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12. MUCOSAL IMMUNITY 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 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) 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 13. TRANSPLANTATION 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 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) 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 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 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 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) 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 XENOREACTIVITY Similar to alloreactivity; paradoxically even smaller (partial inter-species incompatibility of adhesive and signaling molecules). Big problem – “natural“ xenoantibodies MOST COMMON TRANSPLANTATIONS - Blood transfusion - Kidney (> 30 000 per year) - Heart (3 000) - Liver (5 000) - Cornea – mostly no imunological problems; a “privileged“ site 14. ANTI-TUMOUR IMMUNITY 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 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 ANTITUMOUR IMMUNE MECHANISMS - HYPOTHESIS OF “IMMUNOLOGICAL SURVEILLANCE” (?) - Inflammation; macrophages (possible stimulation by BCG injection, Corynebacterium) - NK (anomalous expression of MHC I) - Antibodies, TC 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 Tlymphocytes - “Blocking factors“ (soluble forms of tumour antigens shedded from the cell surface) (privileged tissue!) 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 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) 15. REGULATION OF IMMUNE RESPONSES 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) REGULATION BY CYTOKINES AND INTERCELLULAR CONTACT PROBABLY THE MOST IMPORTANT MECHANISM OF REGULATION! APC – T TH1- M FDC – B TH2 – B TH1 x TH2 (TH – TC) Development of various leukocyte subpopulations REGULATION BY ANTIBODIES - Competition for antigen between BCR and soluble antibodies - Crosslinking of BCR and FcR on Bcells by immunocomplexes – negative signal - Idiotypic network 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) ESSENTIAL IMPORTANCE OF Treg MECHANISMS OF Treg DEVELOPMENT AND SELECTION IN THYMUS – ALSO Treg!!! REGULATORY IMPORTANCE OF DC 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? 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 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). 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 nonprofessional APC (missing costimulatory signal) - Activity of various types of TREG, TS 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…) Th1 x Th2 („they don’t like each other …“) IFNg vs. IL-4 16. IMMUNOPATOLOGIC REACTIONS - ALLERGIES 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) 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) 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“) Incidence of prototypical infectious diseases and immune disorders 1950 to 2000 N Engl J Med, Vol 347, No. 12, 09/2002 HUGE INCREASE OF ALLERGIES AS „CIVILIZATION DISEASES“ Epidemiological studies - hygienic hypothesis: Early childhood on a (primitive) farm (mycobacteria, LPS?) Intestinal parasites Breast feeding Non/pasteurized milk “Good” intestinal flora Hepatitis A Diesel exhaust particles? Life style in general (DDR vs. FRG, Turkish immigrants, anthroposophy..) Allergens that get to blood circulation may cause systemic anaphylaxis (anaphylactic shock) - insect venoms - penicillin (alergens are penicilloylated proteins) 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. 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 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 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 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 17. IMMUNOPATOLOGIC AUTOIMMUNE REACTIONS 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 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 Disease Autoantibodies to Systemic lupus erythematodes Nuclear antigens; blood elements Rheumatoiod arthritis Fc-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 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 Disease HLA Relative risk* Ankylosing spondyloarthritis (Bechterev disease) B27 87.4 Uveitis B27 10 Goodpasture syndrom DR2 15.9 Multiple sclerosis DR2 4.8 DR3 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 Graves-Basedow disease THERAPY OF AUTOIMMUNE DISEASES Immunosupression (corticosteroids, antibodies to T-lymphocytes, cyclosporin A) Ideal – re-establishing of tolerance by manipulation of the immune system 18. IMMUNODEFICIENCIES 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 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 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!) 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 gc 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. Nu/nu mouse (athymic) 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 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) 19. IMMUNOPROPHYLAXIS AND IMMUNOTERAPY 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 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) 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!) 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 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 Unconjugated mAbs Nature Biotechnology 23, 1147 - 1157 (2005) Trastuzumab (Herceptin) Humanized Rituximab (Rituxan) Murine-human Human CD20 chimeric IgG1 Lymphoma Cetuximab (Erbitux) Murine-human Human EGF chimeric IgG1 receptor Colorectal cancer 2004 Bevacizumab (Avastin) Murine-human Human VEGF chimeric IgG1 Colorectal, lung cancers 2004 Chronic lymphocytic leukemia 2001 Alemtuzumab (Campath-1H) Humanized Human HER2/neu Breast cancer IgG1 Human CD52 IgG1 1998 1997 Immunoconjugates Ibritumomab tiuxetan (Zevalin) together Murine with rituximab Tositumomab and 131I Murine tositumomab (Bexxar) Gemtuzumab (Myelotarg) Human (drug derived from streptomycete) 90 Y-radiolabeled CD20 murine IgG1 Lymphoma 2002 131 I-radioabeled CD20 murine IgG2a Human IgG4 conjugated to calicheamicin CD33 Lymphoma 2003 Acute myelogenous 2000 leukemia 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…)