Suppression of cellular functions in the clinical practice  I mmun o suppression

1. 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 Cytokinereceptor antibodies • Leukopheresis; the removal of white blood cells • Intravenous immunglobulins(IVIg)

2. Indications for immunosuppression: • Inflammation (dermatology, pulmonology) • Allergic diseases • Autoimmune diseases • Transplantation

3. Corticosteroids I 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. ). Inhibiting leukocyte adhesion, migration, chemotaxis, phagocytosis and cytokine secretion

4. Corticosteroids II Very important anti-inflammatory mechanisms of corticosteroids are the inhibition of phospholipase A2directly 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 (PGE2 for example) and leukotrienes (LTs).

5. Corticosteroidsreliable 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 limitation, alternating dosage, gradual dose decreasing! • Local administration: fewer (not significant) side effects!

6. Immunosuppressive drugscorticosteroids Prednisolone Methylprednisolone Budesonide Triamcinolone betamethasone

7. Cytostatic drugs • Agents fortumor therapy can inhibit the proliferation of lymphocytes. • Effective alongside aggressive andsevere side effects. • Alkylating agents (Cyclophosphamide, Chlorambucil) • Bind to guanine nucleotides, inhibiting DNA-replication; • Effective, but causessevere 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 checksof liver enzymes are needed! • Purine antagonist drugs (6-mercaptopurine, Azathioprine and • Mycophenolate mofetil) • T- and B-cells have no runaround scavangerrecovery pathway, they can produce purine nucleotidesthrough denovo pathway.

8. Immunosuppressive drugsCytostatic drugs Mycophenolatemofetil Azathioprine Methotrexate Cyclophosphamide

9. Non-cytostatic immunosuppressive drugs: • Cyclosporin A.Cyclic peptide of 11 amino acid that bindscyclophylin, acytosolic protein.This complex of cyclosporin and cyclophylinprevents 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 cisisomeration od peptides during protein folding.

10. Cyclosporin A and tacrolimus (FK506) inhibits cell activation by neutralyzing the serine/threonine phosphatase calcineurin

11. Immunosuppressive drugsnon-Cytostatic drugs acting on T cells Tacrolimus Rapamycin (Sirolimus) Cyclosporin A

12. Cytokine and cytokine receptor antibodies: • Cytotoxic and blocking monoclonal antibodies (MAB) targeting different cytokines or receptors. • MAB targeting CD3on 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-αused for autoimmune disorders like RA and IBD  Infliximab and Adalimumab. • MAB targeting IL-2 used for preventing transplant organ rejection  Basiliximab and Daclizumab. • MAB targetingIgEused for allergic asthma  Omalizumab. • Act by either blocking different receptors  inhibiting cell function, or opsonizing the targeted cells activating complement pathways resulting in phagocytosis.

13. Immunosuppressive drugsMab targeting cytokines or cytokine receptors Basiliximab Daclizumab Omalizumab Infliximab

14. 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). • LTB4 chemoattractant • LTC4 and LTD4  increase bronchial reactivity, constriction, mucosal edema and mucus secretions. • Zileuton inhibits 5-lipooxygenase. • Zafilukast and Montelukastare LTD4receptor antagonists.

15. Immunosuppressant drugsLeukotriene antagonists Montelukast Zileuton Zafirlukast

16. Other immunosuppressive agents: • Fingolimod (FTY720) Acts on adhesion molecules (α4/β7 integrin) • on lymphocytes causing their accumulation in thelymphnodes, 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 • frequencyof relapses but not he progression of disability. • Mechanism not fully known. Th1  Th2 shifting ? • diverting the autoimmune response against myelin.

17. Treating inflammation: NSAIDs Aspirin DMARDs Corticosteroids • Goals: • Relief pain • 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. Down-regulation of IL-1 expression • 4. Decrease free radicals and superoxides

18. Immunostimulants

19. 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.

20. Interferons • IFN-γ immune enhancing properties. • Increases antigen presentation, MHC molecules • Increases activation of macrophages, NK cells and cytotoxic T cells • USE of IFNγ: CGD • IFN-α and β inhibit cell proliferation, increase MHC expression. • USE of IFNα: Hairy cell leukaemia, Chronic Myeloid Leukemia, Melanoma, Kaposi sarcoma, Hepatitis B, C, Renal carcinoma, T-cell leukemia • USE of IFNβ: Relapsing MS * Since they have a short half life- s.c administered

21. Cytokines applied in therapy:

22. Immunostimulant drugs IL-2 Imiquimod Inosinepranobex Peginterferon alpha 2b Peginterferon alpha 2a

23. Natural immune system “boosters” Some examples of the 50 fundamental traditional Chinese medicinal herbs: * Astragaluspropinquus (huángqí) Forsythiasuspensa (liánqiào) Lonicera japonica / Japanese honeysuckle (Jinyinhua) Echinacea Esberitox (A mix of Thujaoccidentalis, Baptisia and Echinacea) Olive leaf and Olive leaf extract (Oleaeuropaea) Black elderberry(Sambucus) Pelargonium sidoidesextract (Kaloba, Umcka) Vitamin C, Zinc and other antioxidants in different combinations and formulations. Limited use  questionable effectiveness  lacking evidence and clinical trials!