Immune modulating therapies 2 Flashcards
What drugs suppress the immune response?
Steroids Anti-proliferative agents Plasmapheresis Inhibitors of cell signalling Agents directed at cell surface antigens Agents directed at cytokines
What are corticosteroids?
Synthetic glucocorticoids Based upon naturally occuring steroids No mineralocorticoid activity Prednisolone in Europe Prednisone in USA metabolised by liver into prednisolone Endogenous secretion equivalent to 5-7.5 mg prednisolone
Hench, Kendall and Reichstein received Nobel Prize in 1950
What are steroids used for?
Allergic disorders Auto-immune disease Auto-inflammatory diseases Transplantation Malignant disease
What is the action of steroids on prostaglandins?
Phospholipase A2
- Breaks down phospholipids to form arachidonic acid which is converted to eicosanoids (eg prostaglandin)s, leukotrienes) by cyclo-oxygenases
Corticosteroids inhibit phospholipase A2
- Blocks arachidonic acid and prostaglandin formation and so reduces inflammation
What is the action of steroids on phagocytes?
Decreased traffic of phagocytes to inflamed tissue
Decreased expression of adhesion molecules on endothelium
Blocks the signals that tell immune cells to move from bloodstream and into tissues
Results in transient increase in neutrophil counts
Decreased phagocytosis
Decreased release of proteolytic enzymes
What is the action of steroids on lymphocytes?
Lymphopenia
Sequestration of lymphocytes in lymphoid tissue
Affects CD4+ T cells > CD8+ T cells > B cells
Blocks cytokine gene expression
Decreased antibody production
Promotes apoptosis
What are the SEs of steroids?
Diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsuitism, adrenal suppression
Cataracts, glaucoma, peptic ulceration, pancreatitis, avascular necrosis
Immunosuppression
What are the Cytotoxic agents Anti-proliferative immunosuppressants?
Cyclophosphamide
- Mycophenolate
- Azathioprine
- Methotrexate
What is the action anti proliferative immunosuppressants?
Inhibit DNA synthesis
Cells with rapid turnover most sensitive
What is the SEs of anti proliferative immunosuppressants?
Bone marrow suppression
Infection
- Malignancy
- Teratogenic
What is the MOA of cyclophosphamide?
Alkylates guanine base of DNA
Damages DNA and prevents cell replication
Affects B cells > T cells, but at high doses affects all cells with high turnover
What is the indications of cyclophosphamide?
Multisystem connective tissue disease or vasculitis with severe end-organ involvement
eg GPA (Wegener’s granulomatosis), SLE
Anti-cancer agent
What are the SEs of cyclophosphamide?
Toxic to proliferating cells
Bone marrow depression
Hair loss
Sterility (male»female)
Haemorrhagic cystitis
Toxic metabolite acrolein excreted via urine
Malignancy
Bladder cancer
Haematological malignancies
Non-melanoma skin cancer
Infection
Pneumocystis jiroveci
What is the MOA and indications of azathioprine?
Mechanism of action
Metabolised by liver to 6 mercaptopurine
Blocks de novo purine (eg adenine, guanine) synthesis – prevents replication of DNA
Preferentially inhibits T cell activation & proliferation
Indications
Transplantation
Auto-immune disease
Auto-inflammatory diseases, eg Crohn’s, ulcerative colitis
What is the SEs of azathioprine?
Bone marrow suppression
Cells with rapid turnover (leucocytes and platelets) are particularly sensitive
1:300 individuals are extremely susceptible to bone marrow suppression s
Thiopurine methyltransferase (TPMT) polymorphisms
Unable to metabolise azathioprine
Check TPMT activity or gene variants before treatment if possible; always check full blood count after starting therapy
Hepatotoxicity
Idiosyncratic and uncommon
Infection
Serious infection less common than with cyclophosphamide
What is the MOA and indications of mycophenolate mofetil?
Mechanism of action
Blocks de novo nucleotide synthesis
– prevents replication of DNA
Prevents T>B cell proliferation
Major Indications
Widely used in transplantation as alternative to azathioprine
Also used in auto-immune diseases and vasculitis as alternative to cyclophosphamide
What is the SEs of mycophenolate mofetil?
Bone marrow suppression Infection
Cells with rapid turnover (leucocytes and platelets) are particularly sensitive
Infection
Particular risk of herpes virus reactivation
Progressive multifocal leukoencephalopathy (JC virus)
What is plasmapheresis?
Aim: removal of pathogenic antibody
Patient’s blood passed through cell separator
Own cellular constituents reinfused
Plasma treated to remove immunoglobulins and then reinfused (or replaced with albumin in ‘plasma exchange’)
Problems
Rebound antibody production limits efficacy, therefore usually given with anti-proliferative agent
Indications for plasmapheresis?
Severe antibody-mediated disease
Goodpastures syndrome
Anti-glomerular basement membrane antibodies
Severe acute myasthenia gravis
Anti-acetyl choline receptor antibodies
Severe vascular rejection
Antibodies directed at donor HLA molecules
What are Inhibitors of cell signalling (Calcineurin inhibitors)?
Ciclosporin
Tacrolimus
What do Inhibitors of cell signalling (Calcineurin inhibitors) do?
Block cytokine transcription, therefore prevent T lymphocyte proliferation and effector functions
Used for Transplant, SLE and psoriatic arthritis
What are the side effects of calcineurin inhibitors?
Nephrotoxicity HTN Neurotoxic Diabetes (Ciclosporin) Dysmorphic features
