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Manipulation of Immune Response 免疫反應的操控 Chapter 16 陳炳宏副教授 KMU生物科技學系 第一教學大樓N1020/1023 (分機: 2676) [email protected] http://allergy.kmu.edu.tw 1

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Page 1: Manipulation of Immune Responseallergy.kmu.edu.tw/~ivue2752/content/lectures_download/Immunology... · Manipulation of Immune Response 免疫反應的操控 Chapter 16 陳炳宏副教授

Manipulation of Immune Response 免疫反應的操控

Chapter 16

陳炳宏副教授 KMU生物科技學系

第一教學大樓N1020/1023 (分機: 2676) [email protected]

http://allergy.kmu.edu.tw

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Learning objectives

Understand how unwanted immune responses can be extrinsically regulated.

How tumors can be regulated by immune responses.

How can we manipulate the immune responses to fight infections.

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Extrinsic regulation of unwanted immune responses

1. Anti-inflammatory drugs 2. Cytotoxic drugs 3. T-lymphocyte signaling inhibitors 4. Anti-lymphocyte Ab

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Conventional immunosuppressive drugs in clinical use

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1

2

3 3 3

Fig. 16-1

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1. Corticosteroids (皮質類固醇) Refers to both glucocorticoids and

mineralocorticoids ; steroid hormones Example:

cortisol (natural), prednisone (synthetic) Cortisol receptors are widely expressed on

almost all cell types in the body!! Cortisol-cortisol receptor interaction will result

(mostly) the increased expression of responsive genes Could have both beneficial and harmful effects

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Structures of anti-inflammatory corticosteriod drugs

Introduction of a double bond enhances the anti-inflammatory potency

(Natural) (Synthetic)

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Mechanism of steroid hormone

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DNA-binding domain exposed

Translocation

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Anti-inflammatory effects of

corticosteroids (Nitric oxide synthase)

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(Annexin 1)

Fig. 16-2

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2. Cytotoxic drugs Interfere with DNA synthesis

Originally developed for the treatment of cancers Affect dividing tissues and lymphocytes

Wide range of toxic effects Decreased immune function

Anemia, leukopenia, and thrombocytopenia

Tissue damages Hair loss Intestinal epithelial necrosis

Commonly used to destroy all dividing lymphocytes Usually requires subsequent B.M transplantation

e.g. Azathioprine, mycophenolate, cyclophosphamide

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3. Inhibitors on T-cell signaling Cyclosporin A A fungal peptide derived from Tolypocladium

inflatum (initially discovered in 1970s) Blocks T-cell proliferation

Inhibits action of phosphatase calcineurin Calcineurin is found in T cells (lower conc.) and other cell types

(higher conc.) Signal transmitted from TCR to nucleus is disrupted

Only requires nanomolar (10-9) level to be effective !! Results: reduced expression of several cytokine genes (e.g.

IL-2) activated upon T-cell activation

Widely used in organ transplant recipients 10

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Cyclosporin A and Tacrolimus inhibit T-cell activation be interfering with calcineurin

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Fig. 16-4

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Effects of cyclosporin A and tacrolimus

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Fig. 16-3

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Rapamycin inhibits cell growth & proliferation by blocking mTOR activation

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Fig. 16-5

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Downsides of immunosuppressive drugs

Affect all immune responses indiscriminately Cause generalized immunosuppression Balance the doses being administered

Affect other organs/tissues e.g. high toxicity to kidneys (kidney failure)

Expensive Most are natural products Required prolonged treatment (toxicity) The need for semisynthetic products with

comparable efficacy

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4. Anti-lymphocyte antibodies Advantage of Ab

can interfere with immune responses in a non-toxic and more selective/specific manner!!!

Antibodies can be engineered for the therapeutic use in humans Because most therapeutic Abs come from animal

sources (e.g. mouse, rat, rabbit, donkey,…etc.) Animal Abs will cause a ‘human-against-animal’ Ab

responses 15

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Depleting vs non-depleting Abs Depleting Abs

Trigger the destruction of lymphocytes in vivo Examples:

Anti-lymphocyte globulin (polyclonal) Immunize horse with human lymphocytes Can be used to treat acute graft rejection Disadvantage: can cause serum sickness with high doses

Campath-1H (also called “alemtuzumab”) (monoclonal) Similar to anti-lymphocyte globulin Against CD52 common lymphocyte marker

Non-depleting Abs Blocking functions of lymphocytes 16

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How to reduce immunogenecity of engineered antibodies?

Clone human Ig V gene segments into phage display library

Mice deficient of Ig genes can be made transgenic of human Ig genes (e.g. KM mice)

“Humanization” of mouse Ig into human backbone Graft CDRs from mice source into human Ig

cassette (usually human IgG backbone) 17

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Monoclonal Abs for treating human diseases

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Fig. 16-6

Mouse Mouse x Human Humanized Fully

mab = monoclonal Ab

Also, refer to Fig. 16-7 (參考用, 不會考)

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Management of autoimmune diseases

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How to manage autoimmune diseases?

Treatment with anti-inflammatory agents Reduction of autoimmune responses Treatment aimed at compensating pathological

damages caused by autoimmune responses ‘biological agents’

Treatments comprising Natural proteins (e.g. Abs, cytokines), or fragment of proteins Synthetic peptides

Examples insulin to compensate the damaged pancreatic β cells anti-TNFα Ab or TNFα receptor:Ig Fc recombinant

proteins for the removal of TNFα in various rheumatoid arthritis

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Potential targets of immune intervention strategies

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Anti-TNFα therapies currently in use

Infliximab Humanized anti-TNFα mAb

Etanercept Recombinant fusion protein

TNF receptor:Ig Fc complex

Binds TNFα, thereby neutralizing it

Both are currently used in clinical settings

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Anti-inflammatory effects of anti-TNFα therapy in rheumatoid arthritis

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Fig. 16-8

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Antibodies for the blocking of cell migration to inflammatory sites of brain in multiple

sclerosis (natalizumab)

Anti-α4 mAb (natalizumab) prevents Lymphocytes from interacting with VCAM-1

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Fig. 16-9a

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Natalizumab effectively reduces inflammatory lesions caused by

lymphocytes and monocytes

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Fig. 16-9b

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Immune surveillance and tumor immunology

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Tumor

Tumor vs. cancer One of the leading causes of death among

most countries Resulted from uncontrolled proliferation of a

single transformed cell (‘self’ cell) How to attack and eliminate tumors?

Induction of immune responses solely against tumor cells

Therefore, the identification of specific ‘tumor antigen’ becomes crucial!!

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T cells are the most critical mediator of tumor immunity

Tumors can be induced via chemical carcinogens in experimental animals (esp. mice)

Induced tumors are ‘transplantable’ among inbred mice harbors matching MHC types

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T cells are the most critical mediator of tumor immunity

When transplanted into an inbred mouse of matching MHC, an irradiated tumor, can induce protective immunity against a subsequent injection of viable tumor

cells of the same tumor type not seen in T-deficient mice (nude mice) protection can also be demonstrated via ‘adoptive

transfer’ (BM transfer)

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Tumor rejection is a specific process

Tumor-specific transplantation antigens (TSTAs)

Also called “tumor rejection antigens” (TRAs)

Not expressed on normal cells 30

Fig. 16-11

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Tumors can escape rejection in many ways

Immune surveillance (1) Elimination phase (2) Equilibrium phase (3) Escape phase 31

(1) (2) (3)

Fig. 16-12

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How do tumors escape immune surveillance? (often occurs at the equilibrium phase)

1. Low immunogenicity 2. Tumor Ags treated as self-Ags

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3. Antigenic modulation

1. 2. 3.

Fig. 16-13

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4. Direct immunosuppression by tumor-secreted factors (e.g. TGF-β) 5. Induction of tumor privileged site

33

Could be either singular

or multifactorial events

How do tumors escape immune surveillance? (often occurs at the equilibrium phase)

4. 5.

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Categories of known human tumor-specific antigens

1. Point mutation (or gene rearrangement) of self-protein during the process of oncogenesis

2. Germ cell-encoded proteins - When normally expressed in male germ cells

(lack of MHC molecules), not processed nor presented to T lymphocytes

- When abnormally expressed in tumor, presented by MHC-I to T lymphocytes

3. Differentiation antigens - Genes expressed only in particular tissue types 34

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4. Abnormal gene expression - overexpression of HER-2/neu in ovarian cancer

5. Abnormal post-translational modification - underglycosylated MUC-1 in breast or pancreatic

cancer 6. Abnormal post-transcriptional modification - retention of introns in mRNA 7. Oncoviral proteins - viral transforming gene products

Categories of known human tumor-specific antigens

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Point mutations in self proteins may give rise to new tumor rejection antigens

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Fig. 16-17

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Transplanted tumor without MHC-I expression is more susceptible to NK-killing

37 Fig. 16-15

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NK

Leukemic cell NK

Leukemic cell (membrane fragmented)

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mAbs as therapeutic agents against tumors

immunotoxin

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Fig. 16-18

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Herceptin

Rituximab

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Fig. 16-19

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Vaccination

Manipulating the immune response to fight infection

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Common vaccines

Herd immunity: when a large proportion of the population is immune (vaccinated), the pathogen reservoir is reduced and transmission of the pathogen is difficult. Thus, even those that are not immune are at reduced risk for infection

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Effective vaccines

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Fig. 16-23

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Types of vaccines

Dead organism

Live attenuated organism (減毒疫苗)

Toxoid (類毒素)

Purified protein

Recombinant protein

DNA vaccine

Require adjuvants

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Attenuation of virus for the use of vaccine

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Could be a time-consuming process!!!

Fig. 16-24

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Attenuation by recombinant DNA

technology

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Fig. 16-25

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Summary

Unwanted immune responses can be regulated by the use of various drugs and biological agents.

Controlling activity of T cells can best impose regulation on unwanted immune responses.

Vaccination can help manipulate the immune responses to fight both bacterial and viral infections.

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End of Chapter

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