetus damage

Prevention: passive immunization anti-RhD before the first delivery

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TYPE III HYPERSENSITIVITY

Antigen (animal sera, bacterial product, autoantigen) – elicits antibodies

Repeated contact with antigen – massive formation of immunocomplexes

Binding to Fc-receptors of phagocytes, activation of ccomplement, deposition in kidney glomerules

Important component of pathology of pathologies of some infectious and autoimmune diseases

“Serum sickness“ – damage of kidney, blood vessels, joints, skin

Experimental model: Arthus reaction

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TYPE IV HYPERSENSITIVITY (DTH)

- Sensitising antigen natural – e.g. mycobacteria experimental – protein given in adjuvans

- Following injection subcutaneous, intradermal: local characteristic reaction after 24-72 hr.

- Mechanism: TH1 – activated macrophages; inflammation

- Tuberculin reaction

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CONTACT HYPERSENSITIVITY

- Low-molecular substances (Ni, CrO42-,

components of cosmetics, varnish, dyes). Experimental – DNP, DNFB

- Modification of proteins, stimulation of TH1

- Skin manifestations – essentially DTH

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17. IMMUNOPATOLOGIC AUTOIMMUNE REACTIONS

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AUTOIMMUNITY Immune system reacts to autoantigen.

Causes:

- Molecular mimikry?

- Exposure of hidden autoantigens and cryptic eptitopes (infection, inflammation)

- Reaction against primary autoantigen intensifies the inflammation, reaction against further autoantigens (cryptic epitopes) develops. “Determinant spreading“

Linkages to MHC polymorphism

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AUTOIMUNE DISEASES CAUSED BY AUTOANTIBODIES

Lupus erythematosus autoantibodies to DNA, histones ribonucleoproteins; DR3

Graves disease autoantibodies to TSH-R; mimick TSH → overprodukce of thyroxin; DR3

Myasthenia gravis autoantibodies to AChR; - block effects of ACh; DR3

Hashimoto thyroiditis autoantibodies to thyroid antigens; decreased production of thyroid hormones; DR5

Acute rheumatic fever Antibodies to streptococcal antigens cross-react with surface antigens of heart muscle. The only clear case of antigenic mimikry

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Disease Autoantibodies to

Systemic lupus erythematodes Nuclear antigens; blood elements

Rheumatoiod arthritisFc-fragments of immunoglobulins ("rheumatoid factor")

Dermatopolymyositis Extractable nuclear antigens Jo-1, PM/Scl

Sjögren’s disease Extractable nuclear antigens (SS-A, SS-B)

Systemic sclerodermy Extractable nuclear antigens (Scl-70)

Anti/phospholipide syndrom Phospholipids

Some vasculitis Cytoplasmatic antigens of neutrophils

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DISEASES CAUSED BY AUTOREACTIVE T-CELLS

Juvenile diabetes mellitus (IDDM)

TC, TH1 against antigens of -cells of pancreatic of Langerhans islets Primary autoantigens – glutamic acid decarboxylase, Hsp60? Elicited after local inflammation following a viral infection? DR3, DR4, (protective DR2)

Multiple sclerosis

TH1 against antigens of myelin (presented by microglia); inflammation; demyelination DR2

Rheumatoid arthritis

TH1 (secondary??) against joint antigens (collagen, Hsp); antibodies to immunoglobulins (“rheumatoid factor”); damage of kidney

DR4

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Disease HLA Relative risk*

Ankylosing spondyloarthritis (Bechterev disease)

B27 87.4

Uveitis B27 10

Goodpasture syndrom DR2 15.9

Multiple sclerosis DR2 4.8

Graves-Basedow diseaseDR3 3.7

Systemic lupus erythematodes

DR3 5.8

Myasthenia gravis DR3 2.5

Pemphigus DR4 14.4

Rheumatoid arthritis DR4 4.2

Hashimotova thyreoiditis DR5 3.2

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THERAPY OF AUTOIMMUNE DISEASES

Immunosupression (corticosteroids, antibodies to T-lymphocytes, cyclosporin A) Ideal – re-establishing of tolerance by

manipulation of the immune system

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18.IMMUNODEFICIENCIES

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DEFECTS OF NON-ADAPTIVE (INNATE) PART OF THE IMMUNE SYSTEM

Missing of some complement components (Neisseria; accumulation of immunocomplexes) serious defect – missing of C1 inhibitor

Defects of NADPH oxidase (chronic granulomatous disease)

Chédiak-Higashi syndrome: defect of lysosome-phagosome fusion

Leukocyte adhesion deficiency (LAD): defect of leukocyte integrins (leukocytosis, defective extravasation, no puss formation)

LAD-2 – defect of L-selectin

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DEFECTS ANTIGEN PRESENTATION

“Bare lymphocyte syndrome”: missing MHC II (defect of a regulatory transcription factor).

CD4+ T cells are missing

Very rarely – missing MHC I (defect in peptide transport). Very few CD8+ T

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DEFECTS OF B-LYMPHOCYTES AND Ig PRODUCTION

X-linked agammaglobulinemia (XLA):

almost no B cells and Ig (O.C.Bruton 1952; the first described inborn immunodeficiency)

Defect in the tyrosine-kinase Btk

X-linked hyper-IgM syndrome

Defect of CD40L (on TH): no affinity maturation, isotype switch. Only large amounts of IgM against TH independent antigens.

Selective Ig (e.g. IgA) deficits

Surprisingly mild consequences; predisposition to respiratory infections, allergies, a risk for transfusion (anti-IgA!)

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DEFECTS OF T-CELLS

DiGeorge syndrome – developmental defect, anatomic abnormalities, including missing of thymus.

Nu/nu mice – an important model

Deficiency of adenindeaminase (ADA):

Missing T-cells. Attempts at gene therapy.

Severe combined X-linked immunodeficiency (SCID):

defect in common subunit c of the receptors for cytokines IL-2, -4, -7, -9, -13, -15.

Similar severe diseases in defects of several other signaling molecules.

Autosomal recessive SCID – defect of recombination of the Ig and TCR genes. Missing T and B lymphocytes.

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Nu/nu mouse (athymic)

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ACQUIRED IMMUNODEFICIENCIES

Temporary or chronic – consequence of some infections, malnutrition, malignancies, stress (injury trauma), irradiation, chemicals (high doses of antibiotics, immunosupressants)

AIDS: infected > 40 000 000 people

HIV – retrovirus (lentivirus); tropism for CD4+ T, monocytes/macrophages

Potentially a number of possible mechanisms of immune system destruction, e.g.:

direct and indirect destruction of TH destruction of APC including FDC affecting TH1 x TH2 loss of memory T-cells

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AIDS - therapy:

virostatics – (AZT), HAART

(vaccine development)

looking for immunotherapy (cytokines; IL-16)

rare cases of natural resistance (absence of chemokine receptors)

(successful experimental immunization; HIV-2; chimps)

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19. IMMUNOPROPHYLAXIS AND

IMMUNOTERAPY

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IMMUNOPROPHYLAXIS TERMS:

Active, passive immunization

Vaccines: microorganisms or their components

Atenuated microorganisms Inactivated microorganisms “Subunit“ vaccines Toxoids

Prophylactic x therapeutic vaccination

Danger of infection or anaphylaxis

Adjuvants (incomplete, complete Freund adjuvans; alum)

The way of administration is important – immunogenic x tolerogenic:

- monomeric x polymeric, aggregated antigen

- parenteral x subcutaneous x peroral

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PASSIVE IMMUNIZATION

Natural – maternal antibodies (transplacental, milk)

Prophylactic, therapeutic:

animal antisera to toxins (danger of anaphylaxis after repeated administration)

human IgG (hepatitis, rabies, tetanus; Ig-deficiency); intramuscular, resp. highly purified intravenous

Anti-Rh (prevention of production of own anti-Rh)

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ACTIVE IMMUNIZATION

E. Jenner: Vaccinia – against pox (variola) (ERADICATION 1970!)

Atenuated live vaccines (most efficient)

measles, mumps, rubella, polio (peroral), yellow fever, tuberculosis (BCG – only in risk groups, total - 2,5 billion)

Subunit vaccines (in adjuvans)

pertussis (toxoid), hepatitis B (recombinant surface antigen), hemophilus, meningococcus (polysaccharide antigens)

Killed bacteria, inactivated viruses

pertussis, tetanus, cholera, plague, typhoid, influenza, rabies (therapeutic immunization - “outruns“ slow infection!)

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NEW TYPES OF VACCINES (UNDER DEVELOPMENT)

Recombinant Vaccinia virus or other vectors (bird poxviruses, adenoviruses, genetically modified Salmonella, BCG and other bacteria)

Futuristic approach – expression in edible plants

“Genetic vacination“ directly by expression plasmid (injection into muscle, “gene gun“)

Better adjuvantsand immunostimulatory substances

Experimentally – carrier KLH, immunostimulators (cytokines, LPS); severe side effects

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MARKED SUCCESS – THERAPEUTIC

MONOCLONAL ANTIBODIES:

Discovery 1976, Nobel prize 1984.

Not patented…

>15 years technical difficulties in therapeutic uses

Last cca 10 years – huge progress (humanized mAb), most dynamic field of pharmaceutic industry, sales over 20 billion USD per year…

Cca 30 approved by FDA, other cca 100 under testing

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Unconjugated mAbs

Nature Biotechnology 23, 1147 - 1157 (2005)

Trastuzumab (Herceptin)

Humanized Human IgG1

HER2/neu Breast cancer 1998

Rituximab (Rituxan)

Murine-human chimeric

Human IgG1

CD20 Lymphoma 1997

Cetuximab (Erbitux)

Murine-human chimeric

Human IgG1

EGF receptor

Colorectal cancer 2004

Bevacizumab (Avastin)

Murine-human chimeric

Human IgG1

VEGF Colorectal, lung cancers

2004

Alemtuzumab (Campath-1H)

Humanized Human IgG1

CD52 Chronic lymphocytic leukemia

2001

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Immunoconjugates

Ibritumomab tiuxetan (Zevalin) together with rituximab

Murine 90Y-radiolabeled murine IgG1

CD20 Lymphoma 2002

Tositumomab and 131I tositumomab (Bexxar)

Murine 131I-radioabeled murine IgG2a

CD20 Lymphoma 2003

Gemtuzumab (Myelotarg)

Human (drug derived from streptomycete)

Human IgG4 conjugated to calicheamicin

CD33 Acute myelogenous leukemia

2000

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HOPEFULLY IN FUTURE:

- BETTER VACCINES (HIV, WEAK AND TUMOR ANTIGENS?)

- BETTER IMMUNOSUPPRESSION (AUTOIMMUNE DISEASES, ALLERGIES, TRANSPLANTATION)

- EFFECTIVE IMMUNOTHERAPIES OF TUMOURS (A WEAK SPOT OF IMMUNITY…)

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