What are immunosuppressive drugs?
What are immunostimulatory drugs?
Immunosuppressive- used to dampen the immune response in organ transplantation and autoimmune diseases
Immunostimulatory- applicable to the treatment of infection, immunodeficiency, cancer
What is innate and acquired immunity?
Innate- immediate onset of action, recognizes antigens by receptors that recognize commune molecules on microbes and viruses
Ex: macrophages, neutrophils, mast cells,
Acquired- days to weeks onset of action, recognizes antigens by unique antigen specific receptors (T cell receptors, B cell receptors)
Ex: antigen presenting cells, T lymphocytes, B lymphocytes
What are the 2 types of acquired immune responses?
Cell mediated response- involve Th1-mediated activation of macrophages and generation of CD8+ cytotoxic T lymphocytes (CTLs)
Humoral responses- involve that Th2 cells secrete cytokines that stimulate proliferation and differentiation of B cells to antibody secreting plasma cells
What are the 5 cardinal signs of acute inflammation?
- Redness (rubor)
- Heat (calor)
- Swelling (tumor)
- Pain (dolor)
- Loss of function
What do each of these cells do: Neutrophils Eosinophils Monocytes/macrophages Platelets Mast cells/basophils T lymphocytes B lymphocytes NK cells Dendritic cells Endothelium Fibroblasts
Neutrophils- first line defence (not found in normal tissues)
Eosinophils- can kill worms
Monocytes/macrophages- Kelly’s of chronic adaptive inflammation
Platelets- upkeep of normal endothelium, key role in blood clotting
Mast cells/basophils- loaded with histamine, can produce many cytokines (triggers a cut inflammation)
T lymphocytes- T cell immune responses (secrete cytokines, kill cells)
B lymphocytes- B cell immune responses, produce antibodies, become plasma cells
NK cells- cell killer not dependant on immune
Dendritic cells- antigen presentation
Endothelium- mediated exchanges of fluid/cell
Fibroblasts- produce matrix
What role do TNFα and IL-1 play in rheumatoid arthritis (RA)?
- Increased cellular infiltration into the endothelium due to release of histamine, kinins, and vasodilators PGs
- Increased production of C-reactive protein by hepatocytes
- Increased production and release of proteolytic enzymes (collagenases) by chondrocytes (cell that contain cartilage), which leads to degradation of cartilage and joint space narrowing
- Increased osteoclast activity resulting in focal bone erosions and bone demineralization around joints
- Systematic manifestation in which organs such as the heart, lungs and liver are adversely affected
What are the 2 types of chemical mediators in inflammation?
What’s the difference between them?
Cytokines (interleukins, interferons, tumor necrosis factor)
Bacterial chemotaxins (fMLP)
Anti-leukocytic factors (leukocidin)
Macrophage activators (endotoxin)
Difference between endo and exo is exo N-formyl methionine terminal amino acids from bacteria (lipids from destroyed bacterial membranes) and endo complement proteins (C5a)
What are chemokines?
Family of chemotactic cytokines that are secreted or membrane bound
Key players in inducing leukocyte transendothelial migration
50 chemokines in humans
α, β, γ, δ categories
They transmit signals to cells via binding to chemokine receptors which are all 7 transmembrane G protein coupled receptors
What are the 4 categories of immunosuppressive drugs?
- Glucocorticoids- prednisone, prednisolone, methylprednisolone
- Cytokine inhibitors (Calcineurin inhibitors)- cyclosporine, tacrolimus, sirolimus,
- Cytotoxic drugs- antimetabolites, alkylating agents
- Antibodies & biologic agents- antithymocyte globulins, muromonab CD3, basiliximab, daclizumab
What are the first category of immunosuppressive drugs: glucocorticoids?
Regression of lymphoid tissues
Enhance destruction of lymphocytes (especially T cells)
Interfere with the cell cycle of activated lymphoid cells
Inhibit leukocyte functions
Inhibit antibody formation
Inhibit inflammatory mediators
Prednisone inhibits action of COX-2
Adverse effects- suppresses pituitary adrenal axis, increased risk of serious infections, peptic ulcer, catabolic effects
What are the 2nd category of immunosuppressive drugs: cytokine inhibitors?
Cytokines are soluble antigen non specific signalling proteins that bind to cell surface receptors on cells
IL-2 is cytokine that stims proliferation of antigen primed (helper) T cells
Cyclosporine preferentially suppresses cell mediated immune reactions
Sirolimus binds FKBP-12 firming complex woth mTOR, blocking progression of activated T cells
Adverse effects: nephrotoxicity, hepatotoxicity, predispose time infections, lymphoma may occur, hypertension, hyperkalemia, tremor
What are the 3rd category of immunosuppressive drugs: cytotoxic drugs?
Used in combo with glucocorticoids and Calcineurin inhibitors
Immunosuppressive antimetabolites interfere with the availability of normal purine and pyrimidine nucleotide precursors either bun inhibiting their synthesis or by competing with them in DNA or RNA synthesis
Alkylation of DNA (covalent bonding) is the cytotoxic reaction that is lethal to the cells
Methotrexate- decreases biosynthesis of adenine, guanine, methionine, and serine
Leflunomide- reversibly inhibits dihydroorotate dehydrogenase
Mechlorethamine- alkylates N7 nitrogen of guanine residue
Cyclophosphamide- most common, alkylates DNA
What are the 4th category of immunosuppressive drugs: antibodies?
Polyclonal, monoclonal, humanized, chimeric antibodies
Antithymocyte globulins- purified polyclonal antibiotics causes depletion of T cells
Muromonab-CD3- depletes human T cells used for autoimmune disorders
AE: cytokine release syndrome
Intravenous immunoglobulins (IVIg)- IV use of polyclonal human Ig
Hyperimmune immunoglobulins- IVIg with high titers of antibiotics
Omalizumab- anti-IgE recombinant
IL-2 receptor antagonists- basiliximab, daclizumab
What are TNFα antagonists (TNFα blockers)?
Infliximab- chimeric antibody
Adalimumab- humanized antibiotic
Etanercept- fusion protein comprising part of TNF p75 receptor and the Fc portion of human IgG
Certolizumab- pegylated antibody lacking Fc region
Golimumab- humanized antibody
AE: injection site reactions, active infections must be treated before administering anti-TNFα, increased risk for malignancies
What is anakinra?
Recombinant form of IL-1 receptor antagonist which differs from the natural protein by a single methionine residue at its amino terminus
Similarly clinic uses and adverse effects as TNFα antagonists
Asthma may be comorbid risk factor for serious infections
Increases risk of neutropenia and serious infections
What is interleukin-2 (IL-2)?
Recombinant human IL-2 is produced by recombinant DNA technology
Enhances cellular immunity (promotes proliferation and differentiation of lymphocytes into CTLs and activation of NK cells)
Used as treatment for breast cancer, metastatic renal cell carcinomas and AIDS
AE: severe CV toxicity from capillary leak syndrome
What are coming stimulating factors (CSFs)?
Granulocyte CSF stimulates the production of neutrophils
Granulocyte macrophage CSF stimulates production of granulocytes, platelets, erythrocytes, eosinophils, and macrophages