Manipulation of the Immune Response Chapter 14 ://www.nearingzero.net/screen_res/nz360.jpg
Dec 20, 2015
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
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
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
Immunomodulation
• Interfere with costimulation– Soluble CTLA-4 blocks CD28 : B7
interactions
• Induce regulatory T cells or tolerance??
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