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Immunology Jenny > 14. Antitumor immunity; immunodeficiency > Flashcards

14. Antitumor immunity; immunodeficiency Flashcards

1
Q

How tumors escape control

A
  1. Fast proliferation
  2. Mutations
  3. High diversity (“mini evolution”)
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2
Q

Oncogenes

A
  • encode proteins that can induce malignant transformation
  • viral (v-onc)
  • exons
  • modulate proliferation/apoptosis
  • well-conserved structures

proto-oncogenes -> function in physiologically intact cells, cellular (c-onc), exons or introns

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3
Q

Potential sources of tumor ags

A

Oncogene product

  • mutation in RAS codon 12 (pancreatic cancer)
  • bcr/abl proten (CML)

Embryonic proteins
- MAGE family (melanoma, brest cc.)

Viral proteins

  • EBV (Hodgkin’s lymphoma)
  • Hep. B (hcc)

Tissue specific ag
- Tyrosinase (melanoma)

Mutant tumor suppressor protein
- p53 (many cancers)

Idiotypic epitopes
- TCR idiotypes (T cell lymphoma)

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4
Q

Types of tumor ags

A

TSA - tumor cells only, presented with MHCI, evoke Tcyt response (FasL)
TAA - tumor cells and some normal cells

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5
Q

Production of TSA

A
  • Chemical carcinogens
  • X-rays
  • Somatic mutations
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6
Q

MAGE-1

A

= melanoma ag-encoding gene

In:

  • 40% melanomas
  • 20% breast cc.
  • 30% lung small cell cc.
  • embryonal protein
  • expression is de-repressed in tumors
  • present in some normal cells as well (e.g. testis)
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7
Q

TAAs

A
  • Oncofetal ags

- Differentiation specific ags (DSA)

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8
Q

Oncofetal ags

A
  • Normally expressed during a specific phase of embryogenesis
  • Practically in mature, differentiated tissues
  • Not immunogenic
  • No functional role in tumor immunity
  • Significance: diagnostic, prognostic markers
  • Serum cc. correlates with tumor mass, level of differentiation and response to therapy
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9
Q

Ideal tumor markers

A
  • Specific for tumor type
  • Released only in response to tumor
  • Results proportional to tumor mass
  • Quantitatively reflects tumor response
  • Elevated even with low tumor burden
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10
Q

Carcinoembryonic ag (CEA)

A
  • discovered in adenocc of colon
  • group of heterogenous glycoproteins (mw. 200 kD)
  • Normally in embryotic and fetal digestive tissues
  • Detected by RIA or IHC
  • Elevated (over 5ng/ml) in GI, breast, pancreas, lung tumors and alcoholic cirrhosis, inflammations
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11
Q

alpha-fetoprotein (AFP)

A
  • increased in hcc and malignant teratomas

- increased in serum in metastatic tumors in liver and acute hepatitis

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12
Q

Host immune response to tumor (experimental)

A
  • Colony inhibiton of tumors by sensitized lymphocytes
  • Tumors extract induce lymphocyte blast transformation
  • Lymphocyte-enhanced cytotoxicity
  • Macrophage-enhanced phagocytosis
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13
Q

Host immune response to tumors (clinical)

A
  • Spontaneous regression
  • Regression of tumors in response to sublethal doses of chemotherapy
  • Regression of metastasis from resection of primary tumor
  • Mononuclear cell infiltration
  • High incidence of tumor after clinical immunosuppression
  • High incidence of tumor in immunodeficiency
  • Increased incidence of tumor in aging
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14
Q

Cellular effectors that mediate immunity

A

Tcyt -> protect against virus-associated neoplasms (e.g. EBV)

NK ly -> lysis of tumor cells without prior sensitization via NKR-P1
(only tumor cells without MHC are lysed as activity is blocked by Ly49 receptor that recognizes MHCI)

IL-2 (from T cell) -> NK lymphocytes can lyse a variety of tumors (complement)

Macrophages -> selective cytotoxicity against tumor cells (ROS, TNFalpha)

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15
Q

Humoral mediators against tumors

A

Activation of complement

Induction of ADCC by NK lymphocytes

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16
Q

Immunodeficiencies role in cancer development

A

Congenital immunodeficiency -> 5% develop cancer (200x risk)

Immunodepressed patients -> 80x risk

  • AIDS
  • Lymphomas
  • Chronic infections mononucleosis
  • Malignant lymphomas
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17
Q

How tumors escape immunity

A
  • Shedding of tumor ags (soluble)
  • Loss of HLA ags
  • No costimulation -> anergic T-cell -> apoptosis of T-cell
  • Selective outgrowth of ag negative variants
  • Expression of local inhibitory molecules (e.g. TNFbeta, FasL)
  • Immunosuppression (chemicals, radiation, TGFbeta)

-> only NK lymphocytes can detect them, but these are no present everywhere

18
Q

Effects of NK-lymphocytes

A

Activation of killer inhibitory receptor (KIR) on NK -> No apoptosis of target cell

Activation of killer activated receptor (KAR) on NK -> Apoptosis of target cell

19
Q

Failure of immuno response to tumor

A
  • Tumors in areas not accessible to effector cells (e.g. eye, CNS)
  • Antigenic modulation: ags of tumor cells may undergo several changes
  • Blocking factors: immune complexes or cytophilic abs can mask tumor ags/prevent binding by effector cells or lytic abs
20
Q

Antitumor immunotherapy

A
  1. Tumor cell vaccines - increasing antitumor T cells with autologous or allegenic tumor cells
  2. Immunization with tumor-specific peptides - only for tumors where TAA have been cloned and peptides synthesized
  3. Cytokine therapy - increasing the levels of some cytokines (Il-2, IFN, CM-CSF, IL-7, IL-12)

Problems:

  • short life-time
  • toxicity
  • non-specific cytokines
  1. Monoclonal abs - to deliver immunotoxins, radioisotopes. Bivalent abs recognize both T cells and TAA (guide T cells to tumor)
  2. Gene therapy - combines “tumor cell vaccines” with “cytokine therapy” by expressing genes coding for cytokines, costim. molecules or MHC
  3. Adaptive immunotherapy - antitumor cells (tumor infiltrating lymphocytes=TIL or lymphokine-activated killer cells=LAK)

Problems:

  • Growing the large amount of cells required
  • Loss of ag specificity for T cells
  • Altering homing pattern
21
Q

Causes of secondary immune deficiencies

A
  • IV drug abuse
  • Unsafe sexual activity
  • Other risk behaviors
  • Malnutrition
  • Chronic diseases (e.g. diabetes)
  • Medications (e.g. corticosteroids)

-> Development of AIDS or other secondary immue deficiency

22
Q

Primary immune deficiencies

A

Genetic

  • IgA deficiency
  • CVI
  • SCID
  • other..
23
Q

Leukocyte adhesion deficiency

A

Widespread pyogenic bacterial infections

24
Q

Chronic granulomatous deficiency

A
  • I.c. and e.c. infections
  • granulomas
  • decresed no. and function of phagocytes
  • no NADH/NADPH oxidase in neutrophils -> less ROS
  • decreased bactericidal activity
25
Q

G6PD deficiency

A

defective respiratory burst, chronic infection

26
Q

MPO deficiency

A

Defective i.c. killing, chronic infection

27
Q

Chediak-Higashi syndrome

A

I.c. and e.c. infections, granulomas

28
Q

Primary immune deficiencies

A
  • IgG deficiency XLA (B-cells)
  • Hyper IgM syndrome (B-cells)
  • IgA defiencye (B-cells)
  • SCID, DiGeorge’s (T-cells)
  • C3, Factors I and H, late C components
29
Q

SCID

A

= Severe combined immunodeficiency disease

  • No T cells
  • No adaptive immunity

Result of complete deficiency of T cell ag receptor/CD3 complex Cd3epsilon chain

30
Q

DiGeorge’s syndrome

A

22q11.2 deletion syndrome

  • 1:4000
  • Recurrent infections
  • Congenital HF
  • Closing palate disorders
  • Velo-pharyngeal closing defects
  • Learning ability disorder
  • Face deformities
31
Q

XLA (Brutons agammaglobulinemia)

A
  • Deficiency of B cells and IgG in peripheral blood
  • Impaired differentiation and growth of pre-B cells
  • Genes: XR, males
  • Recurrent bacterial infections, no Ab responses in vaccination
  • Treatment: pooled gamma globulin products
32
Q

Hyper IgM syndrome

A
  • No class switch to IgG, IgA, IgE (levels decrease)
  • Increased IgM
  • No T cell CD40L -> no B cell stim.
  • Genetics: XR, male (frequently), AR (rare)
  • Recurrent pyogenic infections
33
Q

Selective IgA deficiency (SIGAD)

A
  • serum IgA <50mg/l
  • problem with terminal B cell differentiation
  • recurrent resp., intestine and UG infections
  • Treatments: sometimes spontaneously by breast feeding
34
Q

Wiskott-Aldrich syndrome (WAS)

A
  • XR
  • eczema
  • thrombocytopenia -> blood in stool
  • immune deficiency
35
Q

Secondary immune deficiencies

A
  • Tumors (especially of bone marrow and peripheral blood: leukemia, lymphoma, multiple myeloma)
  • Iatrogenic factors (immunosuppressive drugs, DMARDs, chemotherapy, radiotherapy)
  • Malnutrition
  • Aging
  • Some chronic infections
  • AIDS
36
Q

Diagnostic tests of HIV

A

Antibodies (1-2 months lag time): ELISA, Western blot

Viral RNA: PCR

37
Q

HIV structure

A
  • Membrane from host

- gp160, gp120 (ectoprotein, noncovalent membrane association), gp41 (transmembrane)

38
Q

HIV infection needs..

A

CD4 antigen (main target cell: CD4+ cells)

Chemokine receptors:

  • CCR5 -> Macrophage tropism (deficiency = immune to AIDS)
  • CXCR4 -> T cell tropism
39
Q

HIV internalization into macrophages

A
  1. gp120:CD40 binding
  2. conformational change
  3. CCR-5 recruitment
  4. gp41 membrane insertion
  5. Membrane fusion
40
Q

Genes that delay/inhibit AIDS

A

Prevents:
- Dominant CCR5 allele 32

Delays:

  • Dominant CCR5 allele 32 (also prevents lymphoma)
  • Dominant CCR2 allele I64
  • Recessive CXCL12 allele 3’A
  • Codominant HLA allele B27 or B57
  • KIR3D51 allele 3DS1

Limits infection:
- IL10 (dominant) allele 5’A

41
Q

Progression of HIV infection

A
  1. Acute infection - Virus increases, anti-HIV ab production
  2. Chronic lymphadenopathy - CD4T cells decrease
  3. Subclinical immune dysfunction - many anti-HIV abs
  4. Skin and mucous membrane immune defects -> Virus increases and anti-HIV ab decreases
  5. Systemic immune deficiency - anti-HIV ab depletion, CD4 T cell depletion, CD8 T cell depletion, virus increases
42
Q

AIDS complications

A

Opportunistic infections

  • parasites
  • fungi
  • i.c. bacteria
  • viruses

Malignancies

  • KS (HHV8)
  • Non-hodkin lymphoma
  • Primary lymphoma of brain

Immunology Jenny (16 decks)

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