28 Immunopharmacology Flashcards
What are the three main reasons that Immunosuppressive drugs are used?
- Suppression of rejection of transplanted organs and tissues
- Suppression of ‘Graft-vs-Host’ disease (GVHD) which may arise from donor lymphocytes reacting against host, especially in bone marrow transplants
- Autoimmune diseases
- eg lupus (systemic lupus erythematosus), rheumatoid arthritis, psoriasis, ulcerative colitis, idiopathic thrombocytopenic purpura
If there are immunocompetent cells in a donor graft, what phenomenon might occur? What are the four main tissues targeted during this?
- Graft-vs-Host Disease (GVHD)
- Four tissues
- liver
- skin
- mucosa
- gut
What happens during rejection in the context of host recognition of the donor organ during transplantation?
Antigens may be recognized as non-self and elicit an immune response that attacks the donor organ
What is rheumatoid arthritis?
Auto-immune disease primarily affecting the joints
What is Ulcerative colitis?
T-cell infiltration (auto-immune) and ulceration in the colon
What are the two major phases of the immune response?
- Induction phase
- Effector phase
What happens during the induction phase of the immune response?
The induction phase includes recognition and presentation of foreign antigen, activation and proliferation of naive Th0 cells into Th1 and Th2 cells
The induction phase of the immune response begins with _________
The induction phase of the immune response begins with Antigen presentation
What is antigen presentation?
(first step of the first phase (induction) of the immune response)
- What cytokine signalling molecule is major here?
- Antigen-presenting cell (APC) - eg a macrophage - absorbs and processes an antigen
- exposes fragments of the antigen on the receptor of a T-helper precursor cell (Thp cell)
- triggers differentiation into T-helper 0 cells
-
Interleukin-2 (IL-2)
- Exerts positive feedback on Thp cells stimulating them to divide and differentiate into Th0 cells
What happens during the induction phase following antigen presentation?
What Cytokine signaling molecule is important here?
- Clonal Expansion and Maturation
- Th0 cells divide into Th1 or Th2 cells
-
Interleukin-4 (IL-4)
- Exerts positive feedback on Th0 cells, stimulating them to divide and differentiate into either Th1 or Th2
What happens during the Effector Phase of immune response?
The effector phase includes
- the cell-mediated T-cell responses (cells ‘killing’ infected or foreign cells) derived from Th1 cells
- Antibody-mediated responses derived from Th2 cells (leading to activation of B-cells)
What is clonal expansion?
Clonal expansion is the process by which daughter cells arise from a parent cell.
Repetitive cell division to increase the number of Th1 and Th2 cells
During the effector phase of the immune response, Th2 cells differentiate into ______
Th2 cells differentiate into B-cells
- Antibody producing cells
B-cells are the _____________ cells
B-cells are the anti-body producing cells
During the Effector phase of the immune response, Th1 cells release _______ or become Tc cells and __________
During the Effector phase of the immune response, Th1 cells release cytokines or become Tc (cytotoxic T) cells and kill virally infected cells
What phase of the immune response do most of the drugs we learned about influence?
Most of the drug effects influence the induction phase
What are five several critical steps/regulators of the immune response that are targeted by available immunosuppressant drugs?
- Inhibiting positive feedback cycle of IL-2 by inhibiting IL-2 production
- Inhibition of cytokine gene expression (glucocorticoids)
- during the effector phase
- 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
- (eg antigen presentation machinery)
What are two examples of Calcineurin inhibitors?
Cyclosporine
Tacrolimus
What is the mechanism of action of calcineurin inhibitors (eg Cyclosporine and tacrolimus)
-
Cyclosporine and tacrolimus bind to their targets (cyclophilin, FKBP respectively).
- The drug-bound targets suppress calcineurin
- suppresses the pathway that leads to IL-2 gene transcription
- The drug-bound targets suppress calcineurin
- pathway leading to IL-2 gene transcription:
- Activation of naive Th0-cells and clonal expansion of T cells requires activation of several signaling pathways including the Calcineurin-NFAT (nuclear factor of activated T-cells) pathway
- Activation of T-cell receptor generates a Ca2+ Signal leading to activation of calcineurin (phosphatase) 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
What leads to the transcription of Interleukin-2 (IL-2)?
pathway leading to IL-2 gene transcription:
- Activation of naive Th0-cells and clonal expansion of T cells requires activation of several signaling pathways including the Calcineurin-NFAT (nuclear factor of activated T-cells) pathway
- Activation of T-cell receptor generates a Ca2+ Signal leading to
- activation of calcineurin (phosphatase) and
- dephosphorylation of NFAT
- Dephosphorylated NFAT migrates to the nucleus, leading to the expression of IL-2 that is required for activation and proliferation of T-cells
Target of cyclosporine?
Effect?
- Cyclosporine is a Calcineurin inhibitor
- Cyclosporine binds to cyclophilin and suppresses calcineurin which prevents IL-2 gene transcription
- Inhibition of calcineurin by the cyclophilin: cyclosporin complex
- prevents NFAT-mediated gene transcription, leading to inhibition of t-cell maturation and proliferation
- prevents activation of naive Th0 cells and clonal expansion of T-cells
Target and effect of tacrolimus?
Tacrolimus is a Calcineurin inhibitor
- binds to FKBP
- suppresses calcineurin
-
inhibition of calcineurin by the FKBP:tacrolimus complex
- prevents NFAT-mediated gene transcription (especially important is the suppression of IL-2)
- prevents activation of naive Th0 cells and clonal expansion of T-cells
- prevents NFAT-mediated gene transcription (especially important is the suppression of IL-2)
-
inhibition of calcineurin by the FKBP:tacrolimus complex
What do Proliferation Signal Inhibitors do and what is an example?
Proliferation signal inhibitors interfere with the downstream signals of IL-2 receptor activation
- examples
- Rapamycin/sirolimus
Rapamycin binds to ________ and inhibits ___________
Rapamycin (a proliferation signal inhibitor) binds to FKBP and inhibits a protein complex called mTOR (mammalian target of rapamycin)
-
Inhibition of mTOR by the FKBP:SIROLIMUS complex
- suppress cellular responses to IL-2 receptor activation
- mTOR is a major pathway responsible for promoting cell growth and proliferation
*
What is cyclophosphamide?
- Cytotoxic agent
- alkylating agent
- leads to cross-linking of neighboring bases
- interferes with DNA replication
- leads to cross-linking of neighboring bases
- Most effective in rapidly dividing cells (useful in cancer tx and suppression of rapidly dividing immune cells)
What is Azathioprine?
- Cytotoxic agent
- metabolized to 6-mercaptopurine (a fraudulent nucleotide)
- inhibits synthesis of nucleotides and interferes with cell division
- effective against rapidly dividing cells during clonal expansion
- inhibits synthesis of nucleotides and interferes with cell division
What part of monoclonal antibodies determines antigen specificity?
The Fab region
Describe the structure of an antibody
- 2 heavy chains
- 2 light chains
- Fab region
- determines antigen specificity
- 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 region of an antibody determines the class of antibody and in turn the cellular response that occurs?
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
How do we prevent antibodies raised from other animals from being rapidly degraded in our bodies?
By using ‘Chimeric’ or ‘humanized’ versions
reduces their antigenicity - increases their lifetime in the body
What is humanization/chimerization?
Replacement of conserved regions of the mouse monoclonal antibody with the corresponding sequence from human antibodies (ie combination of mouse Fab fragment with human Fc fragment)
- umab or -zumab for humanized antibodies
- imab or -ximab for chimeric products
What is Alemtuzumab?
Mab = monoclonal antibody = antibody based therapy
- Humanized IgG1 that recognizes CD52 receptor on many immune cell types
- The IgG1 Fc domain is recognized by phagocytic immune cells (eg macrophages, neutrophils, dendritic cells) complement and NK cells
- Leads to cell death by lysis or phagocytosis
- Healthy and destructive T and B cells are destroyed
- The IgG1 Fc domain is recognized by phagocytic immune cells (eg macrophages, neutrophils, dendritic cells) complement and NK cells
What is Basiliximab?
- Chimeric mouse-human IgG1 that binds to CD25 (part of the IL-2 receptor alpha chain) on activated lymphocytes
- causes immunosuppression by blocking IL-2 from binding to activated lymphocytes (IL-2 Antagonist)
