Immunopharmacology Flashcards
Describe the differences between immunosuppression and cancer therapy.
Immunosuppression: normally, immune cells are synchronized and respond to a presenting antigen. Thus, immunosuppressive drugs are given in low doses, continuously. No recovery time is required.
Cancer therapy: Cancer cells are unsynchronized cell division, thus, anti cancer drugs are given in bursts, with a recovery time afterwards.
It is necessary to use the immunosuppressant drug at the time of the initial antigen exposure, before the immune cells can become sensitized to the antigen. Once sensitized, immunosuppressive drugs are not very effective.
Note that there is a GREATER degree of selective toxicity with immunosuppressants
Describe the use of RhoGam
RhoGam is an Rh immunoglobulin aimed at minimizing the chance of “Rh incompatibility”. When a mother is Rh-, but her fetus is Rh+, RhoGam is given during critical points in pregnancy and at least 72 hours after birth to ensure that the mother does not make Rh+ antibodies upon exposure to Rh+ blood. If RhoGam is not given, the mother will make antibodies to the Rh+ antigen, and make have complicated future pregnancies, as the mother’s body will attack any Rh+ blood cell. This can result in hemolytic anemia for the infant.
Explain monoclonal antibody technology:
Mouse cells that are HPRT+ and myeloma (plasma cell tumor) that is HPRT- (mutated HPRT1 gene). Cells are fused into a hybrid. The hybrid is cultured on a HAT medium (Hypoxanthine, aminopterin, thymidine). Aminopterin inhibits HPRT, which is necessary for de novo synthesis of purine bases.
Successfully hybridized HPRT+ cells will use the salvage pathway to form purine bases. However, the HPRT- myeloma cells, will not be able to use the salvage pathway, and will die.
Successful hybrids can be proliferated.
Rituximab
Chimeric mouse/human monoclonal Ab to CD20 protein on normal and malignant B lymphocytes.
- treatment of non-Hodgkin’s lymphoma; depletes B cells
- arthritis adjunct with methotrexate
Basiliximab
IL-2 receptor antagonist; recombinant monoclonal Ab to CD25, which is expressed on T cells and requires activation for T cell proliferation.
Decreases IL-2 activation by blocking its receptors.
Prophylaxis of acute rejection of renal transplants; used with cyclosporine and corticosteroids.
Muromomab
Binds to CD3 glycoprotein on T-cells; CD3 is next to the antigen recognition complex on T cells. Thus, Muromomab blocks antigen recognition by T-cells.
Abatacept
Blocks CD28 on T cells.
CD26 and CD80 are co-stimulators on APC that will normally bind to CD28 on T cells and enlist a response. Blocking of CD28 however, means that a response will not be formed even after binding of CD26/CD80.
Used for rheumatoid arthritis in patients with low response to methotrexate or TNF antagonists
Describe the necessary two steps for T cell activation:
- Binding of the T cell receptor to the antigen-MHC complex on the APC
- Co-stimulatory molecules CD80 & CD86 binding to T cell protein CD28 to the B7 protein on the APC
Give examples of four drugs that are useful in blocking either PD-1 or PD-L1 receptor/ligand. What is the normal role for these receptors/ligand?
Drugs: Pembrolizumab, Nivolumab, Atezolizumab, Avelumab
Tumor cells have a high expression for PD-1 receptors on T cells. Activation of this receptor via binding of PD-L1 of the tumor cells allows for the invasion of the T cell. These drugs thus allow for the T cell to recognize and kill the tumor cell, or ensure that a tumor cell cannot use this mechanism to evade cytotoxicity.
Anti-TNF-alpha drugs are useful in preventing TNF-a from binding to receptors and further stimulating the pro-inflammatory response. List three treatments that are used as anti-TNF-a drugs:
- Infliximab- antibody that binds TNF-a
- Adelimumab- antibody that binds TNF-a
- Etanercept- fusion protein
These are also arthritis adjunct to methotrexate
What is the principal signaling cytokines for T and B cell proliferation?
IL-2
Calcineurin inhibitors
Inhibits transcription of IL-2, IL-3, IFN-gamma; does NOT block IL-2 effect on T-cells, just inhibits transcription of IL-2 and therefore drastically decreases T cell activation.
Calcineurin acts to dephosphorylate NFAT (a transcription regulator), leading to transcription of proteins.
Describe the mechanisms leading to protein translation of IL-2, IFN, Bcl-Xb and TNF within T cells.
Recall, T cell activation requires 2 hits: CD80/CD86 activating CD28 on T cells, binding of T cell to antigen MHC.
- T cell is activated at CD3, initiating a tyrosine phosphate rxn *Gq mechanism
- Phospholipase C gamma 1 is phosphorylated
- IP3/Ca2 initiates signal transduction through transcription proteins Fos/Jun and activation of the phosphatase calcineurin
- Calcineurin dephosphorylates transcription factor of activated T cells (NFAT).
- Dephosphorylated NFAT leads to transcription of proteins.
Interfering with IL-2 expression is useful as a chemotherapeutic/immunosuppressive therapy. Describe how Sirolimus, everolimus, cyclosporine, and tacrolimus can be useful in minimizing expression of IL-2.
Cyclosporine/Tacrolimus- binds to FKBP proteins, preventing their interaction with calcineurin. This will decrease calcineurin’s ability to dephosphorylate NFAT, which ultimately prevents the transcription of IL-2 (and others).
Sirolimus- binds FKBP12 and thus inhibits mTOR kinase and ultimately inhibits IL-2 transcription
T or F: Calcineurin is the principal drug used to inhibit B and T cell activation? What was used prior to the development of calcineurin?
True. Corticosteroids were previously used. Corticosteroids exert their effects by inhibiting the release of IL-1 and IL-2 from T cells as well as TNF. These cytokines are required for T and B cell activation, as well as activation of macrophages and NK cells.
