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Anti-tumor immunity

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Anti-tumor immunity Regulatory T cells prevents removal of cancer cells and thus contribute to the development of the tumor. Regulatory T cells prevents removal of ... – PowerPoint PPT presentation

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Title: Anti-tumor immunity


1
  • Anti-tumor immunity

2
  • Malignant transformation
  • Failure of regulation of cell division and
    regulation of "social" behavior of the cells
  • The uncontrollable proliferation, dissemination
    to other tissues
  • Mutations in protoonkogenes and antionkogenes

3
  • Mutagens (carcinogens)
  • - physical (eg various forms of radiation)
  • - chemical (eg aromatic
    hydrocarbons)
  • - biological (mainly various
    oncogenic
    viruses)

4
Tumor antigens Antigens specific for tumors
(TSA) a) complexes of MHCgp I with abnormal
fragments of cellular proteins - chemically
induced tumors - leukemia with chromosomal
translocation b) complexes of MHC gp with
fragments of proteins of oncogenic viruses -
tumors caused by viruses (EBV, SV40,
polyomavirus) c) abnormal forms of
glycoproteins - Sialylation of surface
proteins of tumor cells d) idiotypes of myeloma
and lymphoma - clonotyping TCR and BCR
5
Antigens associated with tumors (TAA) - also on
normal cells - differences in quantity, time and
local expression - auxiliary diagnostic
markers a) onkofetal antigens - on normal
embryonic cells and some tumor cells -
?-fetoprotein (AFP) - hepatom -
canceroembryonal antigen (CEA) - colon
cancer b) melanoma antigens - MAGE-1,
Melan-A
6
  • c) antigen HER2/neu
  • - receptor for epithelial growth factor
  • - mammary carcinoma
  • d) EPCAM
  • - epithelial adhesion molecule
  • - metastases
  • e) differentiation antigens of leukemic cells
  • - present on normal cells of leukocytes
    linage
  • - CALLA -acute lymphoblastic leukemia (CD10
    pre-B cells)

7
  • Anti-tumor immune mechanisms
  • Hypothesis of immune control
  • tumor cells normally arise in tissues and are
    eliminated by T lymphocytes (probably wrong
    hypothesis)
  • Defensive immune response
  • tumor cells are weakly immunogenic
  • occurs when tumor antigens are presented to T
    lymphocytes by activated dendritic cells
  • in defense may be involved non-specific
    mechanisms (neutrophilic granulocytes,
    macrophages, NK cells, interferons) and
    antigen-specific mechanisms (complement
    activating antibodies or ADCC, TH1 and TC)

8
Regulatory T cells prevents removal of cancer
cells and thus contribute to the development of
the tumor.
9
  • DC are necessary for activation of antigen
    specific mechanisms
  • cancer-associated antigens are processed by DC
    and recognized by T lymphocytes in complex
    with HLA I. and II. class with providing
    costimulus signals
  • predominance of TH1 (IFN ??? TNF??)
  • specific cell-mediated cytotoxic reactivity TC
  • activation TH2 ? support B lymphocytes? tumor
    specific antibodies (involved in the ADCC)
  • tumor cells are destroyed by cytotoxic NK cells
    (low MHC gpI expression on tumor cells)
  • interferons - antiproliferative, cytotoxic
    effect on tumor cells -
    INF? - DC maturation

10
  • Mechanisms of tumors resistance to immune system
  • high variability of tumor cells
  • low expression of tumor antigens
  • sialylation
  • tumor cells do not provide costimulus signals ?
    T lymphocyte anergy
  • 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-??

11
Tumor immunotherapy Therapy - surgical
removal of tumor - chemotherapy or
radiotherapy - immunotherapy Immu
notherapy - induction of anti-tumor immunity, or
the use of immune
mechanisms to targeting drugs
to the tumor site
12
Immunotherapy using antibodies Antibodies
functions - opsonization
- activation of complement
- induction of ADCC
- carriers of
drugs or toxins
13
1) Monoclonal antibodies - against TAA - mouse
and humanised antibodies - imunotoxins,
radioimunotoxins - the possibility of damage
surrounding tissues - HERCEPIN - Ab against
HER2/neu, breast cancer - RITUXIMAB - Ab against
CD20, lymphoma 2) Bispecific antibodies - bind a
tumor antigen and the T lymphocyte or NK cell -
Fc fragment of antibody binds to Fc receptors on
phagocytes and NK cells 3) Elimination of
tumor cells from the suspension of bone
marrow cells using monoclonal antibodies
for autologous transplantation
14
Immunotherapy using cell-mediated mechanisms 1)
stimulation of inflammation at the tumor
site 2) stimulation of LAK and TIL - isolation
of T and NK cells, stimulation by cytokines, and
return to the patient - LAK (lymphokine
activated killers) - TIL (tumor infiltrating
lymphocytes) 3) improving of tumor cells
antigenpresenting function - genetic modification
of tumor cells - expression of CD80, CD86

- production of IL-2, GM-CSF - modified cells are
irradiated and returned to the patient
15
4) the dendritic cell immunotherapy- in vitro
cultivation of monocytes in an appropriate
cytokine environment (GM-CSF, IL-4) ?
transformation into dendritic cells- cultivation
of dendritic cells with tumor antigens
16
  • 5) tumor vaccines
  • - in vitro stimulation of TH1 cells and TC with
    tumor antigens
  • 6) immunotherapy by donor T lymphocytes
  • - after allogeneic transplantation
  • - causing graft-versus-host disease
  • 7) immunotherapy by immune system products
  • - IL-2 - renal cell carcinoma
  • IFN ? - hematoonkology
  • 8) Anti CTLA-4 antibody
  • - Treg inhibition, longer activation of effector
    T cells

17
Transplantation
18
  • Transplantation
  • transfer of tissue or organ
  • autologous - donor recipient
  • syngeneic - genetically identical donor
    recipient (identical
    twins)
  • allogeneic - genetically nonidentical donor of
    the same species
  • xenogenic - the donor of another species
  • implant - artificial tissue compensation

19
Allogeneic transplantation - differences in
donor-recipient MHC gp and secondary
histocompatibility Ag - alloreactivity of T
lymphocytes - the risk of rejection and
graft-versus-host - direct recognition of
alloantigens recipient T lymphocytes recognize
the different MHC gp and non-MHC molecules on
donor cells - indirect recognition of
alloantigens - APC absorb different MHC gp from
donor cells and present the fragments to T
lymphocytes - CD8 T cells recognize MHC gp
I. - CD4 T cells recognize MHC gp II.
20
Recognition of alloantigens
21
Tests prior to transplantation ABO
Compatibility -risk of hyperacute or accelerated
rejection formation of Ab against A or B Ag on
graft vascular endothelium) HLA typing
(determining of MHC gp alelic forms) phenotyping
and genotyping by PCR Cross-match -
lymfocytotoxic test - testing preformed Ab (after
blood transfusions, transplantation, repeated
childbirth) Mixed lymphocyte test - testing
of alloreactivity T lymphocytes monitor for
reactivity of lymphocytes to allogeneic HLA
22
HLA typing a) phenotyping Evaluation of HLA
molecules using typing serums Typing antiserums
alloantiserums of multipar (created cytotoxic
Ab against paternal HLA Ag of their children),
serum of patients after repeated blood
transfusions, monoclonal Ab - molecules HLA
class I separated T lymphocytes - molecules HLA
class II separated B lymphocytes b)
genotyping evaluation of specific alleles
23
  • Cross-match test
  • determination of preformed antibodies
  • recipient serum donor lymphocytes rabbit
    complement ? if cytotoxic Ab against donor
    HLA Ag are present in recipient serum (called
    alloantibodies Ab activating complement) ?
    lysis of donor lymphocytes. Visualization of
    dye penetration into lysis cells.
  • positive test the presence of preformed Ab ?
    risk of hyperacute rejection! ?
    contraindication to transplantation

24
  • Mixed lymphocyte reaction (MRL)
  • determination of alloreactivity T lymphocytes
  • mixed donor and recipient lymphocytes ? T
    lymphocytes after recognition allogeneic MHC
    gp activate and proliferate
  • the total proliferation of lymphocytes is
    measured by adding 3H-thymidine to the
    culture medium and monitoring its integration
    to DNA of new cells

25
  • One-way MRL
  • determination of recipient T lymphocytes
    reactivity against donor cells
  • donor cells treated with chemotherapy or
    irradiated lose the ability of proliferation

26
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 much APC
(skin) The activity of the immune system of the
recipient - the immunodeficiency recipient has a
smaller rejection reaction immunosuppressive
therapy after transplantation suppression of
rejection Status transplanted organ - the length
of ischemia, the method of preservation,
traumatization of organ at collection
27
  • Hyperacute rejection
  • minutes to hours after transplantation
  • antibodies type of immune response
  • mechanism
  • in recipients blood are present before
    transplantation preformed or natural Ab (IgM
    anti-carbohydrate Ag) ? Ab Ag of graft (MHC
    gp or endothelial Ag) ? graft damage by
    activated complement (lysis of cells)
  • the graft endothelium activation of coagulation
    factors and platelets, formation thrombi,
    accumulation of neutrophil granulocytes
  • prevention
  • negat. cross match before transplantation, ABO
    compatibility

28
  • Accelerated rejection
  • 3 to 5 days after transplantation
  • caused by antibodies that dont activate
    complement
  • cytotoxic and inflammatory responses activated
    by antibodies binding to Fc-receptors on
    phagocytes and NK cells
  • prevention
  • negative cross match before transplantation, ABO
    compatibility

29
  • Acute rejection
  • days to weeks after the transplantation or after
    a lack of immunosuppressive treatment
  • cell-mediated immune response
  • mechanism
  • recipient TH1 and TC cells response against Ag
    of graft tissue
  • infiltration of lymphocytes, mononuclears,
    granulocytes around small vessels ?
    destruction of transplant tissue

30
  • 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 responses with production alloantibodies,
    pathogenetic role of cytokines and growth
    factors (TGF ß)
  • replacement of functional tissue by connective
    tissue, endothelial damage ?impaired
    perfusion of graft ? gradual loss of its
    function
  • dominating findings vascular damage

31
Bone marrow transplantation
  • hematopoetic stem cell collection
  • myeloablation
  • transplantation
  • engraftment
  • rejection
  • graft versus host disease

32
  • Graft-versus-host disease (GVHD)
  • after bone marrow transplantation
  • GVHD also after blood transfusion to
    immunodeficiency recipients
  • T-lymphocytes in the graft bone marrow recognize
    recipient tissue Ag as foreign
    (alloreactivity)

33
  • Acute GVHD
  • days to weeks after stem cells transplantation
  • damage of liver, skin and intestinal mucosa
  • Prevention appropriate donor selection, T
    lymphocytes removal from the graft and
    effective immunosuppression

34
  • Chronic GVHD
  • months to years after transplantation
  • TH2 lymphocytes infiltration of tissues and
    organs, production of alloantibodies and
    production of cytokines ? fibrotization
  • process like autoimmune disease vasculitis,
    scleroderma, sicca-syndrome
  • chronic inflammation of blood vessels, skin,
    internal organs and glands, which leads to
    fibrotization, blood circulation disorders and
    loss of function

35
  • Graft versus leukemia effect (GVL)
  • donor T lymphocytes react against residual
    leukemick cells of recipient
  • mechanism is consistent with acute GVHD
  • associated with a certain degree of GVHD
    (adverse reactions)

36
Immunopathological reactions
37
Classification by Coombs and Gell Immunopathologi
cal 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 IgG and IgM antibodies Type III reaction -
response based on the formation of immune
complexes Type IV
reaction - cell-mediated response
38
  • Immunopathological reaction based on IgG and IgM
    antibodies (reaction type II)
  • Cytotoxic antibodies IgG and IgM
  • complement activation
  • ADCC
  • binding to phagocytes and NK cells Fc receptors
  • Haemolytic reactions after transfusion of ABO
    incompatible blood
  • Binding of antibodies to antigens of
    erythrocytes ? activation of the classical way
    of complement ? cell lysis
  • Hemolytic disease of newborns
  • Caused by antibodies against RhD antigen

39
  • Autoimmune diseases
  • organ-specific cytotoxic antibodies
    (antibodies against erythrocytes,
    neutrophils, thrombocytes, glomerular basement
    membrane ...)
  • blocking or stimulating antibodies Graves
    - Basedow disease - stimulating antibodies
    against the
    TSH receptor

  • Myasthenia gravis - blocking of
    acetylcholin receptor? blocking
    of neuromuscular
    transmission
  • Pernicious anemia - blocking of vitamin B12
    absorption
  • Antiphospholipid syndrome - antibodies
    against fosfolipids
  • Fertility disorders - antibodies against
    sperms or oocytes

40
  • Immunopathological reactions based on immune
    complex formation (reaction type III)
  • caused by IgG antibodies ? bind to antigen ?
    creation of immunecomplexes
  • immunocomplexes - bind to Fc receptors on
    phagocyte
  • - activate
    complement
  • immune complexes (depending on the quantity and
    structure) are eliminated by phagocytes or
    stored in tissues
  • pathological immunocomplexes response arises
    when is a large dose of antigen, or antigen in
    the body remains
  • immune complexes are deposited in the kidneys
    (glomerulonephritis), on the endothelial cells
    surface (vasculitis) and in synovial joints
    (arthritis)

41
  • Serum sickness
  • after 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 antibodies against inhaled antigens (molds,
    pollens)
  • Poststreptococcal glomerulonephritis

42
  • Immunopathological delayed-type reaction
    (reaction type IV)
  • delayed-type hypersensitivity (DTH)
  • local reaction caused by TH1 cells and monocytes
    / macrophages (physiologically elimination
    of macrophage intracellular parasites)
  • antigen immunization ? formation of antigen
    specific TH1 cells (and memory cells)
  • 12-48 hours after next contact with antigen
    arise local reaction granuloma (TH1 and
    macrophage infiltration)
  • Tuberculin reaction
  • Tissue damage in tuberculosis and leprosy
  • Sarcoidosis

43
Subtype IV - Cellular cytotoxic response (Tc
activation)
  • similar to DTH reaction
  • TH1 cells activate CD8 T lymphocytes
  • viral rashes
  •  viral hepatitis
  • acute rejection of transplanted organ
  • some autoimmune thyroiditis
  • contact dermatitis

44
  • 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

45
Patch test
  • patch test is a method used to determineif 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

46
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