Presentation on theme: "Immunosuppression Suppression of cellular functions in the clinical practice Immunosuppression Groups of immunosuppressive drugs: Corticosteroids "— Presentation transcript:
Immunosuppression Suppression of cellular functions in the clinical practice Immunosuppression Groups of immunosuppressive drugs: Corticosteroids Cytostatic drugs (alkylating agents, folic acid antagonists, purine/pyrimidien inhibitors) Non-cytostatic immunsuppressive agents (Cyclosporine A, Tacrolimus and Rapamycin) Cytokine and Cytokine receptor antibodies Leukopheresis; the removal of white blood cells Intravenous immunglobulins (IVIg)
Are apolar steroid hormones with broad biological effects. Able to penetrate the cell membrane and bind glucocorticoid receptors (GRs) in the cytosol. The newly formed receptor-ligand complex translocates to the nucleus where it binds glucocorticoid response elements (GRE) in the promoter region of different target genes. Transactivation Up-regulating the expression of anti-inflammatory cytokines. Transrepression Preventing translocation of pro-inflammatory transcription factors and cytokines repressing their expression (Ex. NF-κB, AP-1, IL-1β, IL-2, IL-4, IL-8, TNF-α etc. ). CORTICOSTEROIDS I Inhibiting leukocyte adhesion, migration, chemotaxis, phagocytosis and cytokine secretion
Very important anti-inflammatory mechanisms of corticosteroids are the inhibition of phospholipase A2 directly and indirectly (by synthesizing lipocortin-1; a PA2 inhibitor) and, the inhibition of cyclooxygenases (like NSAIDs). Inhibition of the arachidonic acid pathway decreases the pro-inflammation mediators prostaglandins (PGE 2 for example) and leukotrienes (LTs). CORTICOSTEROIDS II In addition as does endogenous cortisol: ↓ proliferation and differentiation of mast cells ↓ platelet activating factor ↓ NO production ↓ number of circulating T cells ↓ interleukin production ↓ IFN-γ production
CORTICOSTEROIDS RELIABLE EFFECTS & RELIABLE SIDE EFFECTS - Central obesity - Growth reatardation in childhood - Susceptibility to infections - Increased risk of thrombosis, coronary heart disease - Lengthened wound healing, ulcers - Gastric ulcer - Osteoporosis, aseptic bone necrosis - Hypertension - Hirsutism (excessive hairiness), atrophy of skin - Glaucoma, cataract Strict dose limitations, alternating dosage, gradual dose decreasing! Local administration: fewer (not as significant) side effects!
CYTOSTATIC DRUGS Agents for tumor therapy can inhibit the proliferation of lymphocytes. Effective alongside aggressive and severe side effects. Alkylating agents (Cyclophosphamide, Chlorambucil) Bind to guanine nucleotides, inhibiting DNA-replication; Effective, but causes severe leukopenia and lymphopenia. Anticancer treatment while for autoimmune disorders purine antagonists are prescribed more often. Folic acid antagonists (Methotrexate) Inhibition of nucleotide synthesis (Folic acid dependent) Hepatotoxic, so regular checks of liver enzymes are needed! Purine antagonist drugs (6-mercaptopurine, Azathioprine and Mycophenolate mofetil) T- and B-cells have no runaround scavanger recovery pathway, they can produce purine nucleotides through de novo pathway.
NON-CYTOSTATIC IMMUNOSUPPRESSIVE DRUGS: Cyclosporin A. Cyclic peptide of 11 amino acid that binds cyclophylin, a cytosolic protein. This complex of cyclosporin and cyclophylin prevents the activation of calcineurin that is responsible for activating IL-2 transcription factor NF-AT. Tacrolimus (FK506). Large cyclic compound that acts like the cyclosporin but on different cyclophillin (FKBP-12). Rapamycin (Sirolimus) binds FKBP-12, but this complex acts on an other serine/threonine phosphatase (mammalian target of rapamycin or "mTOR" = PP2A), not on calcineurin (PP2B). Used in transplant medicine to prevent rejection, psoriasis, atopic dermatitis, arthritis and related diseases. * Cyclophilin is an isomerase catalyzing trans to cis isomeration od peptides during protein folding.
Cyclosporin A and tacrolimus (FK506) inhibits cell activation by neutralyzing the serine/threonine phosphatase calcineurin
Tacrolimus Rapamycin (Sirolimus) Cyclosporin A IMMUNOSUPPRESSIVE DRUGS NON-CYTOSTATIC DRUGS ACTING ON T CELLS
CYTOKINE AND CYTOKINE RECEPTOR ANTIBODIES: Cytotoxic and blocking monoclonal antibodies (MAB) targeting different cytokines or receptors. MAB targeting CD3 on the surface of T cells. Transplant medicine. many more tagets…CD4, CD2, CD7, CD20, CD25 HLA-D, IL-17, IL-23, IL-6. MAB targeting TNF-α used for autoimmune disorders like RA and IBD Infliximab and Adalimumab. MAB targeting IL-2 used for preventing transplant organ rejection Basiliximab and Daclizumab. MAB targeting IgE used for allergic asthma Omalizumab. Act by either blocking different receptors inhibiting cell function, or opsonizing the targeted cells activating complement pathways resulting in phagocytosis.
IMMUNOSUPPRESSIVE DRUGS MAB TARGETING CYTOKINES OR CYTOKINE RECEPTORS Basiliximab Daclizumab Infliximab Omalizumab
LEUKOTRIENE PATHWAY INHIBITION: Used as prophylaxis for asthma. Improve asthma control and reduce frequency of exacerbations. Leukotrienes are arachidonic acid derivatives synthesized by inflammatory cells in the airway (eosinophils, mast cells, macrophages and basophils). LTB 4 chemoattractant LTC 4 and LTD 4 increase bronchial reactivity, constriction, mucosal edema and mucus secretions. Zileuton inhibits 5-lipooxygenase. Zafilukast and Montelukast are LTD 4 receptor antagonists.
OTHER IMMUNOSUPPRESSIVE AGENTS: Fingolimod (FTY720) Acts on adhesion molecules (α4/β7 integrin) on lymphocytes causing their accumulation in the lymph nodes, rather than the peripheral circulation, preventing their movement into the CNS. Reduce relapses and delay disability progression in patients with relapsing forms of multiple sclerosis (MS). Glatiramer acetate Prescribed for MS. Reduces the frequency of relapses but not he progression of disability. Mechanism not fully known. Th1 Th2 shifting ? diverting the autoimmune response against myelin.
TREATING INFLAMMATION: Goals: 1)Pain reliefe 2)Slow or arrest tissue-damaging processes NSAIDs have analgesic and antipyretic effects, but its their anti-inflammatory action that makes them useful in management of disorders where pain is related to the intensity of an inflammatory process (rheumatic disease for ex.) NSAIDs mechanism of action: 1. Inhibiting prostaglandin synthesis 2. Inhibiting chemotaxis 3. Downregulation of IL-1 expression 4. Decrease free radicals and superoxides NSAIDs Aspirin DMARDs Corticosteroids
MYELOID GROWTH FACTORS: Stimulate proliferation and differentiation of myeloid stem cells. Used in transplantation. Recombinant human G-CSF (Filgrastim) increase stem cells mobilization to the periphery (↑ peripheral blood stem cells PBSCs) and stimulates the neutrophil lineage. and GM-CSF (Sargramostin) stimulates early and late granulocytic progenitor cells (as well as erythroid). GM-CSF + IL-2 ↑ T cell proliferation. Used to treat neutropenia after cytotoxic chemotherapy and after stem cell transplantation.