Immune response to cancer

Normal cellmutation

Loss of growth control Tumor cells

Localized (benign)

Invasive (malignant)(transformation)

Tumor rejection in mouse

Mouse

carcinogen

Tumor

Mouse (inbred, same MHC)

Tumor

Irradiated tumor cellsinduce immune responsetoward the tumor.

The protection can betransferred by T cells, not by serum.

Tumor antigens

Mutations alters the normal cellular protein to create new antigenic peptide.

Tumor specific transplantation antigens (TSTAs)

*

*

MHC

*

*

*

MHC

*

Idiotypic sequence of antigen receptor is TSTA for B and T cell tumors.

Difference between differentantigen binding sites

Antigen receptors may remain expressed by the B and Tcell tumors. The antigenbinding site is a unique feature (antigen) for the tumor.

Difference of the same IgC region betweendifferent alleles in a population.

Tumor associated transplantation antigens (TATAs)Tumor cells can express proteins of male germ cells.

Male germ cells do not express MHC and do not normally present these antigens.

Reactivation of genes normally expressed during embryonic development.

Overexpression of normal self antigen.

Oncofetal tumor antigens (alpha-fetoprotein, AFP; carcinoembryonic antigen, CEA)

Immune surveillance?

Tumors may not present tumor antigen/MHC.

Tumors tend to be genetically unstable and may lose the Expression of MHC or the tumor antigen.Such variants would have selective advantage.

Brown staining: HLA

Many cells in the prostate cancer sectionhave lost MHC expression.

MHC-loss variants could become a target for NK cells.

Nude mice are deficientIn T cells. They have higherlevels of NK cells.

Antibody binding to tumor antigens could induce endocytosis and degradation of the antigen.

Antigen presentation in the absence of co-stimulationmay cause T cell anergy.

Tumors do not induce inflammation.Inflammatory cytokines are needed to activate APCsto express co-stimulatory molecules.

Antibodies can modulate tumor antigens.

Tumors may suppress immune response.

Many tumors produce immunosuppressive cytokines such as TGF-, IL10, which inhibits TH1 and cell-mediated immune responses.

Tumors may be inaccessible to immune system.

Tumors may grow in nodules surrounded by collagens and fibrin.

Type I Hypersensitivity (immediate-type hypersensitivity, allergy)

IgE-mediated immune response to harmless environmental antigens (allergens).

Aeroallergens: pollens

Food allergens: nuts, seafood

Latex allergens

Pharmaceuticals: penicillin

Insect venom allergens: wasp venom

Der p 1 (dust mite)

Substilisin (bacteria)

Papain (Papaya)

Proteins (T cell response)

Low molecular weight

Soluble

Stable

Other features

Enzymatic activity may facilitate the entry of allergens.

Allergens are presented by DCs to CD4 T cells.

Antigen (microbial)

DCs

inflammation

CD4 T cells

IL12

TH1

IFN-, IL-2

Cell-mediatd immunity

allergen

No inflammation

DCs

CD4 T cells

TH2

Default?

IL4, IL5, IL13

IgE, allergic response

Low dose

IgE activates mast cells and basophils.

High affinity FcRI

(Basophil)

Degranulation Inflammatory mediatorscytokines

Mucosal tissues

Histamine(immediate)

Contraction of smooth muscles

Vascular permeability

Mucus secretion

LeukotrienesProstaglandins

(potent, lasting)

Cytokines

IL4, IL13 TH2

IL5, IL3, GM-CSF eosinophil

TNF- inflammation

Mast cell mediators

Recruitment of eosinophils.HSC

IL5, IL3, GM-CSF

Eosinophil

Bone marrow

Eosinophil (eosinophilia)blood

Eosinophil

Eotaxin 1 (CCL11) Eotaxin 2 (CCL24) Eotaxin 3 (CCL26)

CCR3 (eosinophil)

Mucous tissue

Cell adhesion molecules

chemokines

Activated eosinophil-FcR for IgE, IgA, IgG

Activated eosinopil-FcR-IgE Allegen

Inflammatory mediators

IL5, IL3, GM-CSF (survival, activation)

Eosinophil degranulation

Tissue damage

Allergic response

Basophils are recruited to allergic site.

Basophil Histamine, IL4, IL13

IL13 induces mucous secretion, bronchoconstriction, fibrotic process.

Primary exposure to allergen sensitize mast cells

Allergen

DC

CD4 T cell

TH2B cell

IgE

Mast cell-IgE

Sensitized mast cell

Re-exposure elicits allergic response.

Allergen

Mast cell-IgE (basophil-IgE)

Histamine, leukotrienes, Prostaglandins, IL13

Smooth muscle constrictionVasodilation, Vascular permeability

Acute phase (within minutes) Late phase (4-48 hr)

Eosinophilsneutrophils

Degranulate

TH2 cells

TH2 cytokines

Allergic responseTissue damage and remodeling

Chronic response (e.g. allergic asthma)

Peak expirationflow rate

Asthmatic response

8 hours

Mucous plugin airway

EosinophilsNeutrophilsLymphocytesin bronchial wall

The route and dose of allergen entry determineoutcome of allergic reaction.

allergen

Blood circulation

gut

Widespread activationof mast cells

Widespread vasodilationAirway constriction

Systemic anaphylaxis(anaphylactic shock)

epinephrine

Food (peanut) Drug (penicillin)

Penicillin can conjugates to proteins.

protein carrier

Hapten (antigen)

immunogen

immunizationimmunization

No response

Penicillin-protein conjugates are immunogens.

Signal 1

TH

Signal 2CD40-CD40L

cytokine

Activation

B cell

Allergen

skin

Insect bite

Wheal-and-flare

WidespreadEdematous response

Allergen (food, pepsin resistant protein)

gut

skin

circulation

DisseminatedWheal-and-flare(hives, urticaria)

Contraction of intestineOutflow of fluid into gut

Vomitingdiarrhea

Prolonged inflammation

Eczema, atopic dermatitis(persistent skin rash)

Allergen (pollen, etc)

Upper airway

Allergic rhinitis

eye

Allergicconjunctivitis

Lower airway

Allergic asthma

Genetic factors of allergy

Atopy

Chromosome 11: FcRI chain

Chromosome 5: Cluster of TH2 cytokines (IL4, IL5, IL13), IL-3, GM-CSF

IL-12 p40

Adrenergic receptor (smooth muscle responsiveness)

Chromosome 6: Class II MHC. Presentation of allergen peptides

ADAM33: Metalloproteinase expressed by bronchial smooth muscle cells and lung fibroblasts. Airway remodeling in asthma.

Chromosome 12:STAT6. IL4R signaling.

Environmental factor

Hygiene hypothesis

Exposure to infectious disease in early childhood protects against atopy.

TH0

DC

TH1 TH2

DC

IL12

TH0

TH1 TH2

inflammation

clean unclean

Inverse correlation between helminth infection and allergy?

Exposure to allergen in early childhood.

Treatment

Desensitization:Injection with increasing doses of allergen.

High density antigen presentation

TH0

TH1 TH2

Low density antigenpresentation

IgG IgE

Compete for allergen

(Unmethylated CpG?)

Anti-IgE antibodies (omalizumab)

Antihistamines block histamine H1 receptor.

Corticosteroids suppress inflammation.

Relevant part in book

Type I hypersensitivity: page 361-378.