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

Cytotoxic DrugsLymphoid drugs Azathioprine Cyclophosphamide Methotrexate Corticosteroids Antithymocyte immunoglobulin Muromonab – CD3 Drugs acting on a subpopulation of immunocompetent cells Drugs acting on cytokinesOther immunosuppressives Cyclosporine Tacrolimus Sirolimus Mycophenolate mofetil Daclizumab Infliximab Etanercept Thalidomide RhO (D) immune globulin Drug List

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)

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)

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).

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

Immunosuppressant Drugs

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 are highly effective in treating conditions such as organ transplant rejection and severe autoimmune disorders. 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). 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).

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.

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%)

Therapeutic uses Clinical uses Organ transplantation (to prevent rejection) (Graft-versus-host disease). Selected autoimmune disorders ( psoriasis, rheumatoid arthritis, IBD, SLE)

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.

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.

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

Cytotoxic drugs  Inhibitors of purine or pyrimidine synthesis (Antimetabolites): – Azathioprine – Myclophenolate Mofetil – Leflunomide – Methotrexate

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.

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.

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.

MYCOPHENOLATE MOFETIL – 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.

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.

ADVERSE EFFECTS: – GIT toxicity: > 10%. nausea, vomiting, diarrhea, abdominal pain. – Bone marrow suppression > 20% Contraindicated during pregnancy

Antibodies Block T cell surface molecules involved in signaling immunoglobulins – antilymphocyte globulins (ALG). – antithymocyte globulins (ATG). – Rho (D) immunoglobulin. – Basiliximab – Daclizumab

Muromonab – CD3 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.

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. Prednisolone, diphenhydramine are given to reduce cytokine release syndrome.

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).

Rh o (D) immune globulin Rho (D) is a concentrated solution of human IgG containing higher titer of antibodies against Rh o (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

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

USES Myeloma Rheumatoid arthritis Graft versus host disease. Leprosy reactions treatment of skin manifestations of lupus erythematosus

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

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

Immunostimulants

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.

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)

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

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.

Aldesleukin Mode 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. Toxicity 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

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

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

Adverse effects 1. Elevation of liver enzymes 2. Renal impairment 3. Teratogenicity 4. Cardiovascular effects (tachycardia).

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

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

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 A 2, platelet aggregation and effects on the immune system

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

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)

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