Manipulation of the Immune Response

Chapter 14

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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

Anti-inflammatory drugs: NSAIDs

phospholipids

phospholipase A2

arachidonic acid

cyclo-oxygenase (COX)-1 or -2

prostaglandinsthromboxane

leukotrienes

lipoxygenasexNSAIDs

inflammation

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

Anti-inflammatory drugs: steroids

Corticosteroid physiology

Corticotropin releasing hormone

(CRH)

Adrenocorticotropic hormone (ACTH)

cortisol+

+

-

-

STRESS

+

+

Corticosteroid physiology

from P. Stewart, Williams Textbook of Endocrinology, 2003

•Many side effects are possible

•Used in combination with other drugs to limit toxicity

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

Cytotoxic immunosuppressive drugs

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

Immunosuppression

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

Anti-CD4 Ab and graft tolerance

Anti-TNF Ab in autoimmune disease

Anti-integrin Ab in multiple sclerosis

Immunomodulation

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

interactions

• Induce regulatory T cells or tolerance??

Cancer immunology

Escape from immune surveillance

Escape from immune surveillance

Escape from immune surveillance

mAbs and cancer

mAbs and cancer

Fighting infectious disease: vaccines

Fighting infectious disease: vaccines

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

Making a vaccine

Making a vaccine using molecular biology

DNA vaccines

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