manipulation of the immune response
DESCRIPTION
Manipulation of the Immune Response. Chapter 14. http://www.nearingzero.net/screen_res/nz360.jpg. 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 - PowerPoint PPT PresentationTRANSCRIPT
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Manipulation of the Immune Response
Chapter 14
http://www.nearingzero.net/screen_res/nz360.jpg
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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
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Anti-inflammatory drugs: NSAIDs
phospholipids
phospholipase A2
arachidonic acidcyclo-oxygenase (COX)-1 or -2
prostaglandinsthromboxane
leukotrienes
lipoxygenasexNSAIDs
inflammation
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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
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Anti-inflammatory drugs: steroids
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Corticosteroid physiology
Corticotropin releasing hormone
(CRH)
Adrenocorticotropic hormone (ACTH)
cortisol+
+
-
-
STRESS
+
+
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Corticosteroid physiology
from P. Stewart, Williams Textbook of Endocrinology, 2003
•Many side effects are possible
•Used in combination with other drugs to limit toxicity
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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
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Cytotoxic immunosuppressive drugs
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Halloran P. New England Journal of Medicine 351:2715-2729, 2004.
Immunosuppression
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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
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Anti-CD4 Ab and graft tolerance
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Anti-TNF Ab in autoimmune disease
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Anti-integrin Ab in multiple sclerosis
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Immunomodulation• Interfere with costimulation
– Soluble CTLA-4 blocks CD28 : B7 interactions
• Induce regulatory T cells or tolerance??
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Cancer immunology
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Escape from immune surveillance
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Escape from immune surveillance
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Escape from immune surveillance
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mAbs and cancer
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mAbs and cancer
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Fighting infectious disease: vaccines
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Fighting infectious disease: vaccines
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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
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Making a vaccine
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Making a vaccine using molecular biology
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DNA vaccines
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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