1. Immunomodulators (drugs that modulate immune response)
Dr. Kaukab Azim

2. Drug List Cytotoxic Drugs Lymphoid drugs Azathioprine Cyclophosphamide
Methotrexate
Corticosteroids
Antithymocyte immunoglobulin
Muromonab – CD3
Drugs acting on a subpopulation of immunocompetent cells
Drugs acting on cytokines
Other immunosuppressives
Cyclosporine
Tacrolimus
Sirolimus
Mycophenolate mofetil
Daclizumab
Infliximab
Etanercept
Thalidomide
RhO (D) immune globulin
Azathioprin
Muromonab-CD3
Infliximab
Cyclosporin
Sirolimus
Mycophenolate
Thalidomide
Rho(D) immune globulin
interferons
Aldesleukin

3. Immune System
Functions to protect the host from harmful foreign molecules
Inappropriate activation of immune cells can result in autoimmune disorders
Allograft introduction can elicit a damaging immune response
Immune system include two main arms
1) Cell –mediated immunity
2) Humoral (antibody –mediated immunity)

5. Cytokines
Cytokines are soluble signaling proteins that bind to cell surface receptors on a variety of cells
Cytokines include
Interleukins (IL)
Interferons (IFNs)
Tumor Necrosis Factors (TNFs)
Transforming Growth Factors (TGFs)
Colony-stimulating factors (CSFs)

6. IL-2 stimulates the proliferation of antigen-primed (helper) T cells.
Cell-mediated Immunity
Activate
NK cells (kill tumor & virus-infected cells).
Cytotoxic T cells (kill tumor & virus-infected cells).
Macrophages (kill bacteria).

7. Humoral Immunity
B-lymphocytes TH2 produces (interleukins) IL-4 & IL-5 which in turn causes:
 B cells proliferation & differentiation into
memory B cells
Antibody secreting plasma cells

8. Immunosuppressant Drugs

9. General Features
Immunosuppressant drugs suppress primary immune responses (i.e antigen processing, cell proliferation, lymphokine synthesis, etc.) more effectively than secondary immune responses (i.e. those related to re-encountering antigen, that is those related to immunologic memory)
Immunosuppressant drugs work better if they are given before rather than after the exposure of the body to the antigen (unfortunately most autoimmune diseases are treated after autoimmunity is established).

10. Immunosuppressant drugs are highly effective in treating conditions such as organ transplant rejection and severe autoimmune disorders.
Therapies with these drugs often require lifelong use, so exposing the patient to increased risk of infections and some cancers (lymphomas, Kaposi’s sarcoma, skin cancer).

11. 1. Cyclosporine Mechanism of action
The drug binds to cyclophilin to form a complex which in turn binds to calcineurin, a cytoplasmic phosphatase, and inhibits its action.
Since calcineurin regulates the ability of a nuclear factor of activated T cells (NFAT) to translocate to the nucleus and increase the production of interleukin-2, the production of IL-2 is suppressed.
As a consequence T-helper cells cannot proliferate and die by apoptosis.

12. Pharmacokinetics
The drug is given PO or IV.
It is totally metabolized by the CYP3A system (its metabolism is affected by a lot of drugs that inhibit or induce the p450 system).
Toxicity
Nephrotoxicity (up to 80%).
Neurotoxicity, including paresthesias (up to 50%) tremor (up to 55%), hallucinations and seizures
Hypertension (up to 50%)
Hirsutism (common), gingival hyperplasia (up to 20%)

13. Therapeutic uses Clinical uses
Organ transplantation (to prevent rejection) (Graft-versus-host disease).
Selected autoimmune disorders ( psoriasis, rheumatoid arthritis, IBD, SLE)
Clinical uses
Organ transplantation (to prevent rejection) (Graft-versus-host disease).
Selected autoimmune disorders ( psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn’s disease, idiopathic thrombocytopenic purpura, lupus erythematosus, myasthenia gravis, type I diabetes newly diagnosed in children)

14. 2. Tacrolimus (FK506)
A fungal macrolide antibiotic.
Chemically not related to cyclosporine
Both drugs have similar mechanism of action.
The internal receptor for tacrolimus is immunophilin ( FK-binding protein, FK-BP).
Tacrolimus-FKBP complex inhibits calcineurin.

15. 3. Sirolimus (Rapamycin)
Mechanism of action
The drug resembles tacrolimus and binds to the same intracellular Fk binding proteins.
However, whereas tacrolimus and cyclosporine block IL-2 gene transcription, sirolimus acts later to block IL-2 dependent lymphocyte proliferation.
This blockade is likely due to the inhibition of mammalian kinase, an enzyme which is essential for cell-cycle progression. Therefore the drug inhibits substantially T and B cell proliferation.

17. Sirolimus Pharmacokinetics The drug is given orally.
It is totally metabolized by the CYP3A4 system.
Toxicity
Hyperlipidemia (up to 50%).
Hypertension(up to 50%).
Anemia, leukopenia, thrombocytopenia.
Clinical uses
Organ transplantation (to prevent rejection)
Atopic dermatitis, psoriasis

18. Inhibitors of purine or pyrimidine synthesis (Antimetabolites):
4. Cytotoxic drugs
Inhibitors of purine or pyrimidine synthesis (Antimetabolites):
Azathioprine
Myclophenolate Mofetil
Leflunomide
Methotrexate

19. A. Azathioprine Chemistry: Derivative of mercaptopurine. Prodrug.
Cleaved to 6-mercaptopurine then to 6-mercaptopurine nucleotide, thioinosinic acid (nucleotide analog).
Inhibits de novo (new) synthesis of purines required for lymphocytes proliferation.
Prevents clonal expansion of both B and T lymphocytes.

21. Pharmacokinetics
Orally or intravenously.
Widely distributed but does not cross BBB.
Metabolized in the liver to 6-mercaptopurine or to thiouric acid (inactive metabolite) by xanthine oxidase.
Excreted primarily in urine.
Drug Interactions
Co-administration of allopurinol with azathioprine may lead to toxicity due to inhibition of xanthine oxidase by allopurinol.

22. USES
Acute glomerulonephritis
Systemic lupus erythematosus
Rheumatoid arthritis
Crohn’ s disease.
Adverse Effects
Bone marrow depression: leukopenia, thrombocytopenia.
Gastrointestinal toxicity.
Hepatotoxicity.
Increased risk of infections.

23. B. Mycophenolate Mofetil
It is a semisynthetic derivative of mycophenolic acid from fungus source.
Prodrug; is hydrolyzed to mycophenolic acid.
Mechanism of action:
Inhibits de novo synthesis of purines.
Mycophenolic acid is a potent inhibitor of inosine monophosphate dehydrogenase (IMP), crucial for purine synthesis deprivation of proliferating T and B cells of nucleic acids.

24. Pharmacokinetics:
Given orally, I.V. or I.M.
Rapidly and completely absorbed after oral administration.
Clinical Use:
Solid organ transplants for refractory rejection.
Steroid-refractory hematopoietic stem cell transplant patients.
Combined with prednisone as alternative to cyclosporine or tacrolimus.
Rheumatoid arthritis, & dermatologic disorders.

25. Adverse Effects:
GIT toxicity: > 10%. nausea, vomiting, diarrhea, abdominal pain.
Bone marrow suppression > 20%
Contraindicated: during pregnancy

26. 5. Thalidomide A sedative drug. Teratogenic Can be given orally.
Has immunomodulatory actions
Inhibits TNF-α
Reduces phagocytosis by neutrophils
Increases IL-10 production
Inhibits angiogenesis.
Used in multiple myeloma
Multiple myeloma is a cancer of plasma cells (responsible for producing antibodies). Collections of abnormal plasma cells accumulate in the bone marrow, where they interfere with the production of normal blood cells.
Treatment: Thalidomide, dexamethasone, bortezomib. Autologous (patient’s own) stem cell transplantation after chemotherapy.
Infliximab
Thalidomide
Aldesleukin

27. Uses
Myeloma
Rheumatoid arthritis
Graft versus host disease.
Leprosy reactions
Treatment of skin manifestations of lupus erythematosus

28. 6. Antibodies
Block T cell surface molecules involved in signaling immunoglobulins
Antilymphocyte globulins (ALG).
Antithymocyte globulins (ATG).
Rho (D) immunoglobulin.
Basiliximab
Daclizumab

29. A. Muromonab – CD3 It is a murine monoclonal antibody
Prepared by hybridoma technology
Directed against glycoprotein CD3 antigen of human T cells.
Given I.V.
Metabolized and excreted in the bile.

30. Mechanism of action
The drug binds to CD3 proteins on T lymphocytes (antigen recognition site) leading to disruption of T-lymphocyte function, their depletion and decreased immune response.

31. To deplete T cells from bone marrow donor prior to transplantation.
Uses
Used for treatment of acute renal allograft rejection & steroid-resistant acute allograft
To deplete T cells from bone marrow donor prior to transplantation.
Adverse effects
Anaphylactic reactions (infusion related).
Pulmonary edema
Secondary malignancy
Infection
Cytokine release syndrome (Flu-like illness to shock like reaction). Prednisolone, diphenhydramine are given to reduce cytokine release syndrome.
Cytokine release syndrome : The pathogenesis is that the antibodies bind to the T cell receptor, activating the T cells before they are destroyed. The cytokinesreleased by the activated T cells produce a type of systemic inflammatory response similar to that found in severe infectioncharacterised by hypotension, pyrexia and rigors. The patient feels very unwell, as if in a high fever – indeed, the cytokine release syndrome is effectively a type of non-infective fever.

32. B. Rho (D) immune globulin
Rho (D) is a concentrated solution of human IgG containing higher titer of antibodies against Rho (D) antigen of red cells.
Given to Rh-negative mother within hours after delivery of Rh positive baby (2 ml, I.M.) to prevent hemolytic disease of the next Rh positive babies (erythroblastosis fetalis).
Adverse Effects
Local pain
Fever
Infliximab
Mycophenolate
Thalidomide
interferons
Aldesleukin

33. CLINICAL USES OF IMMUNOSUPPRESSIVE AGENTS
DISEASE
AGENT USED
Autoimmune Disease:
Acute glomerulonephritis
Autoimmune haemolytic anaemia.
Prednisone, mercaptopurine.
Cyclophosphamide.
Prednisone, cyclophosphamide, mercaptopurine, azathioprine, high dose -globulin.

34. Organ transplant: Renal Heart
Cyclosporine, Azathioprine, Prednisone, ALG (antilymphocyte globlin), Tacrolimus.
Liver
Cyclosporine, Prednisone, Azathioprine, Tacrolimus.
Bone marrow
Cyclosporine, Cyclophosphamide, Prednisone, Methotrexate, ALG, total body radiation.

35. Immunostimulants

36. 1. Interferons Three families: Type I IFNs ( IFN-α, β ):
Acid-stable proteins
induced by viral infections
leukocyte produces IFN-α
Fibroblasts & endothelial cells produce IFN-β
Type II IFN (IFN-γ):
Acid-labile
Produced by Activated T lymphocytes.
Infliximab
Thalidomide
interferons
Aldesleukin

37. Interferon Effects:
IFN- γ : Immune Enhancing
Increased antigen presentations with macrophage, natural killer cell, cytotoxic T lymphocyte activation
IFN- α, β :
Effective in inhibiting cellular proliferation
(more effective than IFN- γ in this regard)

38. INTERFERONS
Recombinant DNA cloning technology.
Antiproliferative activity.
Antiviral action
Immunomodulatory effect.

39. USES:
Treatment of certain infections e.g. Hepatitis C (IFN- α ).
Autoimmune diseases e.g. Rheumatoid arthritis.
Certain forms of cancer e.g. melanoma, renal cell carcinoma.
Multiple sclerosis (IFN- β): reduced rate of exacerbation.
SE:
Fever, chills, myelosuppression.

40. 2. Aldesleukin Mechanism of action
The drug is a recombinant version of interleukin-2.
It induces proliferation of B and T cells (including cytotoxic T cells) and activation of natural killer cells and lymphokine-activated killer cells.
The mechanism of antitumor activity is unknown but is probably related to the activation of cytotoxic T cells.

41. Adverse effects
Hypotension (70%),sinus tachycardia (70%), pulmonary congestion (50%) and edema (50%).
Acute renal failure(60%)
Mental status changes (70%)
Nausea/vomiting and diarrhea (70%)
Anemia, thrombocytopenia (70%).
Clinical uses
Renal cell carcinoma, malignant melanoma

42. Disease modifying anti-rheumetic drugs (DMARDs)
DMARDs are used in the treatment of Rheumotoid arthritis (RA) and have been shown to slow the course of the disease and prevent further destruction of the joints and involved tissues

43. A. Leflunomide A prodrug
Active metabolite undergoes enterohepatic circulation.
Has long duration of action.
Can be given orally
Antimetabolite immunosuppressant.
Pyrimidine synthesis inhibitor
Approved only for rheumatoid arthritis

44. Adverse effects
Elevation of liver enzymes
Renal impairment
Teratogenicity
Cardiovascular effects (tachycardia).

45. B. Methotrexate A folic acid antagonist
Orally, parenterally (I.V., I.M).
Excreted in urine.
Inhibits dihydrofolate reductase required for folic acid activation (tetrahydrofolic)
Inhibition of DNA, RNA & protein synthesis
Interferes with T cell replication.
Rheumatoid arthritis & psoriasis and Crohn disease
Graft versus host disease

46. Adverse effects
Nausea-vomiting-diarrhea
Alopecia
Bone marrow depression
Pulmonary fibrosis
Renal & hepatic disorders

48. C. Hydroxychloroquine
Used for early, mild RA and has relatively few side effects
Does not slow joint damage, therefore it is often used in combination with methotrexate
Mechanism of action may include inhibition of phospholipase A2 , platelet aggregation and effects on the immune system

49. D. Gold Salts
Cannot repair existing damage, only prevent further injury
Gold compounds are used infrequently due to constant monitoring for serious toxicity
Currently available gold preparation is auranofin, given orally
Auranofin is taken up by macrophages and suppresses phagocytosis and lysosomal enzyme activity resulting in slower progression of bone and articular destruction

50. E. Biological therapies in RA
IL-1 and TNF-a are proinflammatory cytokines involved in the pathogenesis of RA
TNF inhibitors (etanercept, adalimumab and infliximab)
IL-1 receptor antagonist (anakinra)

51. Infliximab
Monoclonal antibody that binds specifically to TNF-a, thereby neutralizing the cytokine
Approved for use in combination in patients with RA who have had inadequate response to methotrexate monotherapy
Not indicated for use alone, because it allows the body to develop anti-infliximab antibodies which reduces efficacy
Infliximab
Aldesleukin