Tumour immunology Tumor antigens a Tumor specific antigens

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Tumour immunology

Tumour immunology

Tumor antigens a) Tumor – specific antigens (TSA) § complexes of MHCgp I with

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, SV 40, 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

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

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 HER 2/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 (CD 10 pre-B cells)

Anti-tumor immune mechanisms Immune control § tumor cells normally arise in tissues and are

Anti-tumor immune mechanisms Immune control § tumor cells normally arise in tissues and are eliminated by T cells

Immune surveillance of tumours

Immune surveillance of tumours

Anti – tumor immune response § tumor cells are weakly immunogenic § occurs when

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

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

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 (TH 1 and TC cells, antibodies).

Anti-tumor immune mechanisms § DC are necessary for activation of antigen specific mechanisms §

Anti-tumor immune mechanisms § DC are necessary for activation of antigen specific mechanisms § predominance of TH 1 (IFN g, TNFa) § specific cell-mediated cytotoxic reactivity – TC § activation of TH 2 → 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

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 Fas. L → T lymphocyte apoptosis § inhibition of the function or durability dendritic cells (NO, IL-10, TGF -b)

Transplantation

Transplantation

Transplantation = transfer of tissue or organ § autologous - donor = recipient §

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

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

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 1) Serotyping (microlymfocytotoxic test)

HLA typing 2) Molecular genetic methods- genotyping 2 a) PCR-SSP 2 b) PCR-SSO 2

HLA typing 2) Molecular genetic methods- genotyping 2 a) PCR-SSP 2 b) PCR-SSO 2 c) PCR-SBT

Tests prior to transplantation Cross-match testing § determination of preformed alloantibodies § recipient serum

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

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

One-way MRL

Rejection § hyperacute § accelerated § acute § chronic

Rejection § hyperacute § accelerated § acute § chronic

Hyperacute rejection § minutes to hours after transplantation § humoral mediated immune response mechanism:

Hyperacute rejection § minutes to hours after transplantation § humoral mediated immune response mechanism: § if in recipients blood are present preformed or natural Ab (Ig. M 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

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

Acute rejection § days to weeks after the transplantation or after a lack of immunosuppressive treatment § cell-mediated immune response mechanism: § reaction of recipient TH 1 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

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 TH 2 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

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 (Gv. H) disease § after bone marrow transplantation § Gv. H also after

Graft-versus-host (Gv. H) disease § after bone marrow transplantation § Gv. H also after blood transfusion to immunodeficiency recipients § T-lymphocytes in the graft bone marrow recognize recipient tissue Ag as foreign (alloreactivity)

Acute Gv. H disease § days to weeks after the transplantation of stem cells

Acute Gv. H 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 Gv. H disease § months to years after transplantation § infiltration of tissues

Chonic Gv. H disease § months to years after transplantation § infiltration of tissues and organs by TH 2 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 (Gv. L) § donor T lymphocytes react against residual leukemick

Graft versus leukemia effect (Gv. L) § donor T lymphocytes react against residual leukemick cells of recipient (setpoint response) § mechanism is consistent with acute Gv. H § associated with a certain degree of Gv. H (adverse reactions)

Immunopathological reactions

Immunopathological reactions

Immunopathological reactions § Immune response which caused damage to the body (Consequence of immune

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

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 Ig. E antibodies Type II reaction - response based on antibodies, Ig. G and Ig. M Type III reaction - response based on the formation of immune complexes Type IV reaction - cell-mediated response

Immunopathological reactions based on antibodies Ig. G and Ig. M (reaction type II) Cytotoxic

Immunopathological reactions based on antibodies Ig. G and Ig. M (reaction type II) Cytotoxic antibodies Ig. G and Ig. M 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:

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 Rh. D antigen

Examples of immunopathological reaction Type II Autoimmune diseases: § organ-specific cytotoxic antibodies (antibodies against

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 B 12 Antiphospholipid syndrome - antibodies against fosfolipids Fertility disorder - antibodies against sperms or oocytes

Immunopathological reactions based on immune complexes formation (reaction type III) § caused by Ig.

Immunopathological reactions based on immune complexes formation (reaction type III) § caused by Ig. G 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

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 § therapeutic application of xenogeneic serum (antiserum to snake venom) § creation

Serum sickness § 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-ds. DNA Farmer's lung § Ig. G antibody against inhaled antigens (molds, hay) Post-streptococcal glomerulonephritis, cryoglobulinemia, revmatoid arthritis, post-infectious arthritis

Immunopathological delayed-type reaction (reaction type IV) • delayed-type hypersensitivity (DTH) • local reaction caused

Immunopathological delayed-type reaction (reaction type IV) • delayed-type hypersensitivity (DTH) • local reaction caused by TH 1 cells and monocytes / macrophages (physiologically – elimination of macrophage intracellular parasites) • immunization by antigen → formation of antigen specific TH 1 cells (and memory cells) • 12 -48 hours after next contact with antigen arise local reaction – granuloma (TH 1 and macrophage infiltration) Tuberculin reaction Tissue damage in tuberculosis and leprosy Sarcoidosis Multiple sclerosis

Subtype IV - Cellular cytotoxic response (Tc activation) • similar to DTH reaction •

Subtype IV - Cellular cytotoxic response (Tc activation) • similar to DTH reaction • TH 1 cells activate CD 8 + T lymphocytes • • • viral rashes viral hepatitis acute rejection of transplanted organ some autoimmune thyroiditis contact dermatitis

Contact dermatitis • is a localized rash or irritation of the skin caused by

Contact dermatitis • is a localized rash or irritation of the skin caused by contact with alergen (nickel , chromium, ingredients in cosmetic products , plant allergens and other) • the first is senzitization • appears in 24 – 48 hours after second contact with alergen • diagnosis : patch test

Patch test • patch test is a method used to determine if a specific

Patch test • patch test is a method used to determine if a specific substance causes allergic inflamation of the skin • Allergens are applied to special hypoallergenic patch on the back skin • Results are evaluated after 48 and 72 hours • In positive reaction appears eczema

Thank you for your attention

Thank you for your attention

 • Tumour immunology and immunotherapy • https: //www. youtube. com/watch? v=K 09 xz.

• Tumour immunology and immunotherapy • https: //www. youtube. com/watch? v=K 09 xz. I Q 8 zsg • This is how your immune system fights cancer • https: //www. youtube. com/watch? v=UM 2 fq. FZV 3 o