Ma. Janetth B. Serrano, M.D., DPBA IMMUNOPHARMACOLOGY Ma. Janetth B. Serrano, M.D., DPBA

IMMUNOPHARMACOLOGY 2 major components of the immune system: INNATE Physical – skin, mucus membrane Biochemical – complement, lyzosyme Cellular – macrophages, neutrophils ADAPTIVE Antibodies – HUMORAL immunity T-lymphocyte – CELL MEDIATED immunity

IMMUNOPHARMACOLOGY COMPLEMENTS in Innate Immunity: 1. C3a, C5a  chemotaxis 2. C3b  opsonization 3. C5b, C6, C7, C8, C9  MAC

IMMUNOPHARMACOLOGY TH1 TH2 0psonized bacteria Macrophage APC B lymphocyte T lymphocyte IL-4,IL-5 IL-2 IL-2 TH1 TH2 IFN- TNF- IFN- IFN- Plasma Cells: IgG - IgM IgA - IgD Activated Macrophage Activated Cytotoxic T cell Activated NK cells Memory B Cells CELL-MEDIATED IMMUNITY HUMORAL IMMUNITY

IMMUNOPHARMACOLOGY T-helper cells: 1. TH1 subset - IFN- , IL-2, TNF- - IL-4, IL-5, IL-6, IL-10

IMMUNOPHARMACOLOGY AUTOIMMUNITY IMMUNODEFICIENCY ABNORMAL IMMUNE RESPONSES: HYPERSENSITIVITY AUTOIMMUNITY IMMUNODEFICIENCY

IMMUNOPHARMACOLOGY Immunosuppressants 1. Corticosteroids 2. Cyclosporine 3. Sirolimus 4. Tacrolimus 5. Interferons 6. TNF-alpha binding drugs 7. Mycophenolate mofetil 8. 15-Deoxyspergualin 9. Thalidomide 10. Glatiramer

Corticosteroids IMMUNOPHARMACOLOGY MOA: inhibit T-cell proliferation & T-cell dependent immunity Inhibit expression of genes encoding cytokines Inhibit production of inflammatory mediators Affects cell-mediated immunity more than humoral immunity

Corticosteroids IMMUNOPHARMACOLOGY Continuous administration: ↑ fractional catabolic rate of IgG Indications: Autoimmune disorders - autoimmune hemolytic anemia, LE - ITP, Inflammatory Bowel Dse,, Hashimoto’s Modulate allergic reactions - asthma Organ transplantation – rejection crisis

Corticosteroids IMMUNOPHARMACOLOGY Immunosuppressive dose: 10-100 mg/day Adverse effects: GI bleeding adrenal suppression fluid retention diabetes proximal muscle wasting superinfections

Cyclosporin IMMUNOPHARMACOLOGY Blocks T-cell activation binds to cyclophillin  inhibits calcineurin activity  inhibits gene transcription of IL-2, IL-3, IFN & other factors Most commonly used immunosuppresant for renal transplantation Indications: transplant rejection (kidney, liver, pancreas, cardiac) Autoimmune disorders (uveitis, RA, DM type1) Toxicities: nephrotoxicity, hyperglycemia, hyperlipidemia, osteoporosis, ↑ hair growth, transient liver dysfunction

Tacrolimus IMMUNOPHARMACOLOGY Binds to FK-binding protein  inhibits T-cell activation 10-100 times more potent than cyclosporine Liver & kidney transplant Oral or IV : t½ = 9-12 hrs Toxicity: nephrotoxicity, neurotoxicity, hyperglycemia, GI dysfunction

Sirolimus (rapamycin) IMMUNOPHARMACOLOGY Sirolimus (rapamycin) Binds also to immunophyllin  blocks the response of T-cell to cytokines Potent inhibitor of B-cell proliferation & Ig production Indications: Kidney & heart allografts C syclosporin  psoriasis & uveoretinitis

Interferons IMMUNOPHARMACOLOGY Type 1: induced by viral inf. IFN-alpha  prod. by leukocytes IFN-beta  fibroblasts & epithelial cells Type 2: IFN-gamma  produced by activated T-lymphocytes Indications: cancer IFN-  multiple sclerosis IFN- chronic granulomatous disease

TNF-α binding drugs IMMUNOPHARMACOLOGY INFLIXIMAB ETANERCEPT Chimeric IgG1 monoclonal antibody with human region & murine regions Suppress generation of cytokines Crohn’s disease; RA ETANERCEPT Chimeric protein with human regiom Similar MOA with infliximab but shorter half-life RA

Mycophenolate Mofetil IMMUNOPHARMACOLOGY Mycophenolate Mofetil Inhibits a series of T & B lymphocyte responses Inhibit de novo pathway of purine synthesis Renal & heart transplantation Mizoribine – inh. nucleotide synthesis PW; kidney transplants Brequinar Sodium – inh. de novo pathway of pyrimidine synthesi; cancer & organ transplantation

15-Deoxyspergualin IMMUNOPHARMACOLOGY Potent antimonocytic & antilymphocytic effect Inhibits T & B lymphocyte response Renal transplants; pancreas & heart transplants

Thalidomide IMMUNOPHARMACOLOGY Sedative drug Favors TH2 over TH1 Suppress TNF-α production Antiangiogenesis action: teratogenicity & anticancer Indications Erythema nodosum leprosum (skin manifestations of SLE) Lung transplantation

Glatiramer IMMUNOPHARMACOLOGY Relapsing-remitting form of multiple sclerosis Subcutaneous injection Toxicities: Transient post-injection reaction

CYTOTOXIC Agents: IMMUNOPHARMACOLOGY 1. Azathioprine 2. Leflunomide 3. Cyclophosphamide

Azathioprine IMMUNOPHARMACOLOGY Metabolized to 6-mercaptopurines Inhibit purine synthesis interferes with nucleic acid metabolism  inhibits cellular & humoral responses Highly teratogenic Well absorbed from GI tract

Azathioprine IMMUNOPHARMACOLOGY Renal allograft, AGN, SLE(renal), RA, Crohn’s disease Prednisone-resistant antibody-mediated ITP Autoimmune hemolytic anemia Toxicities: Bone marrow suppression GI disturbances: N&V, diarrhea Skin rashes, drug fever, hepatic dysfunction

Leflunomide IMMUNOPHARMACOLOGY Prodrug of an inhibitor of pyrimidine synthesis Inhibits lymphoid cells Orally active RA Toxicities: Headache, nausea & diarrhea Hepatic dysfunction, renal impairment Teratogenic

Cyclophosphamide IMMUNOPHARMACOLOGY Most potent immunosuppressive drug Destroys proliferating lymphoid cells Autoimmune disorders: SLE Acquired factor XIII antibodies Bleeding syndromes Toxicities: Pancytopenia, hemorrhagic cystitis

Antibodies as Immunosuppressive Agents IMMUNOPHARMACOLOGY Antibodies as Immunosuppressive Agents Antilymphocytic antibody Immune Globulin IV Hyperimmune Immunoglobulins Monoclonal Antibodies Rho(D) Immune Globulin Micro-Dose Prevention of hemolytic disease of the newborn Given to mother within 72 hrs after delivery of an Rh-negative baby

MONOCLONAL ANTIBODIES: IMMUNOPHARMACOLOGY MONOCLONAL ANTIBODIES: 1.Muromonab- CD3 2. Palivizumab 3. Rituxumab 4.Trastuzumab

Muromonab-CD3 IMMUNOPHARMACOLOGY A T-cell specific antibody Renal transplantation, heart / renal

IMMUNOPHARMACOLOGY Palivizumab – RSV Rituximab – follicular B-cell non-hodgekins lymphma Trastuzumab – metastatic breast CA

IMMUNOMODULATORS Interferon-alpha: - hairy cell leukemia CYTOKINES Interferon-alpha: - hairy cell leukemia - chronic myelogenous leukemia - malignant melanoma - Kaposi’s sarcoma - anticancer  renal cell CA, carcinoid syndrome, T cell leukemia

IMMUNOMODULATORS CYTOKINES Interferon-beta Interferon-gamma Relapsing type multiple sclerosis Interferon-gamma Chronic granulomatous disease Interleukin-2 Metastatic renal cell CA Malignant melanoma TNF-alpha Malignant melanoma Soft tissue sarcoma of extremities Interferons & IL-2 (+) effects in response to Hep B vaccine GM-CSF Melanoma and Prostate cancer

IMMUNOMODULATORS IMMUNOPHARMACOLOGY IMMUNOPHARMACOLOGY LEVAMISOLE: - antiparasitic agent - potentiate action of fluorouracil in adjuvant therapy of Dukes class C colorectal CA - other uses: > hodgkin’s lymphoma > RA

IMMUNOMODULATORS IMMUNOPHARMACOLOGY IMMUNOPHARMACOLOGY BCG (Bacille-Camille-Guarin): - immunization against tuberculosis - Adjuvant in intravesical therapy for SF bladder CA

IMMUNOMODULATORS IMMUNOPHARMACOLOGY IMMUNOPHARMACOLOGY HIV: - Inosiplex - Diethylcarbamate (DTC) DiGeorge Syndrome of T cell deficiency - give THYMOSIN