1. Immunomodulators Pharmacology IV (PHL 425)
Dr. Abdulaziz Saeedan
[PhD, Pharmacology]

2. The Immune Response - why and how ?
Discriminate: Self / Non self
Destroy:
Infectious invaders
Dysregulated self (cancers)
Immunity:
Innate, Natural
Adaptive, Learned

3. ABNORMAL IMMUNE RESPONSE
A. Hypersensitivity reactions:
Refer to undesirable reactions produced by the normal immune system and may be damaging, uncomfortable, or occasionally fatal
Type I (immediate ) e.g. Anaphylactic shock, Allergy
Type II: antibody-dependent (or cytotoxic): Self-cells are marked by antibodies for destruction. e.g. cytopenia (low number of blood cells)
Type III: Immune complexes: (antigen-antibody reactions) deposited in various tissues. e.g. Allergy to a medicine
Type IV: Cell-mediated or delayed: these reactions are mediated by T cells, monocytes, and macrophages. e.g. Contact dermatitis

4. C. Immunodeficiency Diseases:
B. Autoimmunity:
– Autoimmune diseases arise when the body mounts an immune response against itself as a result of failure to distinguish self tissues and cells from foreign antigens.
E.g. Rheumatoid Arthritis, Systemic lupus erythematosus, Diabetes Mellitus, Multiple Sclerosis etc.
C. Immunodeficiency Diseases:
– Occur when one or more of the components of the immune system are inactive
Congenital – Severe combined immunodeficiency (SCID) E.g. Adenosine deaminase (ADA) deficiency. Deficiency of this enzyme results in an accumulation of deoxyadenosine, which in turn leads to:
 1- increase in S-adenosylhomocysteine affecting the differentiations of lymphocytes
2- prevents DNA synthesis, so affecting T and B cells division.
Extrinsic – Cancer and HIV causing AIDS.

5. Organ Transplants/Rejections:
Types of Organ Transplants
Autograft: tissue graft from one body site to another (same person)
Isograft: graft received from a genetically identical donor (identical twin)
Allograft: graft received from genetically non-identical donor (same species)
Xenograft: graft received from another species of animal
Transplant rejection: mediated by the immune system (especially T cells, NK, antibodies)

6. Cytokines
Cytokines are a category of signaling molecules used extensively in intercellular communication.
They are regulators of host responses to infection, immune responses, inflammation, and trauma
Cytokines can be classified as proteins, peptides, or glycoproteins
Cytokines include
Interleukins / lymphokines
Interferons (IFNs),
Tumor Necrosis Factors (TNFs) (causing the apoptosis),
Transforming Growth Factors (TGFs)
Colony-stimulating factors (CSFs) (causing cells to proliferate and differentiate).

7. IMMUNOMODULATORS

8. DEFINITION
Immunomodulators are drugs which either suppress the immune system –Immunosuppressants or
stimulate the immune system –Immunostimulants

9. Immunosuppressant

10. Immunosuppressants
Glucocorticoids: Prednisolone, Methylprednisolone, Prednisone.
Calcineurin inhibitors
Cyclosporine
Tacrolimus
Sirolimus
Antiproliferative / antimetabolic agents
Azathioprine
Mycophenolate Mofetil
Everolimus
Others – methotrexate, cyclophosphamide, thalidomide and chlorambucil
Antibodies
Antithymocyte globulin (ATG)
Anti CD3 monoclonal antibody: Muromonab-CD3 (OKT3)
Anti IL-2 receptor antibody: Daclizumab, basiliximab
Anti TNFα: Infliximab, Etanercept, Adalimumab
Calcineurin activates the T cells of the immune system

12. MAJOR STEPS IN IMMUNE RESPONSES
Antigen
Antigen presenting
Cell (macrophage,
dendritic cell)
CD4
T helper
cell
Primed CD4
T helper cell
CD8 T cell
Cytotoxic
T cells
Plasma cells 1 2 3 4
IL-1
IL-2
B cell
CD 4 = cluster of differentiation, found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells.
CD4+ T helper cells are white blood cells that are an essential part of the human immune system. They are often referred to as CD4 cells, T-helper cells or T4 cells. They are called helper cells because one of their main roles is to send signals to other types of immune cells, including CD8 killer cells. CD4 cells send the signal and CD8 cells destroy and kill the infection or virus. If CD4 cells become depleted, for example in untreated HIV infection, or following immune suppression prior to a transplant, the body is left vulnerable to a wide range of infections that it would otherwise have been able to fight.

13. Inhibitors of Immune Response (site of action)
Antigen recognition: Immune Globulin
IL-1production, cell proliferation: Corticosteroids
T cell receptors/surface proteins: Muromonab-CD3 (OKT3), Anti-thymocyte globulin (ATG) 
IL-2 gene expression (Cyclosporine, Tacrolimus), and IL-2 signal transduction (Sirolimus )
T cell proliferation & differentiation: Mycophenolate
Azathioprine, Cyclophosphamide (all cell proliferation)

14. SITES OF ACTION OF IMMUNOSUPPRESSIVE DRUGS
Antigen
antigen
presenting
cell
CD4
T helper
Primed CD4
T helper cell
CD8 T cell
Cytotoxic T cells
Plasma cells 1 2 3 4
IL-1
IL-2 X A B D E C

15. Drugs Prolonging Organ Transplantation
Cyclosporine (Neoral)
Tacrolimus (FK506, Prograf)
Sirolimus (Rapamune)
Mycophenolate mofetil (Cellcept)
Prednisone, Methylprednisolone

16.  myasthenia gravis: neuromuscular disease that leads to varying degrees of skeletal muscle weakness
ACHR: Acetylcholine receptor

17. Glucocorticoids Uses:
Induce redistribution of lymphocytes: in peripheral blood lymphocyte counts
Intracellular receptors – regulate gene transcription
Down regulation of IL-1, IL-6
Inhibition of T cell proliferation
Neutrophils, Monocytes display poor chemotaxis
Broad anti-inflammatory effects on multiple components of cellular immunity
Uses:
Transplant rejection
Bone Marrow transplantation
Autoimmune diseases – RA, Systemic Lupus Erythematosus
Psoriasis
Inflammatory Bowel Disease (Crohn's disease and ulcerative colitis) , Eye conditions.
Chemotaxis  is the movement of an organism in response to a chemical stimulus.

18. Toxicity Growth retardation Avascular Necrosis of Bone
Risk of Infection
Poor wound healing
Cataract (a clouding of the lens in the eye which leads to a decrease in vision)
Hyperglycemia
Hypertension

19. CALCINEURIN INHIBITORS
Calcineurin (CN) is a protein phosphatase which induces the transcription of interleukin-2 and activates the T cells of the immune system and can be blocked by drugs.
Cyclosporine:
Fat soluble peptide antibiotic
Act at an early stage in the antigen receptor-induced differentiation of T cells and block their activation.
Inhibit the gene transcription of IL-2, IL-3, IFN-γ, and other factors produced by antigen-stimulated T cells.
Bind to the cytosolic protein cyclophilin (an immunophilin). This complex of cyclosporin and cyclophilin inhibits the phosphatase calcineurin.
The drug also inhibits lymphokine production and interleukin release, leading to a reduced function of T-cells.

20. Uses:
Organ transplantation: Kidney, Liver, Heart
Rheumatoid arthritis
Psoriasis and other skin conditions
Aplastic anemia (is a rare disease in which the bone marrow and the hematopoietic stem cells that reside there are damaged,  causing a deficiency of all three blood cell types: RBC, WBC, and platelets).
Toxicity :
Renal dysfunction,
Neurotoxicity, Tremor
Hepatotoxicity,
Hirsuitism
Hypertension
Hyperlipidemia
Gum hyperplasia
Hyperuricemia – worsens gout
Calcineurin inhibitors + Glucocorticoids = Diabetogenic

21. Tacrolimus Macrolide antibiotic.
It binds to the immunophilin FKBP1A, followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity.
It prevents the cell from transitioning from the G0 into G1 phase of the cell cycle.
Tacrolimus is more potent than cyclosporine and has less pronounced side-effects.
Uses:
Prophylaxis of solid-organ allograft rejection
For liver, kidney, heart, pancreas, and bone marrow transplant applications.
Topical preparation available for use in dermatitis and psoriasis.

22. Toxicity - Tacrolimus Nephrotoxicity
Neurotoxicity-Tremor, headache, motor disturbances, seizures
GI Complaints
Hypertension
Hyperglycemia
Hypersensitivity,
Risk of tumors,
Risk of infections
Increased risk of lymphomas,

23. Sirolimus (rapamune) Macrolide similiar to tacrolimus
Contrary to cyclosporine and tacrolimus, drugs that affect the first phase of T lymphocyte activation, sirolimus affects the second one (namely signal transduction and lymphocyte clonal proliferation).
It binds to FKBP1A like tacrolimus, however the complex does not inhibit calcineurin but another protein, mTOR (mammalian target of rapamycin).
It indirectly inhibits several T lymphocyte-specific kinases and phosphatases, hence preventing their transition from G1 to S phase of the cell cycle.
Sirolimus prevents B cell differentiation into plasma cells, reducing production of IgM, IgG, and IgA antibodies.
Contrary = opposite

24. Uses:
Prophylaxis of organ transplant rejection with other drugs
Toxicity:
Increase in serum cholesterol, Triglycerides
Anemia
Thrombocytopenia
Hypokalemia
Fever
GI effects
Risk of infection
Risk of tumors
Thrombocytopenia: decrease of thrombocytes, commonly known as platelets

25. ANTIMETABOLITES / ANTIPROLIFERATVE AGENTS

26. Azathioprine (Imuran )
An imidazolyl derivative of 6-MP
The main immunosuppressive cytotoxic substance. It is non-enzymatically cleaved to mercaptopurine, that acts as a purine analogue and an inhibitor of DNA synthesis.
By preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and the humoral immunity.
Uses
Prevention of organ transplant rejection
Rheumatoid arthritis, systemic lupus erythematosus
Toxicity
Bone marrow suppression- leukopenia, thrombocytopenia, anemia
Increased susceptibility to infection
Hepatotoxicity,
Alopecia,
GI toxicity

27. Mycophenolate Mofetil
Prodrug  Mycophenolic acid
Inhibits Inosine monophosphate dehydrogenase (IMPDH) enzyme (the IMPDH enzyme in guanine synthesis is a major target for both antitumor and immunosuppresive drug design.)
T, B cells are highly dependent on this pathway for cell proliferation
Selectively inhibits lymphocyte proliferation & function , Antibody formation, cellular adhesion, migration

28. Prophylaxis of transplant rejection
Uses
Prophylaxis of transplant rejection
Combination: Glucocorticoids, Calcineurin Inhibitors
Toxicity
GI (Diarrhea)
Hematological (Leukopenia)
Risk of Infection
Increased incidence of lymphomas and other malignancies
Drug Interaction
Decreased absorption when co-administered with antacids
Acyclovir, Ganciclovir compete with mycophenolate for tubular secretion

29. Antibodies Against lymphocyte cell-surface antigens
Polyclonal / Monoclonal
Antibodies are used as a quick and potent immuno-suppression method to prevent the acute rejection reaction

30. Antibodies Antithymocyte Globulin Monoclonal antibodies
Anti-CD3 Monoclonal antibody
E.g. Muromonab-CD3
Anti-IL-2 Receptor antibody
E.g. Daclizumab, Basiliximab)

31. Anti-thymocyte Globulin
Purified gamma globulin from serum of rabbits immunized with human thymocytes
Cytotoxic to lymphocytes & block lymphocyte function
Uses
Treatment of acute transplant rejection
Toxicity
Hypersensitivity
Risk of infection, Malignancy

32. Anti-CD3 Monoclonal Antibody (Muromonab-CD3 )
Binds to CD3, a component of T-cell receptor complex involved in
antigen recognition
cell signaling & proliferation
Uses: Treatment of acute organ transplant rejection
Toxicity
“Cytokine release syndrome: High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness
Prevention: Steroids

33. Anti-IL-2 Receptor Antibodies
E.g. Daclizumab and Basiliximab
Bind to IL-2 receptor on surface of activated T cells  Block IL-2 mediated T-cell activation
Uses
Prophylaxis of Acute organ rejection
Toxicity
Anaphylaxis, Opportunistic Infections

34. Anti-TNF Agents Infliximab
E.g. Infliximab (Remicade), Etanercept (Enbrel), Adalimumab (Humira)
Infliximab
Uses
Rheumatoid arthritis
Psoriasis
Psoriatic arthritis
Ankylosing spondylitis
Toxicity
Infusion reaction – fever, urticaria, hypotension, dyspnoea
Opportunistic infections – TB, RTI, UTI
Infusion related reactions include hypersensitivity reactions and cytokine release syndromes. 

35. Etanercept Adalimumab Uses: Rheumatoid arthritis
Fusion protein produced
through expression of recombinant DNA.
It is TNFα inhibitor ( TNF is a cytokine that  attract white blood cells to sites of inflammation.
Uses: Rheumatoid arthritis
Adalimumab
Recombinant human anti-TNF mAb
Uses : moderate to severely active crohn’s disease
Fc = fragment crystallizable

36. LFA-1 Inhibitor - Efalizumab
Monoclonal Ab Targeting Lymphocyte Function Associated Antigen
Blocks T-cell Adhesion, Activation, Trafficking.
Uses
Organ transplantation
Psoriasis
- Withdrawn from the market due to fatal brain infetion.
- Lymphocyte function-associated antigen 1 (LFA-1) is found on all T-cells and also on B-cells, macrophages, neutrophils and NK cells and is involved in recruitment to the site of infection. It binds to ICAM-1 on antigen-presenting cells and functions as an adhesion molecule.