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 Cytokine receptor 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 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 (PGE2 for example) and leukotrienes (LTs).

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

6. Immunosuppressive drugs corticosteroids
Prednisolone
Methylprednisolone
Budesonide
Triamcinolone
betamethasone

7. 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.

8. Immunosuppressive drugs Cytostatic drugs
Mycophenolate mofetil
Azathioprine
Mycophenolate mofetil- post transplantation. Autoimmune diseases like SLE.
Azathioprine- post transplantation, autoimmune diseases like RA, SLE, vasculitis and IBD (chrons’ disease and ulcerative colitis).
Mercaptopurin- Leukemia, NH-Lymphoma, IBD.
Methotrexate- cancer and autoimmune disorders like RA, MS, Chrons’ disease and vasculitis.
Cyclophosphamide- autoimmune diseases; disease-modifying antirheumatic drugs (DMARD). Anticancer treatment mostly, for autoimmune disorders purine antagonists are prescribed more often.
Methotrexate
Cyclophosphamide

9. 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.

10. Cyclosporin A and tacrolimus (FK506) inhibits cell activation by neutralyzing the serine/threonine phosphatase calcineurin
Cyclosporin A and tacrolimus inhibit T-cell activation by interfering with the serine/threonine-specific phosphatase calcineurin.
As shown in the upper panel, signaling via T-cell receptor-associated tyrosine kinases leads to opening of CRAC channels in the plasma membrane. This increases the concentration of Ca2+ in the cytoplasm and promotes calcium binding to the regulatory protein calmodulin (see Figure 7.16). Calmodulin is activated by binding Ca2+ and can then target many downstream effector proteins such as the phosphatase calcineurin. Binding by calmodulin activates calcineurin to dephosphorylate the transcription factor NFAT (see Section 7-12), which then enters the nucleus, where it activates genes required for T-cell activation to progress. As shown in the lower panel, when cyclosporin A or tacrolimus are present, they form complexes with their immunophilin targets, cyclophilin and FK-binding protein, respectively. These complexes bind to calcineurin, preventing it from becoming activated by calmodulin, and thereby preventing the dephosphorylation of NFAT.

11. Immunosuppressive drugs non-Cytostatic drugs acting on T cells
Tacrolimus
Cyclosporin A, Tacrolimus and sirolimus- prevent rejection of a transplant.
*Cyclosporin is under clinical trials for neuroprotective effect following brain injury.
Cyclosporin A
Rapamycin (Sirolimus)

12. 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.

13. Immunosuppressive drugs Mab targeting cytokines or cytokine receptors
Basiliximab
Daclizumab
Daclizumab and Basiliximab- binds IL-2 Rs on T cells. For prevention of organ rejection.
Infliximab and Adalimumab- bind TNF-α
Omalizumab- targets IgE for allergic asthma.
Infliximab
Omalizumab

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 Montelukast are LTD4 receptor antagonists.

15. Immunosuppressant drugs Leukotriene antagonists
Leukotrienes are very important agents in the inflammatory response. Some such as LTB4 have a chemotactic effect on migrating neutrophils, and as such help to bring the necessary cells to the tissue. Leukotrienes also have a powerful effect in bronchoconstriction and increase vascular permeability.
Montelukast
Zafirlukast
Zileuton

16. 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.

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
DMARDs- disease modifying antirheumatic drugs

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:
Disease
Side effects
Interferon-
(IFN- - type I)
Hairy cell leukaemia
Chronic Myeloid Leukemia
Melanoma
Kaposi sarcoma
Hepatitis B, C
Renal carcinoma
T-cell leukemia
fever, influenza-like symptoms, weight loss, tiredness
Interferon-
(IFN- - type I)
Multiple sclerosis
(relapse-remission)
Interferon-
(IFN- - type II)
Chronic granulomatous disease
IL-2
Metastatic renal carcinoma
GM-CSF
Bone marrow transplantation  stem cell mobilization
Supportive therapy in oncohematology

22. Immunostimulant drugs
Imiquimod
Inosine pranobex
IL-2
Imiquimod- Skin and genitalia cancers. Activates macrophages, NK cells and B cells through TLR7 causing IL-6, TNF-α and INF-α.
IFN alpha- Hepatitis C treatment.
IL-2- Chronic viral infections, HIV and metastatic renal cell carcinoma.
Inosine pranobex- powerful immunostimulant and antiviral agent.
Peginterferon alpha 2a
Peginterferon alpha 2b

23. Natural immune system “boosters”
Some examples of the 50 fundamental traditional Chinese medicinal herbs: *
Astragalus propinquus (huáng qí)
Forsythia suspensa (liánqiào)
Lonicera japonica / Japanese honeysuckle (Jinyinhua)
Echinacea
Esberitox (A mix of Thuja occidentalis, Baptisia and Echinacea)
Olive leaf and Olive leaf extract (Olea europaea)
Black elderberry (Sambucus)
Pelargonium sidoides extract (Kaloba, Umcka)
Vitamin C, Zinc and other antioxidants in different
combinations and formulations.
Limited use  questionable effectiveness  lacking evidence and clinical trials!