Immunopharmacology Flashcards
What are the three applications of Immunosuppressive drugs
- Rejection: Prevent host from rejecting foreign tissue
- GVHD: Prevent Graft-Versus-Host Disease, Prevent lymphocytes in foreign tissue from attacking host body
- Auto-immune: Prevent host rejecting itself
Name some auto immune diseases
Lupus, Rheumatoid arthritis, Psoriasis, Ulcerative colitis, Idiopathic Thrombocytopenic purpura
What does GVHD affect
Liver, Skin, Mucosa, Gut
Rheumatoid arthritis
Auto immune disease affecting primarily the joints
Lupus
Multi organ auto-immune disease
Noticeable by rash on cheek
Many tissues are affected
Ulcerative colitis
T-cell infiltration and cause ulceration in the colon
Psoriasis
Auto-immune disease leading to scaly patches of skin (butterfly rash)
What are the phases of adaptive immunity
What are the sub phases
Induction Phase
Antigen-Presentation
Clonal Expansion and Maturation
Effector Phase
What happens in the antigen presentation step
Antigen presentation cells internalize foreign cells, will present antigens and activate T helper cells
What happens in the clonal expansion and maturation step
T-helper cells differentiate and mature
What is the role of Th1
T-helper cells that attack toxic cells
What is the role of Th2
T-helper cells that are the precursor to B cells
What is the Induction Phase
Recognition and presentation of foreign antigens
Activation and proliferation of naive Th0-cells into Th1 and Th2
What is the Effector Phase
Cell-mediated T-cell responses
Th1 activate macrophages that kill infected/foreign cells
Th2 cause antibody-mediated responses leading to the activation of B cells
Describe T-cell receptor pathway (Calcineurin)
T-cell receptor is activated
Creates Ca2+ signal
Activates calcineurin (a phosphatase)
NFAT is dephosphorylated by calcineurin
Dephosphorylated NFAT migrates to the nucleus
Expression of IL-2
IL-2 is used to activate and proliferate T-Cells
What happens if Calcineurin is inhibited
IL-2 gene transcription is suppressed meaning the activation and proliferation of T-cells is inhibited
Cyclosporine
Binds to cyclophilin forming a complex inhibiting calcineurin
Prevents NFAT from being dephosphorylated and prevents NFAT mediated gene transcription of IL-2
Inhibits T-cell maturation and proliferation
Tacrolimus
Binds to FKBP and forms a complex to inhibit calcineurin
Prevents NFAT from being dephosphorylated and prevents NFAT mediated gene transcription of IL-2
Inhibits T-cell maturation and proliferation
What is the mTOR pathway
mammalian Target of Rapamycin
Responsible for promoting cell growth/division
Rapamycin
Binds to FKBP and forms a complex to inhibit mTOR
Suppresses cell responses to IL-2 receptor activation and blocks its downstream signals
Causes less cell growth and division
IL-2 receptor
Activation of receptor causes T cell maturation and proliferation
What are Cytotoxic Agents
Directly attack DNA to suppress tumour growth
What are Proliferation Signal Inhibitors
Inhibits mTOR to interfere with IL-2 pathway
Less T-cell maturation and proliferation
What are Calcineurin Inhibitors
Inhibits calcineurin (Phosphatase) to prevent the dephosphorylation of NFAT
Without NFAT there is less expression of IL-2 that is needed for T-cell maturation and proliferation
Cyclophosphamide
Interferes with DNA replication by cross linking neighboring bases
Useful in rapidly dividing cells
Used to treat cancer
Used to treat rapidly dividing immune cells
Azathioprine
Metabolized to 6-mercaptopurine
A fraudulent nucleotide
Inhibits synthesis of nucleotides, interferes with cell division, and can prevent DNA replication
Effective against rapidly dividing cells during clonal expansion
6-MP can be incorporated into DNA and prevent replication
What is an antibody’s structure
2 Heavy Chains
2 Light Chains
2 regions
Fab region
Fc region
What is the Fab region of an antibody
Determines antigen specificity, what it can bind and what viruses it can recognize
(Antigen-binding)
What is the Fc region of an antibody
Determines antibody class (lgA, lgG, lgM)
Different classes are recognized by different immune cell types through specific receptors for each class
Determines a different immune response
Describe the structure of the antibody’s Fab region
Variable, creating specificity for different antigens
Made up of the light chain with a bit of the heavy chain
Describe the structure of the antibody’s Fc region
Conserved
Made up of only the heavy chain
How are antibody-based therapies created
Antibodies are raised in other animals, however, if used as they are they will be rapidly degraded by the immune system before they can have an affect
What is humaization/chimerization
Replacement of the conserved region (Fc) of the mouse monoclonal antibody with the corresponding sequence (Fc) from human antibodies.
The monoclonal antibody will not be recognized by the immune system
Reduces their antigenicity (Ability to induce an effect)
Increases their lifetime in the body
What are the naming conventions of therapeutic monoclonal antibodies
-umab / -zumab for humanized antibodies
-imab / -ximab for chimeric products
Murine (mouse) monoclonal antibodies
What is the difference between humanization and chimerization
Humanized: Non-human antibody containing protein sequence to make it more human like
Chimerized: Antibody containing a conserved region from a human antibody and a variable region from a non-human species
Alemtuzumab
Humanized lgG1 that recognizes and binds to CD52 found on many different immune cell types
NK cells, complement, and phagocytic immune cells (macrophages, neutrophils, dendritic cells) recognize the lgG1 Fc domain.
Leads to cell death by lysis or phagocytosis
Effect: Labels cells early in immune response and targets them for destruction
Side Effect: Targets both healthy and destructive T and B cells for destruction
Basiliximab
Chimeric mouse-human lgG1 that binds to CD25 which is part of the IL-2 receptor (the alpha chain), on activated lymphocytes
Interferes with activation of IL-2 receptor
IL-2 antagonist that blocks IL-2 from binding to activated lymphocytes
Ultimately causes immunosuppression
