Tumor immunity

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

Tumor cells
- Unlimited growth (loss of contact inhibition)
- Growth without stimulating growth factors
- Immortality (cancer cells have not a limited number of generations as normal
- Often altered number of chromosomes as frequent chromosomal alteration
- TSA ...

Mutagens (carcinogens) - physical (eg various forms of radiation)
                       - chemical (eg aromatic hydrocarbons)
                       - biological (mainly various oncogenic viruses)
Protoonkogens - promitotic (promoting cell division)
encode - growth factors and other substances affecting cell growth
        - receptors for growth factors
        - signaling proteins (eg protein kinase)
        - factors involved in the regulation of gene expression
         (transcription factors)
        - proteins that regulate apoptosis and cell adhesiveness

For the malignant transformation is enough mutation in one copy of the gene
protoonkogen (dominant oncogenes).

Oncogenes - mutated protoonkogeny ( "carcinogenic" effect)
            - point mutations, chromosome alteration (gene transfer to the
             highly active promoter), gene amplification
Antionkogens - tumor-suppressor genes (suppress the emergence of tumor
              - regulation of cell cycle
              - for the malignant transformation should be excluded from
               function both copies of the gene (recessive oncogenes)
              - TP53, RB1
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
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

c) antigen HER2/neu
   - receptor for epithelial growth factor
   - mammary carcinoma
   - 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)
Anti-tumor immune mechanisms

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
  dendritic cells activated in the inflammatory environment

- If tumor cells detected, in defense may be involved non-specific mechanisms
(neutrophilic granulocytes, macrophages, NK cells) and antigen-specific
mechanisms (complement activating antibodies or ADCC, TH1 and TC)
- cancer-associated antigens are processed by APC and recognized by
  T lymphocytes in complex with HLA I. and II. class with providing costimulus

- 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 (ADCC) action
  perforin and induction of apoptosis (FasL)
Cytotoxic mechanisms of NK cells
Mechanisms of resistance of tumors to the
immune system
- high variability of tumor cells

- low expression of tumor antigens

- sialylation

- tumor cells signals do not provide costimulus → 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-
Tumor immunotherapy

Therapy - surgical removal of tumor
        - chemotherapy or radiotherapy
        - immunotherapy

Immunotherapy - induction of anti-tumor immunity, or the use of immune
                mechanisms to targeted direction of drug to the tumor site
Immunotherapy using antibodies

Function of antibodies - opsonization
                       - activation of complement
                       - induction of ADCC
                       - carriers of drugs or toxins

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
Immunotherapy using cell-mediated
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 antigenpresenting function of tumor cells
- genetic modification of tumor cells - expression of CD80, CD86
                                      - production of IL-2, GM-CSF
- modified cells are irradiated and returned to the patient
4) tumor vaccines
- in vitro stimulation of TH1 cells and TC with tumor antigens

5) 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

6) immunotherapy by T lymphocytes of donor
- after allogeneic transplantation
- causing graft-versus-host

7) immunotherapy by products of the immune system
- IL-2 - renal cell carcinoma
- IFN - hematoonkology
= 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
- differences in donor-recipient MHC gp and secondary histocompatibility Ag

- alloreactivity of T lymphocytes - the risk of rejection and graft-versus-host

- direct detection 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.
Testing before transplantation

Compatibility in the system ABO -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
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
DNA typing of HLA class II: DR, DP, DQ by PCR.
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
Mixed lymphocyte reaction (MRL)
● determination of alloreactivity T lymphocytes

● mixed donor and recipient lymphocytes → T lymphocytes after
  recognition allogeneic MHC gp activate and proliferate

One-way MRL
● determination of reactivity recipient T lymphocytes against donor cells

● donor cells treated with chemotherapy or irradiated lose the ability
  of proliferation

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
Hyperacute rejection
● minutes to hours after transplantation
● antibodies type of immune response

● 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,
  thrombi, accumulation of neutrophil granulocytes.

● negat. 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

● negat. cross match before transplantation, ABO compatibility
Acute rejection
● days to weeks after the transplantation or after a lack of immunosuppressive
● cell-mediated immune response

● recipient TH1 and TC cells response against Ag of graft tissue
● infiltration of lymphocytes, mononuclears, 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 responses with
production allantibodies, pathogenetic role of cytokines and growth factors
(TGF β)

● replacement of functional tissue by connective tissue, endothelial damage
→impaired perfusion of graft → gradual loss of its function

dominating findings: vascular damage
Graft-versus-host (GVH)
● 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 (alooreactivity)

Acute GVH

● 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
● months to years after transplantation

● infiltration of tissues and organs by TH2 lymphocytes, creating of
  allantibodies 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
Graft versus leukemia (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 of mother and
allogenic fetus
● fetal cells have on the surface alloantigens inherited from his father

Tolerance of fetus by mother allow the following mechanisms:
● the relative isolation of the fetus from maternal immune system
(no mixing of blood circulation)

● trophoblast - immune barrier witch protect against mother alloreaktiv
                T lymphocytes
              - don´t express classical MHC gp, expresses non-classical
                HLA-E and HLA-G
● depression of TH1 immune mechanisms in pregnancy

Complications of pregnancy: production of anti-RhD antibodies by RhD- mother
carrying RhD+ fetus (hemolytic disease of newborns)
Immunopathological reaction
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 - a response based on IgE antibodies

Type II reaction - a response based on antibodies, IgG and IgM

Type III reaction - a 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:
● complement activation
● binding to Fc receptors on phagocytes and NK cells

Transfusion reactions in administration of incompatibile 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
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 complex formation (reaction type III)
● caused by IgG antibodies → bind to antigen → creation of immune

● 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

● 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
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)

Postreptokoková Glomerulonephritis
Immunopathological delayed-type reaction
(reaction type IV)
● delayed-type hypersensitivity (DTH)
● local reaction caused by TH1 cells and monocytes / macrophages

Experimental model:
● intradermal immunization by antigen → creation of antigen-specificTH1 cells
● after a few weeks intradermal administration of antigen → creates local
  reaction - TH1 cells and macrophages

Tuberculin reaction

Tissue damage in tuberculosis and leprosy

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