The document discusses various types of immunosuppressive drugs used in clinical practice including corticosteroids, cytostatic drugs, immunsuppressive agents like cyclosporine A and tacrolimus, cytokine and cytokine receptor antibodies, and leukopheresis. These drugs act through different mechanisms such as inhibiting T cell activation, cell proliferation, cytokine production and signaling. The document also covers the indications for immunosuppression including inflammation, allergic diseases, autoimmune diseases, and transplantation. It describes the mechanisms, examples and side effects of the main classes of immunosuppressive medications.

1. By
Shaikh Saniya Mohd Asif

2. 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)

3.  Inflammation (dermatology, pulmonology, rheumatology)
 Allergic diseases
 Autoimmune diseases
 Transplantation
Indications for immunosuppression

4. 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

5. 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 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

6. - 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!

7. Methylprednisolone
Prednisolone
betamethasone
Budesonide
Triamcinolone

8.  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.

9. Azathioprine
Cyclophosphamide
Methotrexate
Mycophenolate
mofetil

10.  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.

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

12. Tacrolimus
Rapamycin (Sirolimus)Cyclosporin A
IMMUNOSUPPRESSIVE DRUGS
NON-CYTOSTATIC DRUGS ACTING ON T CELLS

13. 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.

14. IMMUNOSUPPRESSIVE DRUGS
MAB TARGETING CYTOKINES OR CYTOKINE RECEPTORS
Basiliximab
Daclizumab
Omalizumab

15. 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.

16. Montelukast Zafirlukast Zileuton

17. 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.

18.  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

19. Imiquimod (Aldara©)
Used in creams for some skin conditions and cancers. A TLR7 stimulator
ctivating Langerhans cells (skin DCs), macrophages and B cells, resulting in the
production of IFN-α, IL-6 and TNF-α. In addition to an anti-proliferative effect.
(secondary to surgery)
Echinacea species
Widely marketed but rather controversial (lack of well-controlled trials,
with many studies of low quality)

20.  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.

21. Cytokine 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
Cytokines applied in therapy