Immune modulators Flashcards
What is IL-2 and what does it do?
A cytokine that stimulates the cell-mediated immune response.
What can recombinant IL-2 be used to treat?
Metastatic melanoma and renal cell carcinoma.
How does CsA and FK-506 work to suppress the cell mediated immune response?
IL-2 modulator.
CsA and FK-506 (Tacrolimus) enter the T cell.
Bind to immunophillins (CyP A and B and FKBP 12).
Complex binds to calcineurin.
Calcineurin cannot bind to and de-phosphorylate NF-AT.
NF-AT cannot enter nucleus and bind to IL-2 promoter. Therefore, IL-2 not synthesised.
How does Rapamycin work to suppress the cell mediated immune response?
IL-2 modulator.
Rapamycin (sirolimus) binds to FKBP.
Complex binds to mTOR.
Causes cell cycle arrest at G1.
Therefore, inhibits signalling of IL-2.
Clinical use of CsA and FK-506/Tacrolimus?
To prevent rejection in organ transplants/allografts.
Clinical uses of rapamycin/sirolimus?
- To prevent rejection in organ transplants/allografts.
- To treat cancer.
- To prevent stent-induced intimal hyperplasia by using coated stents.
Toxicity of IL-2 modulators?
Nephrotoxicity.
Rapamycin less toxic but tends to cause dyslipidemia.
Examples of IL-1 modulators?
Anakinra and Canakinumab.
Clinical use of IL-1 modulators?
RA.
Key actions of TNF a?
Increase inflammation Increase cell infiltration Increase angiogenesis Increase CRP in serum Articular cartilage degradation.
Examples of TNFa modulators?
Etanercept Infliximab Adalimumab Golimumab Certolizumab. Thalidomide.
(Refer to cytokine lecture slide 38 on nomenclature and the drug document.)
Examples of stimulatory cytokines?
IL-1, 2 and TNF
Examples of inhibitory cytokines?
IL-4, 10, 13.
What is cyclophoshamide and what does it do?
Alkylating cytotoxic immunosuppressant.
Causes leucopenia (granulocytes, lymphocytes, monocytes, and inhibit NK cells.)
SE’s: Alopecia and nausea.
What are integrins?
Cell adhesion molecules. Usually proteins.
e.g, GPIIb/IIa ( alpha IIb/ beta3) on platelets.
Beta2 on lymphocytes.
What is Natalizumab (Tysabri) and what is it used for?
Monoclonal antibody. Treats MS. Also useful in crohn’s disease.
Binds to Alpha4 integrins (Alpha4Beta7 and Alpha4Beta1).
Blocks binding of inflammatory cells to endothelium. Prevents immune cells entering the brain and causing damage in MS.
SE of Natalizumab?
Causes PML (progressive multifocal leukoencephelopathy).
What does Vedolizumab and Etrolizumab do?
Bind to Alpha4Beta7 integrins. Treat crohn’s disease and ulcerative colitis.
What does S1P do and how does it do it?
S1P promotes the egress of lymphocytes from lymph tissue and into the lymph vessels and blood.
This is because there is a high conc of S1P in blood and lymph but low conc in lymph tissue. Therefore, lymphocytes follow the S1P gradient into the blood.
What does Fingolimod (FTY720) do and what does it treat?
Downregulates S1P receptor.
So prevents egress of lymphocytes by S1P.
Treats MS.
Fingolimod adverse effects?
Heart rate and conduction effects.
Oedema
Some cases of skin cancers and PML.
Increased infections.
What does rituximab do and what does it treat?
B cell depletion:
Binds to CD20 on B cells, triggering complement formation and lysis.
Used to treat B cell lymphoma, leukaemia, and RA.
Adverse effects of rituximab?
SIRS and PML.
What does Alemtuzumab do and what does it treat?
Depletes lymphocytes:
Binds to CD52 on lymphocytes.
Used to treat MS and T cell leukaemia.
