IMMUNOPHARMACOLOGY
9/12/06
2 major components of the immune system:
INNATE
1. Physical – skin, mucus membrane
2. Biochemical – complement, lyzosyme
3. Cellular – macrophages, neutrophils
ADAPTIVE
1. Antibodies – HUMORAL immunity
2. T-lymphocyte – CELL MEDIATED immunity
COMPLEMENTS in Innate Immunity:
1. C3a, C5a  chemotaxis
2. C3b  opsonization
3. C5b, C6, C7, C8, C9  MAC
T-helper cells:
1. TH1 subset
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IFN- , IL-2, TNF-
2. TH2 subset
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IL-4, IL-5, IL-6, IL-10
ABNORMAL IMMUNE RESPONSES:
1. HYPERSENSITIVITY
2. AUTOIMMUNITY
3. IMMUNODEFICIENCY
Immunosuppressants
1. Corticosteroids
2. Cyclosporine
3. Sirolimus
4. Tacrolimus
5. Interferons
1.
2.
3.
6.
7.
8.
9.
10.
TNF-alpha binding drugs
Mycophenolate mofetil
15-Deoxyspergualin
Thalidomide
Glatiramer
Corticosteroids
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MOA:
inhibit T-cell proliferation & T-cell dependent immunity
Inhibit expression of genes encoding cytokines
Inhibit production of inflammatory mediators
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Affects cell-mediated immunity more than humoral immunity
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Continuous administration: ↑ fractional catabolic rate of IgG
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Indications:
Autoimmune disorders

autoimmune hemolytic anemia, LE

ITP, Inflammatory Bowel Disease, Hashimoto’s
Modulate allergic reactions - asthma
Organ transplantation – rejection crisis
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Immunosuppressive dose: 10-100 mg/day
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Adverse effects:
GI bleeding
adrenal suppression
fluid retention
diabetes
proximal muscle wasting
superinfections
Cyclosporine
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Blocks T-cell activation
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binds to cyclophillin  inhibits calcineurin activity  inhibits gene transcription of IL-2, IL-3, IFN & other factors
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Most commonly used immunosuppresant for renal transplantation
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Indications:
transplant rejection (kidney, liver, pancreas, cardiac)
Autoimmune disorders (uveitis, RA, DM type1)
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Toxicities: nephrotoxicity, hyperglycemia, hyperlipidemia, osteoporosis, ↑ hair growth, transient liver dysfunction
Tacrolimus
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Binds to FK-binding protein  inhibits T-cell activation
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10-100 times more potent than cyclosporine
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Liver & kidney transplant
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IMMUNOPHARMACOLOGY
9/12/06
4.
5.
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Oral or IV : t½ = 9-12 hrs
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Toxicity: nephrotoxicity, neurotoxicity, hyperglycemia, GI dysfunction
Sirolimus (Rapamycin)
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Binds also to immunophyllin  blocks the response of T-cell to cytokines
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Potent inhibitor of B-cell proliferation & Ig production
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Indications:
Kidney & heart allografts
C syclosporin  psoriasis & uveoretinitis
Interferon
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Type 1: induced by viral inf.
IFN-alpha  prod. by leukocytes
IFN-beta  fibroblasts & epithelial cells
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Type 2: IFN-gamma  produced by activated T-lymphocytes
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Indications: cancer
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IFN-  multiple sclerosis
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IFN- chronic granulomatous disease
Newer Immunosuppressants
1. TNF-α binding drugs:
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INFLIXIMAB
Chimeric IgG1 monoclonal antibody with human region & murine regions
Suppress generation of cytokines
Crohn’s disease; RA
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ETANERCEPT
Chimeric protein with human regiom
Similar MOA with infliximab but shorter half-life
RA
2. Mycophenolate Mofetil
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Inhibits a series of T & B lymphocyte responses
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Inhibit de novo pathway of purine synthesis
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Renal & heart transplantation
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Mizoribine – inhibits nucleotide synthesis PW; kidney transplants
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Brequinar Sodium – inhibits de novo pathway of pyrimidine synthesis; cancer & organ transplantation
3. 15-Deoxyspergualin
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Potent antimonocytic & antilymphocytic effect
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Inhibits T & B lymphocyte response
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Renal transplants; pancreas & heart transplants
4. Thalidomide
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Sedative drug
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Favors TH2 over TH1
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Suppress TNF-α production
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Antiangiogenesis action: teratogenicity & anticancer
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Indications
i. Erythema nodosum leprosum (skin manifestations of SLE)
ii. Lung transplantation
5. Glatiramer
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Relapsing-remitting form of multiple sclerosis
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Subcutaneous injection
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Toxicities: Transient post-injection reaction
CYTOTOXIC Agents:
1. Azathioprine
Metabolized to 6-mercaptopurines
Inhibit purine synthesis interferes with nucleic acid metabolism  inhibits cellular & humoral responses
Highly teratogenic
Well absorbed from GI tract
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
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IMMUNOPHARMACOLOGY
9/12/06
2.
3.

Skin rashes, drug fever, hepatic dysfunction
Leflunomide
Prodrug of an inhibitor of pyrimidine synthesis
Inhibits lymphoid cells
Orally active
RA
Toxicities:

Headache, nausea & diarrhea

Hepatic dysfunction, renal impairment
Teratogenic
Cyclophosphamide
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
Antibodies as Immunosuppressive Agents
1. Antilymphocytic antibody
2. Immune Globulin IV
3. Hyperimmune Immunoglobulins
4. Monoclonal Antibodies
5. 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
i. Muromonab- CD3
A T-cell specific antibody
Renal transplantation, heart / renal
ii. Palivizumab – RSV
iii. Rituxumab – follicular B-cell non-hodgekins lymphma
iv. Trastuzumab – metastatic breast CA
IMMUNOMODULATORS
1. CYTOKINES
▪
Interferon-alpha:
hairy cell leukemia
chronic myelogenous leukemia
malignant melanoma
Kaposi’s sarcoma
anticancer  renal cell CA, carcinoid syndrome, T cell leukemia
Interferon-beta
Interferon-gamma
Interleukin-2
TNF-alpha
Interferons & IL-2
GM-CSF
2.
3.
Relapsing type multiple sclerosis
Chronic granulomatous disease
Metastatic renal cell CA Malignant melanoma
Malignant melanoma
Soft tissue sarcoma of extremities
(+) effects in response to Hep B vaccine
Melanoma and Prostate cancer
LEVAMISOLE:

antiparasitic agent

potentiate action of fluorouracil in adjuvant therapy of Dukes class C colorectal CA

other uses:
 hodgkin’s lymphoma
 RA
BCG (Bacille-Camille-Guarin):

immunization against tuberculosis

Adjuvant in intravesical therapy for SF bladder CA
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