manipulation of the immune response
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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 acidcyclo-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
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