Immunopharmacology Flashcards
immunosuppressant applications
- suppression of rejection of transplanted organs and tissues
- suppression of graft-vs-host disease: donor lymphocytes reacting against host
- auto-immune diseases (lupus, arthritis)
- suppression of rejection of transplants
antigens may be recognized as non-self and elicit an immune response that attacks the donor organ
- host-vs-graft disease
if there are immunocompetent cells in the donor graft that mount an immune response against the host
main targeted tissues are liver, skin, mucosa, gut
- auto-immune diseases
rheumatoid arthritis - affect joints
lupus - multi-organ
ulcerative colitis - T-cell infiltration + ulceration in the colon
psoriasis - scaly patches of skin
immune response
induction phase
effector phase
induction phase
antigen presentation
clonal expansion and maturation
antigen presentation
recognition and presentation of foreign antigen:
antigen presenting cells will internalize and break down a foregin, invading body by breaking down its proteins to eventually present those antigens through a receptor system to T helper cells
autocrine loop
synthesis of interleukin 2 by T helper cells acts directly back onto its synthesizing cells = positive feedback
clonal expansion and maturation
activation and proliferation of naive T helper 0 cells into T helper 1 and 2 cells
effector phase
cell-mediated T-cell responses derived from T helper 1 cells (killing infected or foreign cells): T cells will directly attack infected cells; T helper 1 cells will secrete cytokines
antibody-mediated responses derived from T helper 2 cells (activation of B cells): B cells generate antibodies that get recognized by T cells → attached tissue will be killed
key drug targets in immune response
- inhibition of IL-2 production/action
- inhibition of cytokine gene expression (glucocorticoids)
- cytotoxicity (killing immune cells or preventing their maturation/expansion)
- inhibition of nucleic acid synthesis
- blockage of various T-cell surface receptors to prevent immune activation (e.g. antigen presentation machinery)
- inhibition of IL-2 action
i) autocrine loop where T cells are generating IL-2 which acts on a receptor on the T helper cell to cause differentiation into T helper 0 and divide and proliferate
ii) proliferation and continued differentiation of the T helper 1 cells into generation of cytotoxic T cells and other cells mediating cell-based immunity
- Inhibition of cytokine gene expression
some T helper cells will generate cytokines after generation → glucocorticoids will have a suppressive effect on the production of cytokines from those T helper cells
- cytotoxicity
any stage of cell response where the cell is undergoing cell division - especially where expansion from precursor cells into larger numbers of the subsequent generations of cells occurs → inhibition with drugs that prevent cell division or DNA replication in a non-specific way
- inhibition of nucleic acid synthesis
nucleic acid synthesis is necessary during the replication and division of cells
- blockage of various T-cell surface receptors to prevent immune activation
receptor complex where there is an interface between the antigen presenting cell and the T helper cell → drugs that block it inhibit immune system activation at the earliest stages of the response
Immunosuppressive drug classes
calcineurin inhibitors
proliferation inhibitors
alkylating agents
nucleotide analogues
T cell expansion signalling pathways
calcineurin-NFAT pathway (nuclear factor of activated T cells)
Jak/STAT pathway
Calcineurin-NFAT pathway
antigen presenting cell interfaces with the T cell receptor in early precursor T helper cells
T cell receptor (trans-membrane) gets activated and produces calcium signal that triggers activity of phosphatase calcineurin
calcineurin dephosphorylates NFAT in cytoplasm → migrate into nucleus and influence gene transcription of cytokine IL-2
Jak/STAT pathway
IL-2 activates IL-2 receptor → mTOR stimulates downstream signalling to promote translation of IL-2 which leads to T-cell differentiation
positive feedback loop leads to gene transcription of IL-2 and other steps to promote cell growth
mTOR is involved in the growth + division of cells
calcineurin inhibitors
cyclosporin: binds to cyclophilin to form a complex that inhibits calcineurin
tacrolimus: binds to FKBP to form a complex that inhibits calcineurin
by suppressing calcineurin’s phosphatase activity, the drugs suppress pathway that leads to IL-2 gene transcription = inhibit T cell maturation and proliferation
proliferation signal inhibitors
act on Jak/STAT pathway
rapamycin: binds to FKBP - complex inhibits mTOR protein complex = inhibitory effect on cell division and growth
Alkylating agents
cyclophosphamide: generates intra-strand cross linking by methylating bases in DNA chain → mutations, interfere with replication
most effective in rapidly dividing cells
Nucleotide analogues
Azathioprine: metabolized into 6-mercaptopurine (fraudulent nucleotide) - inhibits synthesis of nucleotides + intereres with cell division
similar structure to guanine → inhibitor of endogenous bases
