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Page 1: Manipulation of the Immune Response Chapter 14 .

Manipulation of the Immune Response

Chapter 14

http://www.nearingzero.net/screen_res/nz360.jpg

Page 2: Manipulation of the Immune Response Chapter 14 .

Objectives

• Discuss modes of action of common immunosuppressive drugs

• Describe uses of monoclonal antibodies in immune disorders and cancer

• Explain how anti-tumor immune responses are generated

• Describe characteristics of an effective vaccine

Page 3: Manipulation of the Immune Response Chapter 14 .

Anti-inflammatory drugs: NSAIDs

phospholipids

phospholipase A2

arachidonic acid

cyclo-oxygenase (COX)-1 or -2

prostaglandinsthromboxane

leukotrienes

lipoxygenasexNSAIDs

inflammation

Page 4: Manipulation of the Immune Response Chapter 14 .

Anti-inflammatory drugs: steroids

• Corticosteroids are powerful anti-inflammatory drugs– Prednisone (cortisol

analogue)– Used in

transplantation, autoimmunity, allergy

– Activated steroid receptors act as transcription factors

Page 5: Manipulation of the Immune Response Chapter 14 .

Anti-inflammatory drugs: steroids

Page 6: Manipulation of the Immune Response Chapter 14 .

Corticosteroid physiology

Corticotropin releasing hormone

(CRH)

Adrenocorticotropic hormone (ACTH)

cortisol+

+

-

-

STRESS

+

+

Page 7: Manipulation of the Immune Response Chapter 14 .

Corticosteroid physiology

from P. Stewart, Williams Textbook of Endocrinology, 2003

•Many side effects are possible

•Used in combination with other drugs to limit toxicity

Page 8: Manipulation of the Immune Response Chapter 14 .

Cytotoxic immunosuppressive drugs• Azathioprine, cyclophospamide

– Interfere with DNA synthesis– High doses used to eliminate all

lymphocytes prior to bone marrow transplantation

– Originally developed to treat cancer

• Cyclosporin A, tacrolimus, rapamycin– Less toxic– Interfere with clonal expansion of

activated lymphocytes– Used in transplant recipients

Page 9: Manipulation of the Immune Response Chapter 14 .
Page 10: Manipulation of the Immune Response Chapter 14 .

Cytotoxic immunosuppressive drugs

Page 11: Manipulation of the Immune Response Chapter 14 .

Halloran P. New England Journal of Medicine 351:2715-2729, 2004.

Immunosuppression

Page 12: Manipulation of the Immune Response Chapter 14 .

Antibodies as therapeutics

• Monoclonal antibodies are used for transplantation, autoimmunity, cancer– Depleting (antibody-

mediated cytotoxicity)– Nondepleting (block

function of target molecules)

– Monoclonal antibodies are traditionally made in mice… problems???

             

                                

 

             

                                

  

               

                              

 Murine 100%

Mouse Protein

Chimeric 33% Mouse

Protein

Humanized 10% Mouse

Protein

Page 13: Manipulation of the Immune Response Chapter 14 .

Anti-CD4 Ab and graft tolerance

Page 14: Manipulation of the Immune Response Chapter 14 .

Anti-TNF Ab in autoimmune disease

Page 15: Manipulation of the Immune Response Chapter 14 .

Anti-integrin Ab in multiple sclerosis

Page 16: Manipulation of the Immune Response Chapter 14 .

Immunomodulation

• Interfere with costimulation– Soluble CTLA-4 blocks CD28 : B7

interactions

• Induce regulatory T cells or tolerance??

Page 17: Manipulation of the Immune Response Chapter 14 .

Cancer immunology

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Escape from immune surveillance

Page 20: Manipulation of the Immune Response Chapter 14 .

Escape from immune surveillance

Page 21: Manipulation of the Immune Response Chapter 14 .

Escape from immune surveillance

Page 22: Manipulation of the Immune Response Chapter 14 .

mAbs and cancer

Page 23: Manipulation of the Immune Response Chapter 14 .

mAbs and cancer

Page 24: Manipulation of the Immune Response Chapter 14 .

Fighting infectious disease: vaccines

Page 25: Manipulation of the Immune Response Chapter 14 .

Fighting infectious disease: vaccines

Page 26: Manipulation of the Immune Response Chapter 14 .

Vaccines• Antigen sources:

– Small doses of the wild type virus or use of a “safe” counterpart (early smallpox vaccines)

– Killed/inactivated pathogen– Toxoid– Viral subunits– Live attenuated virus

Page 27: Manipulation of the Immune Response Chapter 14 .

Making a vaccine

Page 28: Manipulation of the Immune Response Chapter 14 .

Making a vaccine using molecular biology

Page 29: Manipulation of the Immune Response Chapter 14 .

DNA vaccines

Page 30: Manipulation of the Immune Response Chapter 14 .

Other vaccine development strategies

• Developing better adjuvants– ISCOMs (Immune Stimulatory Complexes)

deliver peptides to MHC I processing pathway

– Mucosal adjuvants (modified pertussis toxin)

• Targeting APCs by coadministration of cytokines

• Developing nasal or oral vaccines