3.1 Immune Modulation & Iatrogenic Immunodeficiency Flashcards
[Boosting the immune response: Bone Marrow Transplant]
Bone marrow transplant offers potential for complete and permanent cure:
• May be autologous (self), allogenic (others), or _______________
• Indications: life-threatening ___________________ (SCID, leukocyte adhesion defects), haematological malignancies
• Side effects: BM transplants given with _________________ (prevent transplant rejection) often damages immune system and increases risk of infections
umbilical cord transplants;
primary immunodeficiencies;
high dose chemotherapy
[Boosting the Immune Response: Antibody Replacement]
Human normal immunoglobulin is prepared from pools of > 1000 donors, and contains pre-formed IgG antibody to a wide range of unspecified organisms (IVIG if given IV):
• Donors are screened for __________________ and blood products are further treated (to kill any remaining live viruses)
• Confers immediate passive immunity (declines after 3 – 4 weeks) → half-life of ___________, so dosing is given every 3 – 4 weeks
Indications
- Primary antibody deficiency: X-linked agammaglobulinaemia, X-linked hyper-IgM syndrome, CVID
- Secondary antibody deficiency: Haematological malignancies (CLL, multiple myeloma), post-bone marrow transplantation
- Post-exposure prophylaxis: Using immunoglobulins derived from plasma donors with _______________ to specific pathogens
• Hepatitis B immunoglobulin
• Tetanus immunoglobulin
• ________ immunoglobulin (given to travellers bitten by animals)
• ______________ immunoglobulin (given to the immunocompromised, pregnant or neonates)
*Under most circumstances, immunisation is given at the same time (offers greater protection).
HBV, HCV and HIV;
18 days;
high titres of IgG antibodies;
Rabies;
Varicella-zoster
[Boosting Immune Response: T CELL REPLACEMENT]
______________ T cells are harvested prior to chemotherapy treatment, and are then expanded in vitro and reinfused:
• May be autologous (self) or donor (HLA-matched)
• Not currently widely available (small clinical trials assessing this treatment) → conducted on people at risk of developing chronic viral infections (e.g. CMV _______________, EBV ________)
Virus-specific;
pneumonitis/retinitis;
lymphoma
[Boosting immune response: Recombinant cytokines]
Recombinant cytokines are used as adjuncts for many conditions, including boosting the immune response to cancer and specific pathogens:
- IFN-α*: Hepatitis B, Hepatitis C, hairy cell leukaemia, CML, multiple myeloma
- IFN-β: Older treatment for _____________ (mechanism unknown)
- IFN-γ: ___________________
- IFN-α has many side effects, including aches, fevers, and depression.
relapsing multiple sclerosis;
Chronic granulomatous disease
[Suppressing the immune response: Corticosteroids]
Corticosteroids are the most widely prescribed immunosuppressants (especially prednisolone), and synthetic glucocorticoids are based on naturally occurring steroids with no _____________ activity:
• Steroids have different formulations (IV preparations, tablets, creams and inhalers)
• Indications: treat allergic disorders, autoimmune diseases, autoinflammatory diseases, transplantation and malignant diseases (especially ______________)
Immune effects
- Reduces prostaglandin synthesis
- Inhibits phagocyte migration and function
- Inhibits lymphocyte function and promotes apoptosis
Metabolic Effects
- Diabetes (increased ___________)
- Obesity
- Hypertension
- Lipid abnormalities
- Osteoporosis
mineralocorticoid;
haematological;
gluconeogenesis
[Corticosteroids: Mechanism of action]
Corticosteroids cause many of their effects by binding to the glucocorticoid receptor (GR):
GR binding
- Upregulates expression of anti-inflammatory proteins in the nucleus of cells via binding to ______________ in target genes
- Represses expression of pro-inflammatory proteins (e.g. cytokines) by interacting with other transcription factors (e.g.__________)
Anti-inflammatory
1. Inhibits ______________ (breaks down lipids to form arachidonic acid, which is converted to eicosanoids by COX) → blocks the formation of arachidonic acid and thus prostaglandins
Phagocytes
- Blocks phagocytic trafficking to inflamed tissue by blocking signals telling immune cells to move into tissues and decreasing expression of ________________ → transient increase in serum neutrophil counts (neutrophilia)
- Decreases phagocytic activity (less phagocytosis)
- Decreases release of _________________
Lymphocytes
- Sequestration in lymphoid tissues → lymphopenia (affecting _____ cells > _______ cells > _______cells)
- Blocks cytokine gene expression
- Decrease antibody production
glucocorticoid response elements (GREs);
NFκB, AP-1;
phospholipase A2;
endothelial adhesion molecules;
proteolytic enzymes ;
CD4+, CD8+, B
[Corticosteroids: side effects]
A patient on high-dose steroids must be weaned off slowly as exogenous steroids suppress the body’s natural production of cortisol, so sudden removal causes low levels of cortisol in the body (_____________crisis):
Effects
- Metabolic (Cushing-like): Diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsutism, _______________ (negative feedback)
- Others: Cataracts, glaucoma, peptic ulceration, pancreatitis, avascular necrosis
- Immunosuppression
Addisonian;
adrenal suppression
Anti-proliferative agents (cyclophosphamide, azathioprine, mycophenolate, methotrexate) act to inhibit ______________, so cells with rapid turnover (e.g. ________________) are the most sensitive.
DNA synthesis;
BM stem cells, skin, GI tract, developing foetus
[Antiproliferative agent: Cyclophosphamide]
Cyclophosphamide is used as a cancer chemotherapy agent and immunosuppressant:
Mechanism: Alkylating agent (adds CnH2n+1 group to a _________ base in DNA) and displaces ______ from within DNA causing the formation of inter-strand crosslinks:
• Detected by ______, which forces the cell to undergo apoptosis
• Affects ____________ (at high doses, it affects all cells with high turnover)
Indications: Toxic medication → reserved from more severe connective tissue diseases or vasculitis with severe end-organ involvement (e.g. Wegener’s granulomatosis, SLE)
Side effects
- Toxic to proliferating cells: BM depletion, hair loss, sterility (males > females)
- ________________: acute haematuria (toxic metabolite acrolein excreted via urine)
- Malignancy: bladder cancer, haematological malignancies, _______________ skin cancer
- Infections: Pneumocystis jirovecii (prophylaxis: ____________)
guanine;
chlorine;
p53;
B cells > T cells;
Haemorrhagic cystitis;
non-melanoma;
cotrimoxazole
[Antiproliferative agent: Azathiprine]
Azathioprine is metabolised in the liver to ________________ (active), which blocks de novo ________ (e.g. adenine, guanine, hypoxanthine) synthesis:
Mechanism: Competitive inhibitor of HGPRT (transferase which catalyses the conversion of hypoxanthine to ___________ and guanine to _____________) which is essential for generation of purine nucleotides through the purine salvage pathway:
• More effective in some tissues (vary in their capacity to synthesise nucleosides de novo) → BM, T cells, macrophages, dendritic cells
Indications: Transplantation, autoimmune disease (e.g. RA), autoinflammatory disease (e.g. Crohn’s disease, ulcerative colitis)
Side effects
1. BM suppression: cells with rapid turnover (leukocytes, platelets) are particularly sensitive, with 1 in 300 individuals being extremely susceptible (including neutropenia):
• __________________ polymorphisms: cannot metabolise azathioprine (high risk of side effects)
• Check TPMT activity/gene variants before treatment (if possible), and always check FBC after treatment
2. Hepatotoxicity: idiosyncratic and uncommon
3. Infections: less common than with cyclophosphamide
6-mercaptopurine;
purine;
inosine monophosphate;
guanosine monophosphate;
Thiopurine methyltransferase (TPMT)
[Antiproliferative agentr: Mycophenolate] Mycophenolate mofetil (active component is \_\_\_\_\_\_\_\_\_\_\_\_\_\_) inhibits an enzyme which controls the synthesis of \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ (in the de novo pathway):
Mechanism: Prevents the synthesis of guanosine monophosphate and thus cell proliferation (affects ____________; also macrophages and DCs)
Indications: Widely used in transplantation (alternative to azathioprine), autoimmune diseases and vasculitis (alternative to cyclophosphamide)
Side effects
- BM suppression: cells with rapid turnover) particularly sensitive
- Infections: particular risk of _______________ → mitigated via valacyclovir or acyclovir), progressive multifocal leukoencephalopathy (JC virus → patchy loss of ___________ rapidly progressive, almost always fatal but rare incidence)
mycophenolic acid;
guanosine monophosphate
T cells > B cells;
herpesvirus reactivation (e.g. HSV, CMV, EBV;
myelin,
[Antiproliferative agent: Methotrexate]
Methotrexate is prescribed more commonly than the other anti-proliferative agents, and is used for a range of rheumatological and dermatological conditions and chemotherapy:
Mechanism: Competitively inhibits dihydrofolate reductase (DHFR) involved in the synthesis of _____________ → folate is essential for base biosynthesis (methotrexate blocks DNA, RNA, thymidylate and protein synthesis):
• DHFR is targeted by antibiotics (___________) and antiprotozoal agents _________________) for malaria/toxoplasmosis
• Sulfonamides block enzymes higher up in the pathway (dihydropteroate synthetase) → ________________ forms co-trimoxazole (used prophylactically and for Pneumocystis jirovecii pneumonia)
Mechanism not fully understood (but DHFR inhibition thought to reduce the proliferation of T cells and other inflammatory cells):
• Inhibits T cell activation and suppression of intercellular adhesion molecule expression by T cells
• Increases ___________________ sensitivity of activated T cells Indications
Widely prescribed for RA, vasculitis, psoriasis, anti-cancer agent, induction of medical termination of pregnancy (avoid in pregnancy or those planning to conceive)
Side effects
1. __________________ (sore, painful mouth)
2. Reduced lymphocytes, BM suppression (at higher doses) → predisposition to infection
3. Pneumonitis and hepatitis
thymidine;
trimethoprim;
(pyrimethamine and proguanil;
sulfamethoxazole + trimethoprim;
CD95 (FasR);
Ulcerative stomatitis
INHIBITORS OF CELL SIGNALLING
The main agents used are cyclosporin and tacrolimus, which are ___________ inhibitors (specific inhibitors of T cell signalling pathways):
• Cyclosporin is a small molecule (11aa cyclopeptide), while tacrolimus is a larger macromolecule
Mechanism: Bind to a family of cytoplasmic proteins found in most cells with high affinity (cyclosporin binds to _________; tacrolimus binds to ______________):
• Once bound to their respective cytoplasmic protein receptors, they then competitively bind to and inhibit calcineurin (calcium and calmodulin-dependent phosphatase)
• Inhibits the translocation of a family of transcription factors (______) → reduced transcription and activation of early cytokine genes (e.g.________________) → reduced lymphocytic proliferation
Indications
- Prevent rejection of solid organ transplant (e.g. liver, kidney, heart)
- Treatment of GVHD post-BM transplant
- Autoimmune conditions (e.g. RA, psoriasis)
- Topical for severe skin conditions (e.g. eczema, lichen sclerosis)
Side effects
- Heavy immunosuppression post-transplant → increased risk of conventional infections (e.g. pneumonia, UTIs, fungal infections)
- Risk of opportunistic infections: normally relatively harmless infectious agents causing severe infections in immunocompromise (e.g. CMV ___________, BK virus _________, PCP)
- Increased risk of malignancies: 100x viral-associated (Kaposi sarcoma/HHV8, lymphoproliferative disease/EBV, anorectal, cervical, vulval, throat/HPV), 20x skin cancer (basal cell carcinoma, squamous cell carcinoma), 2 – 3x other cancers (lung, colon)
calcineurin;
cyclophilin;
FK binding proteins;
NFATc;
IL-2, TNF-α, G-CSF;
retinitis and colitis;
nephritis
Sirolimus is a related compound which acts via a different mechanism of action to cyclosporin and tacrolimus, but with similar indications:
• Blocks the downstream response of T cells to cytokines (e.g. IL-2), inhibiting T cell growth and replication rather than blocking T cell receptor mediated signalling pathway and cytokine generation
• Cyclosporin/tacrolimus blocks cytokine transcription; sirolimus blocks ______________
cytokine response
Muromonab (OKT3)
- ___________ on T cells (T cell co-receptor) by binding to _____________ and inhibits T cell proliferation and causes apoptosis:
• Side effects: cytokine release syndrome before inhibition effects
- Prophylaxis of allograft rejection (given IV before and after surgery)
Anti-CD3;
TCR-CD3 complex
