Immunopharmacology Flashcards
Three Main Applications of Immunopharmacology?
- suppression of rejection of transplanted organs and tissues (eg. bone marrow)
- suppression of Graft-vs- host which may arise from donor lymphocytes reacting against host
- auto immune diseases
- examples include: lupus, rheumatoid arthritis, psoriasis, ulcerative colitis
Rejection in Transplantation
-antigens may be recognized as ‘non-self’ and elicit an immune response that attacks the donors again
- can also happen in reverse, if there are incompetent cells in the donor graft that mount an immune against the host
- immunosuppressant drugs are used in both contexts
rheumatoid arthritis
autoimmune disease primarily affecting the joints, but other tissues as well
Lupus
multi-organ auto-immune disease, (characteristic rash on cheeks)
Ulcerative Colitis
T-cell infiltration (auto-immune) and ulceration in the colon
psoriasis
auto-immune disease leading to scaly patches in the skin
The Immune Response in the context of Immunosuppressant drugs
- focus on the specific immunological response, not the innate immune response
- key phases in the response are in the induction phase and the effector phase
- the induction phase includes recognition and presentation of foreign antigen, activation and proliferation of naive Th0 -cells in Th1 and Th2 cells
- the effector phase includes the cell-mediated T-cell responses (cells ‘killing’ infected or foreign cells) derived from Th1 cells, and antibody-mediated responses derived from Th2 cells (leading to activation of B cells)
Key Drug targets in the 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 receptors to prevent immune activation
Calcineurin Inhibitors
e.g., cyclosporine, tacrolimus
- activation of naive Th0 cells and colonial expansion of T cells requires activation of the calineurin -NFAT (nuclear factor of activated T-cells) pathway
- activation of T-cell receptor generates a Ca2+ signal leading to activation of the calcineurin (phosphotase) and dephosphorylation of NFAT
- dephosphorylated NFAT migrates to the nucleus, leading to expression of IL-2 that is required for activation and proliferation of T-cells
- cyclosporine and tacrolimus bind to their targets (cyclophlin and FKBP) these drug bounded targets suppress calcineurin)
Cyclosporine Mechanism of Action
key detail of this mechanism is the inhibition of calcineurin by the cyclophilin:cylosporine complex
- this prevents NFAT mediated gene transcription, leading to inhibition of T-cell maturation and proliferation
- IL-2 is a major signal
Tacrolimus Mechanism of Action
key detail is the inhibition of calcineurin by the FKBP:tacrolimus complex
- this prevents NFAT-mediated gene transcription, especially important is the suppression of IL-1
Proliferation Signal Inhibitors
e.g., rapamycin, AKA sirolimus
- these drugs interfere with the downstream signals of IL-2 receptor activation
- rapamycin binds to FKBP, but does NOT inhibit calcineurin
Rapamycin Mechanism of Action
key detail of this mechanism is the inhibition of mTOR by the FKBP:sirolimus complex
- mTOR = mammalian target of rapamycin
- mTOR is a major pathway responsible for promoting cell growth and proliferation
- these effects suppress cellular responses to IL-2 receptor activation
Cytotoxic Agrents
e.g., cyclophosphamide (alkylating agent)
- leads to cross linking of neighbouring bases, this interferes with DNA replication
- most effective in rapidly diving cells, so these drugs are useful in cancer treatment and suppression of rapidly dividing immune cells
e.g., azathioprine
- is metabolized to 6-mercaptopurine
- this inhibits synthesis of nucleotides and interferes with cell division
Antibody Structure
- two heavy chains
- two light chains
- the Fab region determines antigen specificity
- the Fc region determines the antibody ‘class’
