IMMUNODEFICIENCIES AND TUMOR IMMUNOLOGY 14th week, 2014 BSc in Public Health

AGE AND HEALTH DEPENDENT IMMUNOSUPPRESSIVE DRUGS IMMUNODEFICIENCIES AGE AND HEALTH DEPENDENT IMMUNOSUPPRESSIVE DRUGS INHERITED (PRIMARY) Loss of function mutation of genes of the immune system Enhanced susceptibility to infections Particular types of pathogens depending on the gene defect Did not show up until 1950 - antibiotics ACQUIRED Due to infectious diseases AIDS Other viral infections Malnutrition Artificial immunosuppression Drugs Radioactive irradiation

PRIMARY IMMUNODEFICIENCIES MOST ARE RECESSIVE MUTATION OF SINGLE GENES Dominant traits have been eliminated from the population Autosomal genes or X-linked genes (different inheritance) DOMINANT: Mutation in the IFNγ receptor results in binding without intracellular signaling f DISSEMINATED INFECTION BY THE BCG STRAIN OF Mycobacterium (M. bovis) USED FOR VACCINATION

Numerous Immunodeficiency loci reside on the X chromosome CGD: Chronic Granulomatous Disease WAS: Wiscott-Aldrich Syndrome SCID: Severe Combined Immunodeficiency XLA: X-linked Agammaglobulinemia XLP: X-linked Lymphoproliferative Disease XLHM: X-linked Hyper-IgM Syndrome

TYPES OF INHERITED IMMUNE DEFICIENCIES B CELL DEFICIENCY recurrent sinopulmonary and GI infections beginning after 3-4 months B cell development X-Linked Agammaglobulinaemia hyper IgM syndrome CD40L – X-linked AID – autosomal CVID selective IgA deficiency T CELL DEFICIENCY opportunistic infections beginning early in infancy SCID T cell development IL-7 signaling defect RAG-1/2 def. (Omenn’s sy.) DNA repair enzyme defect Purin catabolism (metabolites toxic to developing B and T cells) MHC deficiency (Bare Lymphocyte Syndrome) DiGeorge syndrome lacking thymus epithelial cells (aberrant embrional development)

B CELL IMMUNODEFICIENCIES Approx. 70% of all primiary IDs Late Manifestation (3-10 months) Increased sensitivity to epithelial pathogens: pyogenic bacteria (e.g. streptococci) GI pathogens (e.g. enteroviruses) Threatment: intravenous human immunoglobulin (hIVIG) every month

Flow cytometric measurement of peripheral blood leukocytes CD3 = cell surface marker expressed by T cells CD19 = cell surface marker expressed by B cells

DEFECT IN T CELL FUNCTIONS T cells are involved in all aspects of adaptive immunity SEVERE COMBINED IMMUNODEFICIENCY (SCID) (Over 50% of T cell deficiencies) Neither T cell-dependent antibody response nor cellular immunity are functional Small body weight, failure to thrive Persistent and recurrent infections with a broader range of pathogens than in patients with B cell deficiencies Opportunistic infections (Candida albicans, Pneumocystis carnii) Treatment: Bone marrow transplantation, preferably from a histocompatible sibling (Gene therapy)

TYPES OF INHERITED IMMUNODEFICIENCIES 2. PHAGOCYTIC SYSTEM CD18 (CR3, CR4, LFA1) deficiency aka Leukocyte Adhesion Deficiency (LAD) no leukocyte migration to sites of inflammation NADPH oxidase deficiency aka Chronic Granulomatous Disease (CGD) granuloma formation in case of several infections by intracellular pathogens Chédiak-Higashi Syndrome (CHS) defect of phagolysosome formation COMPLEMENT SYSTEM pyogenic infections, primarily with encapsulated microorganisms and Neisseriae

TUMOR IMMUNOLOGY

GLOBAL MORTALITY RATE

What is cancer? Normal tissue Benign tumor Cancer

Most frequent sites of tumors Lungs Liver Stomach Colon Pancreas

GENERATION OF TUMORS if mutations accumulate in tissue cells they may become tumorous cells: gain of function mutations of proto-oncogenes that lead to enhanced proliferation signals loss of function mutations of tumor suppressor genes that inactivate regulation of the cell cycle tumor cells are continuously proliferating cells that have genetic instability  mutations and chromosomal aberrations accumulate invading local tissues benign: respecting tissue borders (basement membranes) malignant: spread to all nearby tissues, can even give off metastases (local ones via the lymph, or distant ones via the blood) Tumor cells are generated in our bodies daily but normally they are cleared by the immune surveillance

THE IMMUNE RESPONSE TO TUMORS Hidden, changing, proliferating, evolving target TUMOR ANTIGENS Tumor associated antigens – TAA Present also in normal cells Aberrant/dysregulated expression in tumor cells Tumor specific antigens – TSA Unique for individual tumors or tumor types IMMUNE SYSTEM Tumor-specific immune responses can be induced Cytotoxic T lymphocytes can eradicate tumors

Activation of tumor-specific T-cells by DC Cross-presentation

INDUCTION OF A PROTECTIVE ANTI-TUMOR IMMUNE RESPONSE REQUIRES THE COLLABORATION OF DENDRITIC CELLS AND T-LYMPHOCYTES APOPTOTIC TUMOR CELL DC IL-2 IFN IL - 12 Tumor Ag CROSS PRIMING

ESCAPE MECHANISMS OF TUMORS production of soluble MIC  inhibition of killing by NK cells Malignant transformation of epithelial cells induces the expression of MIC proteins. These are recognized by the NKG2D receptors of NK cells, γ:δ cells, and CD8 T cells, which enables these cells to kill the tumor cells. Variant tumor cells can evade this response by making a protease that cleaves MIC from the cell surface. This has two effects to the tumor’s advantage: first, the variant tumor now lacks the ligand for NKG2D; and second, the binding of soluble MIC to NKG2D on the lymphocyte surface causes endocytosis and degradation of the receptor:MIC complex.

In normal cells, TGF-β, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. When a cell is transformed into a cancer cell, parts of the TGF-β signaling pathway are mutated, and TGF-β no longer controls the cell. These cancer cells proliferate. The surrounding stromal cells (fibroblasts) also proliferate. Both cells increase their production of TGF-β. This TGF-β acts on the surrounding stromal cells, immune cells, endothelial and smooth-muscle cells. It causes immunosuppression and angiogenesis, which makes the cancer more invasive. TGF-β also converts effector T-cells, which normally attack cancer with an inflammatory (immune) reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction. Manipulation of the immune response by a tumor. Tumors can protect themselves from the immune response by secreting immunomodulatory cytokines, such as TGF-β, which suppress the inflammatory response and recruit regulatory T cells (Treg) into the tumor tissue. The combined effect of TGF-β and IL-10 made by the regulatory T cells is to suppress the actions of effector CD8 T cells and CD4 TH1 helper cells that are specific for tumor antigens.

Biologic tumor therapies

UNCONJUGATED MONOCLONAL ANTIBODIES Antibodies bind to a cell-surface antigen of the tumor cells. The Fc regions of the antibodies engage FcγRIII on an NK cell, which then becomes activated to kill the tumor cell. Shown here are antibodies that function purely as antibodies, not as delivery systems for chemotherapy or radiation therapy. "Year approved" refers to their approval for medical use in the United States by the US Food and Drug Administration.

CONJUGATED MONOCLONALS

surgical removal of the primary tumor Treating cancer with immunotherapy (breaking the tolerance!) immunotherapy primary tumor Tumor vaccines metastases surgical removal of the primary tumor tumor antigen DC adjuvant DC therapy CTL Még az immunrendszer ellenőrző tevékenységét elkerülni, és osztódni képes rákos sejtek is hordoznak valamiféle antigéneket. Ha az ilyen antigének ellen immunválaszt tudnánk kiváltani, az lehetővé tenné a rák gyógyításást. Pontosan ez a célja a napjainkban folyó klinikai vizsgálatoknak. Terápia rák elleni védőoltással A tumor antigéneket és az immunrendszer működését fokozó anyagokat kombináló kezelés a rák elleni védőoltás ígéretét hordozza. Dendritikus sejt terápia Ezzel a módszerrel dendritikus sejteket izolálnak a szervezetből, majd miután megfelelő antigéneket adnak a sejtekhez (amelyeket azok felvesznek), visszajuttatják őket a testbe, hogy megkezdjék a harcot a rák ellen. T-sejt terápia Ölő T-sejteket és dendritikus sejteket izolálnak a szervezetből és tumor antigénekkel stimulálják működésüket. Az aktivált ölő T-sejteket ezután visszajuttatják a szervezetbe, hogy támadást indíthassanak a rák ellen. Az immunterápia önmagában nem képes nagyméretű rákos daganatok elpusztítására. Ezeket a daganatokat először sebészeti úton távolítják el, azután jöhet az immunterápia, hogy eltakarítsa a maradék rákos sejtekből álló apró áttáteket. Így alkalmazva a kezelés hatékony módszernek ígérkezik a rák kiújulásának megakadályozására. (Antitest terápia Az antitest terápia a tumor antigéneket felismerő antitestek alkalmazását jelenti. ) Az immunterápiák többsége még mindig kísérleti fázisban van. De vannak már olyanok, melyeket a gyakorlatban is alkalmaznak, mint például bizonyos rákok ellen kifejlesztett antitest terápiákat. A múltban tehetetlenül álltunk az olyan betegek mellett, akiknek egész szervezetében szétterjedt a rák. Az immunterápia azonban rajtuk is segíthet majd. DC + tumor Ag DC therapy monoclonal antibodies Tumor specific CTL