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

2. 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 antibiotics
ACQUIRED
Due to infectious diseases
AIDS
Other viral infections
Malnutrition
Artificial immunosuppression
Drugs
Radioactive irradiation

3. 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

4. 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

5. 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)

6. 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

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

8. 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)

9. 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

10. TUMOR IMMUNOLOGY

11. GLOBAL MORTALITY RATE

12. What is cancer?
Normal tissue
Benign tumor
Cancer

13. Most frequent sites of tumors
Lungs
Liver
Stomach
Colon
Pancreas

14. 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

15. 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

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

18. 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

19. 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.

20. 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.

21. Biologic tumor therapies

22. 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.

23. CONJUGATED MONOCLONALS

24. 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