34 - Immunopharmacology Flashcards
Why use immunosuppressants?
1) suppression of rejection of transplanted organs and tissues
2) suppression of graft vs host (donor immune cells reacting against host)
3) autoimmune disease: lupus
What is rheumatoid arthritis
autoimmune disease primarily affecting the joints
What is Lupus?
multi organ autoimmune disease (characteristic rash)
Adaptive immunity: induction phase
recognition and presentation of foreign antigen by an antigen presenting cell
activation and proliferation of naive T helper cells (Th0) into differentiates Th1 and Th2 cells
Adaptive immunity: effector phase
cell mediated T cell responses derived from Th1 cells
antibody-mediated responses from B cells derived from Th2 cells
Both processes lead to immune cells killing infected or foreign cells
Key drug targets in immune response
inhibition of IL-2 production/action
inhibition of cytokine gene expression
cytotoxicity
inhibition of nucleic acid synthesis
blockage of various T cell surface
Calcineurin inhibitors
eg cyclosporin and tacrolimus
activation of naive Th0 cells and clonal expansion of T cells require the cytokine IL-2
IL-2 production controlled by intracellular signaling cascades, including calcineurin-nuclear factor of activated T-Cells (NFAT) pathway
What is cyclosporin and what does it do?
calcineurin inhibitor
inhibit calcinerin by the cyclophilin:cyclosporine complex
prevents NFAT mediated gene transcription of IL-2, leading to inhibition of T-cell maturation and proliferation
What is tacrolimus and what does it do?
Calcineurin inhibitor
inhibit calcinerin by the FKBP: tacrolimus complex
NFAT mediated gene transcription of IL-2
What is Rapamycin?
Proliferation Signal Inhibitors
Interfere with the downstream signals of IL2 receptor activation
rapamycin binds to FKBP (same target as tacrolimus)
inhibits mTOR (pathway for cell growth and proliferation)
What do FKPs and cyclophilins do?
immunophilins, help cytokines fold to right shape
What is cyclophosphamide?
cytotoxic agent, leads to cross link of neighbouring DNA base, useful for suppression of rapidly dividing immune cells
What is azathioprine?
metabolized to 6 mercaptopurine, inhibit nucleotide synth
Monoclonal antibodies have
2 light chains 2 heavy chains
Fab region of antibodies
The structure of the antibody can also be portioned into two antigen binding fragments (Fab) and the crystallizable fragment (Fc)
The Fab region determines antigen specificity
The Fc region determines the antibody ‘class’ (IgA, IgG, IgM, etc). Different classes of Fc regions are recognized by receptors on different immune cell types, leading to different immune responses
What is Alemtuzumab?
huamnized IgG1 that recognizes CD52 found on many immune cell types, including T and B ells
IgG1 Fc domain is recognized by phagocytic immune cells, complement, and NK cells
leads to immune-mediated destruction of otherwise healthy and B cells
What is Basiliximab?
chimeric mouse-human IgG1 that binds to CD25, part of the IL2 receptor on activated T cells
causes immunosuppression by blocking IL2 from binding to activated T cells
