Transcript 11th A Immunosuppressionx

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)
Indications for immunosuppression:
 Inflammation (dermatology, pulmonology)
 Allergic diseases
 Autoimmune diseases
 Transplantation
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
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).
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!
IMMUNOSUPPRESSIVE DRUGS
CORTICOSTEROIDS
Prednisolone
Methylprednisolone
Triamcinolone
betamethasone
Budesonide
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.
IMMUNOSUPPRESSIVE DRUGS
CYTOSTATIC DRUGS
Azathioprine
Mycophenolate
mofetil
Methotrexate
Cyclophosphamide
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
IMMUNOSUPPRESSIVE DRUGS
NON-CYTOSTATIC DRUGS ACTING ON T CELLS
Tacrolimus
Cyclosporin A
Rapamycin (Sirolimus)
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).
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.
IMMUNOSUPPRESSANT DRUGS
LEUKOTRIENE ANTAGONISTS
Montelukast
Zafirlukast
Zileuton
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)
Relief pain
2)
Slow or arrest tissue-damaging processes
NSAIDs
Aspirin
DMARDs
Corticosteroids
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
IMMUNOSTIMULANTS
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.
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
Cytokines applied in therapy:
Cytokine
Disease
Interferon-
Hairy cell leukaemia
Chronic Myeloid Leukemia
Melanoma
Kaposi sarcoma
Hepatitis B, C
Renal carcinoma
T-cell leukemia
(IFN- - type I)
(IFN- - type I)
Multiple sclerosis
(relapse-remission)
Interferon-
Chronic granulomatous disease
Interferon-
(IFN- - type II)
IL-2
Metastatic renal carcinoma
GM-CSF
Bone marrow transplantation  stem cell
mobilization
Supportive therapy in oncohematology
Side effects
fever, influenza-like
symptoms, weight
loss, tiredness
IMMUNOSTIMULANT DRUGS
Imiquimod
Inosine pranobex
Peginterferon alpha 2a
IL-2
Peginterferon alpha 2b
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!