12. mucosal immunity. 13. transplantation
TRANSCRIPT
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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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