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:
• 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
The winds and waves are always on the side
of the ablest
navigator“The winds and waves are always on the side
of the ablest navigator”
QUIZ1. Most common adverse effect of corticosteroids2. The most potent immunosuppressive agent.3. Adverse effects of4. CYCLOPHOSPHAMIDE5. Given to mothers to prevent ‘hemolytic disease of
the newborn’ Write B if the drug inhibits B lymphocytes & its
responses; T if the drug inhibits T lymphocytes & its responses; and C if it inhibits both T & B cells:
6. Tacrolimus 9. Azathioprine7. Leflunamide 10. Cyclophosphamide8. Cyclosporin
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