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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
COMPLEMENTS in Innate Immunity:
1. C3a, C5a chemotaxis
2. C3b opsonization
3. C5b, C6, C7, C8, C9 MAC
IMMUNOPHARMACOLOGY
IMMUNOPHARMACOLOGY0psonized bacteria Macrophage
APC
T lymphocyte
IL-2 IL-2
IFN-
Activated
MacrophageActivated
NK cells
Activated
Cytotoxic T cell
CELL-MEDIATED IMMUNITY
B lymphocyte
IL-4,IL-5
TH1
TH2
Memory B Cells
Plasma Cells:
-IgG - IgM
- IgA - IgD
HUMORAL IMMUNITY
IFN-
TNF-IFN-
T-helper cells:1. TH1 subset
- IFN- , IL-2, TNF-
2. TH2 subset- IL-4, IL-5, IL-6, IL-10
IMMUNOPHARMACOLOGY
ABNORMAL IMMUNE RESPONSES:
HYPERSENSITIVITY
AUTOIMMUNITY
IMMUNODEFICIENCY
IMMUNOPHARMACOLOGY
1. Corticosteroids2. Cyclosporine3. Sirolimus4. Tacrolimus5. Interferons6. TNF-alpha binding drugs7. Mycophenolate mofetil8. 15-Deoxyspergualin9. Thalidomide10. Glatiramer
IMMUNOPHARMACOLOGY
Immunosuppressants
IMMUNOPHARMACOLOGY
Corticosteroids• 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
• 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
IMMUNOPHARMACOLOGY
Corticosteroids
• Immunosuppressive dose: 10-100 mg/day
• Adverse effects: GI bleeding adrenal suppression fluid retention diabetes proximal muscle wasting superinfections
IMMUNOPHARMACOLOGY
Corticosteroids
• 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
IMMUNOPHARMACOLOGYCyclosporin
Tacrolimus• 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
IMMUNOPHARMACOLOGY
• 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
IMMUNOPHARMACOLOGY
Sirolimus (rapamycin)
• 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
IMMUNOPHARMACOLOGY
Interferons
• INFLIXIMAB • 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
IMMUNOPHARMACOLOGYTNF-α binding drugs
• 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
IMMUNOPHARMACOLOGYMycophenolate Mofetil
• Potent antimonocytic & antilymphocytic effect
• Inhibits T & B lymphocyte response
• Renal transplants; pancreas & heart transplants
IMMUNOPHARMACOLOGY15-Deoxyspergualin
• Sedative drug
• Favors TH2 over TH1
• Suppress TNF-α production
• Antiangiogenesis action: teratogenicity & anticancer
• Indications• Erythema nodosum leprosum (skin
manifestations of SLE)• Lung transplantation
IMMUNOPHARMACOLOGY
Thalidomide
• Relapsing-remitting form of multiple sclerosis
• Subcutaneous injection
• Toxicities:• Transient post-injection reaction
IMMUNOPHARMACOLOGY
Glatiramer
IMMUNOPHARMACOLOGY
CYTOTOXIC Agents:
1. Azathioprine
2. Leflunomide
3. Cyclophosphamide
• Metabolized to 6-mercaptopurines
• Inhibit purine synthesis interferes with nucleic acid metabolism inhibits cellular & humoral responses
• Highly teratogenic
• Well absorbed from GI tract
IMMUNOPHARMACOLOGY
Azathioprine
• 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
IMMUNOPHARMACOLOGY
Azathioprine
• Prodrug of an inhibitor of pyrimidine synthesis
• Inhibits lymphoid cells
• Orally active
• RA
• Toxicities: • Headache, nausea & diarrhea• Hepatic dysfunction, renal impairment
• Teratogenic
IMMUNOPHARMACOLOGY
Leflunomide
• Most potent immunosuppressive drug
• Destroys proliferating lymphoid cells
• Autoimmune disorders: SLE
• Acquired factor XIII antibodies
• Bleeding syndromes
• Toxicities: • Pancytopenia, hemorrhagic cystitis
IMMUNOPHARMACOLOGY
Cyclophosphamide
Antibodies as Immunosuppressive Agents• Antilymphocytic antibody
• Immune Globulin IV
• Hyperimmune Immunoglobulins
• Monoclonal Antibodies
• Rho(D) Immune Globulin Micro-DosePrevention of hemolytic disease of the
newbornGiven to mother within 72 hrs after
delivery of an Rh-negative baby
IMMUNOPHARMACOLOGY
1.Muromonab- CD3
2. Palivizumab
3. Rituxumab
4.Trastuzumab
IMMUNOPHARMACOLOGYMONOCLONAL ANTIBODIES:
• A T-cell specific antibody
• Renal transplantation, heart / renal
IMMUNOPHARMACOLOGY
Muromonab-CD3
•Palivizumab – RSV
•Rituximab – follicular B-cell non-hodgekins lymphma
•Trastuzumab – metastatic breast CA
IMMUNOPHARMACOLOGY
IMMUNOMODULATORS
• 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 Relapsing type multiple sclerosis
Interferon-gamma Chronic granulomatous disease
Interleukin-2 Metastatic renal cell CA Malignant melanoma
TNF-alpha Malignant melanomaSoft tissue sarcoma of extremities
Interferons & IL-2 (+) effects in response to Hep B vaccine
GM-CSF Melanoma and Prostate cancer
IMMUNOPHARMACOLOGY
IMMUNOMODULATORSIMMUNOPHARMACOLOGY
LEVAMISOLE:
- antiparasitic agent
- potentiate action of fluorouracil in adjuvant therapy of Dukes class C colorectal CA
- other uses:> hodgkin’s lymphoma> RA
IMMUNOPHARMACOLOGY
IMMUNOMODULATORSIMMUNOPHARMACOLOGY
BCG (Bacille-Camille-Guarin):
- immunization against tuberculosis
- Adjuvant in intravesical therapy for SF bladder CA
IMMUNOPHARMACOLOGY
IMMUNOMODULATORSIMMUNOPHARMACOLOGY
HIV:- Inosiplex- Diethylcarbamate (DTC)
DiGeorge Syndrome of T cell deficiency - give THYMOSIN
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