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27. Tumour immunology - tumour antigens, mechanisms of defence. 28. Alloimmune reaction. Types of transplantations and immunological examination before transplantation. Immunologically privileged tissues. 29. Types of graft rejection and their mechanisms. GvH. Principle of maternofoetal tolerance. Rh incompatibility 30. IgG and IgM based immunopathological reaction (reaction of hypersensitivity type II). 31. Immunocomplex based immunopathological reaction (reaction of hypersensitivity type III). Tumour immunology Tumor antigens a) Tumor – specific antigens (TSA) complexes of MHCgp I with abnormal fragments of cellular proteins (chemically induced tumors, leukemia with chromosomal translocation) complexes of MHC gp with fragments of oncogenic viruses proteins (tumors caused by viruses: EBV, SV40, polyomavirus…) abnormal forms of glycoproteins (sialylation of surface proteins of tumor cells) idiotypes of myeloma and lymphoma (clonotyping TCR and BCR) Tumor antigens b) Tumor - associated antigens (TAA) present also on normal cells differences in quantity, time and local expression auxiliary diagnostic markers Tumor - associated antigens onkofetal antigens -on normal embryonic cells and some tumor cells -fetoprotein (AFP) - hepatom carcinoembryonic antigen (CEA) - colon cancer melanoma antigens - MAGE-1, Melan-A antigen HER2/neu -receptor for epithelial growth factor, mammary carcinoma EPCAM – epithelial cell adhesion molecule, metastases differentiation antigens of leukemic cells - present on normal cells of leukocytes linage CALLA -acute lymphoblastic leukemia (CD10 pre-B cells) Anti-tumor immune mechanisms Immune control tumor cells normally arise in tissues and are eliminated by T cells Immune surveillance of tumours Anti – tumor immune response tumor cells are weakly immunogenic occurs when tumor antigens are presented to T cells by dendritic cells activated in the inflammatory environment Regulatory T cells prevents removal of cancer cells and thus contribute to the development of the tumor. Anti-tumor immune mechanisms If tumor cells are detected, in defense may be involved non-specific mechanisms (neutrophilic granulocytes, macrophages, NK cells, complement) and antigen-specific mechanisms (TH1 and TC cells, antibodies). Anti-tumor immune mechanisms DC are necessary for activation of antigen specific mechanisms predominance of TH1 (IFN g, TNF) specific cell-mediated cytotoxic reactivity – TC activation of TH2 → stimulation of B cells→ tumor specific antibodies production (involved in the ADCC) tumor cells are destroyed by cytotoxic NK cells (ADCC) interferons - antiproliferative, cytotoxic effect on tumor cells - INFg - DC maturation Mechanisms of tumor resistance to the immune system high variability of tumor cells low expression of tumor antigens sialylation some anticancer substances have a stimulating effect production of factors inactivating T lymphocytes expression of FasL → T lymphocyte apoptosis inhibition of the function or durability dendritic cells (NO, IL-10, TGF-b) Transplantation Transplantation = transfer of tissue or organ autologous - donor = recipient syngeneic - genetically identical donor and recipient (identical twins) allogeneic - genetically nonidentical donor of the same species xenogenic - the donor of another species implant - artificial tissue compensation Allotransplantation differences in donor-recipient MHC gp and secondary histocompatibility Ag alloreactivity of T lymphocytes - the risk of rejection and graft-versus-host disease Tests prior to transplantation ABO compatibility (matching blood group) -risk of hyperacute or accelerated rejection (= formation of Ab against A or B Ag on graft vascular endothelium) HLA typing (matching tissue type) - determining of HLA alelic forms by phenotyping or genotyping Cross-match - detection of preformed alloantibodies (after blood transfusions, transplantation, repeated childbirth) Mixed lymphocyte reaction - testing of T lymphocytes alloreactivity HLA typing 1) Serotyping (microlymfocytotoxic test) HLA typing 2) Molecular genetic methods- genotyping 2a) PCR-SSP 2b) PCR-SSO 2c) PCR-SBT Tests prior to transplantation Cross-match testing determination of preformed alloantibodies recipient serum + donor lymphocytes + rabbit complement → if cytotoxic Ab against donor HLA Ag are present in recipient serum , Ab activate complement → lysis of donor lymphocytes. Dye penetration into lysis cells. positive test = the presence of preformed Ab → risk of hyperacute rejection! → contraindication to transplantation Tests prior to transplantation Mixed lymphocyte reaction (MRL) determination of T lymphocytes alloreactivity mixed donor and recipient lymphocytes → T lymphocytes after recognition of allogeneic MHC gp activate and proliferate One-way MRL determination of recipient T lymphocytes reactivity against donor cells donor cells treated with chemotherapy or irradiated lose the ability of proliferation One-way MRL Immunologically privileged sites and tissues Transplantation of some tissues doesn´t lead to the induction of allogeneic reactivity Evolutionarily significant- protection of vital organs (brain, eye, gonads) Factors protecting immunologically privileged structures isolation from the immune system (minimal content of lecocytes) preference of TH2 reactoin, supression of TH1 reaction FasL expression production of TGFb Rejection hyperacute accelerated acute chronic Hyperacute rejection minutes to hours after transplantation humoral mediated immune response mechanism: if in recipients blood are present preformed or natural Ab (IgM anti- carbohydrate Ag) before transplantation → Ab + Ag of graft (MHC gp or endothelial Ag) → graft damage by activated complement the graft endothelium: activation of coagulation factors and platelets, formation thrombi, accumulation of neutrophil granulocytes prevention: negative cross match before transplantation, ABO compatibility Accelerated rejection 3 to 5 days after transplantation caused by antibodies that don´t activate complement cytotoxic and inflammatory responses triggered by binding of antibodies to Fc-receptors on phagocytes and NK cells prevention: negative cross match before transplantation, ABO compatibility Acute rejection days to weeks after the transplantation or after a lack of immunosuppressive treatment cell-mediated immune response mechanism: reaction of recipient TH1 and TC cells against Ag of graft tissue infiltration by lymphocytes, monocytes, granulocytes around small vessels → destruction of tissue transplant Chronic rejection from 2 months after transplantation the most common cause of graft failure mechanism is not fully understood: non-immunological factors (tissue ischemia) and TH2 response with production alloantibodies, pathogenetic role of cytokines and growth factors (TGFβ) fibrosis of the internal blood vessels of the transplanted tissue, endothelial damage →impaired perfusion of graft → gradual loss of its function dominating findings: vascular damage Rejection Factors: The genetic difference between donor and recipient, especially in the genes coding for MHC gp (HLA) Type of tissue / organ - the strongest reactions against vascularized tissues containing many APC (skin) The activity of the recipient immune system – the immunodeficiency recipient has a smaller rejection reaction; immunosuppressive therapy after transplantation – suppression of rejection Status of transplanted organ - the length of ischemia, the method of preservation, traumatization of organ at collection Graft-versus-host (GvH) disease after bone marrow transplantation GvH also after blood transfusion to immunodeficiency recipients T-lymphocytes in the graft bone marrow recognize recipient tissue Ag as foreign (alloreactivity) Acute GvH disease days to weeks after the transplantation of stem cells damage of liver, skin and intestinal mucosa prevention: appropriate donor selection, the removal of T lymphocytes from the graft and effective immunosuppression Chonic GvH disease months to years after transplantation infiltration of tissues and organs by TH2 lymphocytes, production of alloantibodies and cytokines → fibrosis process like autoimmune disease: vasculitis, scleroderma, sicca-syndrome chronic inflammation of blood vessels, skin, internal organs and glands, which leads to fibrosis, blood circulation disorders and loss of function Graft versus leukemia effect (GvL) donor T lymphocytes react against residual leukemick cells of recipient (setpoint response) mechanism is consistent with acute GvH associated with a certain degree of GvH (adverse reactions) Immunologic relationship between mother and allogenic fetus Immunologic relationship between mother and allogenic fetus fetal cells have on the surface alloantigens inherited from his father Pregnancy = „semiallogenic transplantation“ Immunologic relationship between mother and allogenic fetus Tolerance of fetus by mother: the relative isolation of the fetus from maternal immune system (no mixing of blood circulation) trophoblast - immune barrier witch protects against mother alloreactive T lymphocytes (don´t express classical MHC gp, expresses non-classical HLA-E and HLA-G) suppressin of TH1 and preference of TH2 immune mechanisms in pregnancy • transfer of small doses of fetal antigens in maternal circulation causes tolerance ... Rh incompatibility Complications in pregnancy: production of anti-RhD antibodies by RhD- mother carrying an RhD+ fetus (hemolytic disease of newborns) During childbirth or abortion (after 8 weeks of gestation) fetal erythrocytes can penetrate into the bloodstream of mother → immunization, formation of anti-RhD antibodies Rh incompatibility Rh incompatibility After childbirth, investigate Rh factor of born child, if is child Rh+, mother gets up to 72 hours after birth injection of anti-RhD antibodies (administered after abortion too) Anti-Rh(D) antibodies bind to RhD Ag on baby´s red blood cells, this Ag than can´t bind to BCR and can´t activate B lymphocytes, this immune comlexes also inhibit B lymphocytes Rh incompatibility During next childbirths, if fetus is Rh+ and mother produce anti-Rh antibodies, this Abb destroy red blood cells of fetus, which can lead to fetal death, or in severe postpartum anemia (anemia neonatorum) and neonatal jaundice (icterus gravis neonatorum) For each pregnant woman during the first trimester investigate blod Rh factor and the presence of antibodies, in Rh- women performed a test for antibodies also in II. and III. trimester Immunopathological reactions Immunopathological reactions Immune response which caused damage to the body (Consequence of immune response against pathogens, inappropriate responses to harmless antigens; autoimmunity) Immunopathological reactions Classification by Coombs and Gell Immunopathological reactions: immune response, which caused damage to the body (secondary consequence of defense responses against pathogens, inappropriate responses to harmless antigens, autoimmunity) IV types of immunopathological reactions: Type I reaction - response based on IgE antibodies Type II reaction - response based on antibodies, IgG and IgM Type III reaction - response based on the formation of immune complexes Type IV reaction - cell-mediated response Immunopathological reactions based on antibodies IgG and IgM (reaction type II) Cytotoxic antibodies IgG and IgM bind to antigens on own cell: complement activation binding to Fc receptors on phagocytes and NK cells (ADCC) Examples of immunopathological reaction Type II Transfusion reactions after administration of incompatibile blood: binding of antibodies to antigens on erythrocytes → activation of the classical pathway of complement → cell lysis Hemolytic disease of newborns: caused by antibodies against RhD antigen Examples of immunopathological reaction Type II Autoimmune diseases: organ-specific cytotoxic antibodies (antibodies against erythrocytes, neutrophils, thrombocytes, glomerular basement membrane ...) blocking or stimulating antibodies Graves - Basedow's disease - stimulating antibodies against the receptor for TSH Myasthenia gravis - blocking of acetylcholin receptor→ blocking of neuromuscular transmission Pernicious anemia - blocking the absorption of vitamin B12 Antiphospholipid syndrome - antibodies against fosfolipids Fertility disorder - antibodies against sperms or oocytes Immunopathological reactions based on immune complexes formation (reaction type III) caused by IgG antibodies → bind to antigen → creation of immune complexes immunocomplexes - bind to Fc receptors on phagocytes - activate complement immune complexes, depending on the quantity and structure, are eliminated by phagocytes or stored in tissues Immunopathological reactions type III pathological immunocomplexes response arises when is a large dose of antigen, or antigen in the body remains; arise 10-14 days after aplication of Ag and induced inflamation (can get to chronic state) immune complexes are deposited in the kidneys (glomerulonephritis), on the surface of endothelial cells (vasculitis) and in synovie joint (arthritis) Serum sickness the therapeutic application of xenogeneic serum (antiserum to snake venom) creation of immune complexes and their storage in the vessel walls of different organs clinical manifestations: urticaria, arthralgia, myalgia Systemic lupus erythematosus antibodies against nuclear antigens, ANA, anti-dsDNA Farmer's lung IgG antibody against inhaled antigens (molds, hay) Post-streptococcal glomerulonephritis, cryoglobulinemia, revmatoid arthritis, post-infectious arthritis Thank you for your attention