Lecture 28: Immunopharmacology Flashcards
What are the three main application of immunosuppressive drugs?
- Suppression of rejection of transplanted organs and tissues
- Suppression of graft-versus-host disease
- Autoimmune diseases
What is Graft-Versus-Host disease?
When donor lymphocytes react against host, especially in bone marrow transplants
What occurs in graft versus host disease?
If there are immunocompetent cells in the donor graft, they can mount an immune response against the host
What tissues are targeted in GVHD?
Liver, skin, mucosa and gut
What are autoimmune diseases?
When the immune system fails to recognize antigens as part of self and attacks them
What is Rheumatoid arthritis?
An autoimmune disease primarily affecting the joints
What is Lupus?
A multi organ immune disease with a characteristic rash on cheeks
What is ulcerative colitis?
T-cell infiltration and ulcertation of the colon
What is Psoriasis?
An autoimmune disease leading to scaly patches of skin
What are the two phases of the immune response?
- Induction phase
* Effector phase
What are the two subdivisions of the induction phase?
- Antigen presenting
* Clonal expansion and mutation
What is the first step in the simplified immune response?
Antigen presentation
What occurs in Antigen presentation?
An antigen presenting cell presents an antigen to a T-helper cell/CD4+ lymphocyte
how does antigen presenting affect the the T-helper cell?
It leads to activation of the T-helper cell
What happens after a T-helper cell is activated?
It divides and propagates
What is released by the T-helper cell once it is activated?
It releases interleukin-2 (IL-2)
What does interleukin-2 released by T-helper cells do?
Acts on the receptors of the same cell and causes them to divide and proliferate
What are the two types of cells that T-helper cells divide into?
Th1 and Th2
What do Th2 cells divide into?
B cells
What are B cells involved in the generation of?
Antibodies
What do Th1 cells differentiate into?
Different types of T-cells
What do Cytotoxic T-cells do?
They bind to and kill cells that are infected with a virus
What do Th1 cells release?
Cytokines that that circulate and promote further activation of the immune response
What happens in the induction phase?
- Antigen presenting
* Activation and proliferation of the Th0 cells
What occurs in the effector phase?
Activation of T cells and B cells
What are the five main steps/regulators targeted by available immunosuppressant drugs?
- Inhibition of IL-2
- 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
What are the two Calcineurin inhibitors?
Cyclosporine and Tacrolimus
What kind of drugs are Cyclosporine and Tacrolimus?
Calcineurin inhibitors
What do Calcineurin inhibitors target?
An early step in the activation of naive Th0 cells
What does the activation of naive Th0 cells require?
Activation of the calcineurin-NFAT pathway
What are the steps after the activation of T-cells?
They generate a Ca2+ signal leading to activation of calcineurin (phosphatase) and dephosphorylation of NFAT
What does NFAT do once dephosphorylated?
Migrates to the nucleus, leading to expression of IL-2 which is required for proliferation of T-cells
What is the target of Cyclosporine?
Cyclophilin
What is the target of Tacrolimus?
FKBP
What do Cyclosporine and Tacrolimus do?
Bind to the targets and suppress calcineurin which suppresses IL-2
What is the key detail in Cyclosporine mechanism?
The generation of cyclophilin-cyclosporin complex which inhibits calcineurin
What does the inhibition of calcineurin do?
Prevents NFAT-mediated gene transcription leading to inhibition of T-cell maturation and proliferation
How does Cyclosporine work?
It forms a complex with cyclophilin which binds to calcineurin preventing it from dephosphorylating NFAT. So NFAT cannot go on to increase gene transcription and increase IL-2
How does Tacrolimus work?
It binds to FKBP which inhibits the activation of calcineurin and prevents the dephosphorylation of NFAT and prevents the downstream signalling of IL-2
What is the Proliferation Signal Inhibitor Drug?
Rapamycin aka sirolimus
What kind of drug is Rapamycin aka Sirolimus?
A proliferation Signal Inhibitors
How do Proliferation Signal Inhibitors work?
They interfere with the downstream signals of IL-2 receptor activation
What does Rapamycin bind to?
FKBP (the same target as tacrolimus)
What does the Rapamycin-FKBP complex inhibit?
A protein complex called mTOR
What is mTOR responsible for?
Promoting cell growth and proliferation
How does mTOR work?
It binds to FKBP which inhibits mTOR. So the cell is unable to create a response to IL-2 receptor activation
What are the two Cytotoxic Agent drugs?
- Cyclophosphamide
* Azathioprine
What kind of drugs are Cyclophosphamide and Azathioprine?
Cytotoxic agents
How does Cyclophosphamide work?
It leads to cross-linking of neighboring bases interfering with DNA replication
Where is Cyclophosphamide most effective?
In rapidly dividing cells
How does Azathioprine work?
It is metabolized into 6-mercaptopurine and it inhibits the synthesis of nucleotides and interferes with cell division by acting as a fraudulent nucleotide
What kind of nucleotide does Azathioprine look like?
A purine
What are the components of antibodies?
- 2 heavy chains
* 2 light chains
What region determines antigen specificty?
The Fab region
What does the Fc region determine?
Antibody class (IgA, IgG, IgM etc)
What do the different Fc regions lead to?
Different types of immune response
Which region binds to the antigen on monoclonal antibodies?
The Fab region
What are antibodies always raised in?
Other animals
Why are antibodies raised in other animals a problem?
Because they are recognized by our immune system and rapidly degraded
What is the solution to the antibody issue?
Use Chimeric or humanized version version of monoclonal antibodies
What is the upside to using Chimeric or Humanized antibodies?
Their antigenicity is reduced so they have a higher lifeltime in the body
What is humanization/chimerization?
The replacement of the conserved (Fc) region of mouse monoclonal antibodies with corresponding sequence from human antibodies
What do therapeutic monoclonal antibodies end with?
mab
What is the suffix for humanized antibodies?
-umab or - zumab
What is the suffix from chimeric products?
-imab and -ximab
What is Alemtuzumab and what does it recognize?
A humanized IgG1 that recognizes CD52 on many immune cell types
What is the IgG1 Fc domain recognized by and what does it do?
Phagocytic immune cells and causes their death
What is the IgG1 Fc domain recognized by and what does it do?
Phagocytic immune cells and causes their death
How does Alemtuzumab work?
It binds to CD52 on immune cells and this signals phagocytic cells to kill the cell through the IgG1 domain
How does Basiliximab work?
It is a chimeric mouse-human IgG1 that binds to CD25 part of the IL-2 receptor on activated lymphocytes and blocks IL-2 from activating lymphocytes as an antagonists
What are the two antibody based therapies?
Basiliximab and Alemtuzumab
