Transcript Anti-tumor immunity

Antitumour immunity
J. Ochotná
Malignant transformation
• Failure of cell division regulation and regulation
of cells "social" behavior
• The uncontrollable proliferation, dissemination
to other tissues
• Mutations in protoonkogenes and antionkogenes
Tumour antigens
Tumour specific antigens (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 oncogenic viruses proteins
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
Tumour associated antigens (TAA)
• expressed also on normal cells
• differences in quantity, time and local of 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
d) EPCAM
• epithelial cell 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
Hypothesis of immune control
• tumor cells normally arise in tissues and are eliminated
by T lymphocytes
•
DC are necessary for activation of antigen specific mechanisms
• cancer-associated antigens are processed by DC and
presented to T lymphocytes in complexes with HLA I. and II.
• predominance of TH1 (IFN  TNF); IFN support DC
maturation
• tumor cells are eliminated by TC
• TH2 activation → support B lymphocytes→ tumor specific
antibodies (involved in the ADCC)
•
tumor cells are also destroyed by NK cells (low MHC gpI
expression on tumor cells)
•
interferons - antiproliferative, cytotoxic effect on tumor cells
- INF - DC maturation
Mechanisms of tumor resistance
 high variability of tumor cells

low expression of tumor antigens

sialylation

tumor cells do not provide costimulatory signals → T lymphocyte
anergy

some antitumor substances have a stimulating effect on tumor

production of factors inactivating T lymphocytes

expression of FasL → T lymphocyte apoptosis

inhibition of the dendritic cell functions and durability (NO, IL-10, TGF-
Transplantation
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 other species
• implant - artificial tissue compensation
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 APC
• 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.
Recognition of alloantigens
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 (determination 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 reaction - test for T lymphocytes alloreactivity
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
b) genotyping: PCR – SSP
PCR – SSO
PCR – SBT
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 T lymphocyte alloreactivity
• 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
One-way MRL
•determination of recipient T lymphocytes reactivity against
donor cells
•donor cells treated with chemotherapy or irradiated lose
the ability of proliferation
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
Hyperacute rejection
• minutes to hours after transplantation
• antibodies 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
Hyperacute rejection
Accelerated rejection
Accelerated rejection
• 3 to 5 days after transplantation
• caused by antibodies that don‘t activate complement
• cytotoxic and inflammatory responses activated
by antibodies which bind 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 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
Chronic rejection
• occures after 2 months from 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 β)
• replacement of functional tissue by fibrous tissue,
endothelial damage →impaired perfusion of graft → gradual
loss of its function
dominating findings: vascular damage
Bone marrow transplantation
• hematopoetic stem cell collection
• myeloablation
• transplantation
• engraftment
• rejection
• graft versus host disease
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)
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
Chronic GVHD
• months to years after transplantation
• TH2 lymphocytes infiltration of tissues and organs, production
of alloantibodies and production of 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 (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)
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 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
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
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
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)
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
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
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
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 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