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
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COMPLEMENTS in Innate Immunity:

1. C3a, C5a  chemotaxis
2. C3b  opsonization
3. C5b, C6, C7, C8, C9  MAC
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0psonized
bacteria Macrophage

APC
B lymphocyte

T lymphocyte
IL-4,IL-5

IL-2 IL-2
TH1

IFN- IFN- TH2

TNF-
IFN- Plasma Cells:
Activated Activated -IgG - IgM
Activated Memory
Macrophage Cytotoxic T B Cells - IgA - IgD
NK cells
cell

CELL-MEDIATED IMMUNITY HUMORAL IMMUNITY

IMMUNOPHARMACOLOGY

T-helper cells:
1. TH1 subset
- IFN- , IL-2, TNF-

2. TH2 subset
- IL-4, IL-5, IL-6, IL-10
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ABNORMAL IMMUNE RESPONSES:

 HYPERSENSITIVITY

 AUTOIMMUNITY

 IMMUNODEFICIENCY
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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
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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
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Corticosteroids
• 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
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Corticosteroids
• Immunosuppressive dose:
 10-100 mg/day

• Adverse effects:
 GI bleeding
 adrenal suppression
 fluid retention
 diabetes
 proximal muscle wasting
 superinfections
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Cyclosporin
• 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
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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
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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
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Interferons
• 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
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TNF-α binding drugs
• 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
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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
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15-Deoxyspergualin
• Potent antimonocytic &
antilymphocytic effect

• Inhibits T & B lymphocyte

response

• Renal transplants; pancreas &

heart transplants
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Thalidomide
• Sedative drug
• Favors TH2 over TH1
• Suppress TNF-α production
• Antiangiogenesis action:
teratogenicity & anticancer
• Indications
• Erythema nodosum leprosum (skin
manifestations of SLE)
• Lung transplantation
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Glatiramer
• Relapsing-remitting form of
multiple sclerosis

• Subcutaneous injection

• Toxicities:
• Transient post-injection reaction
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CYTOTOXIC Agents:

1. Azathioprine

2. Leflunomide

3. Cyclophosphamide
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Azathioprine
• Metabolized to 6-mercaptopurines

• Inhibit purine synthesis interferes

with nucleic acid metabolism  inhibits
cellular & humoral responses

• Highly teratogenic

• Well absorbed from GI tract

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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
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Leflunomide
• Prodrug of an inhibitor of pyrimidine
synthesis
• Inhibits lymphoid cells
• Orally active
• RA
• Toxicities:
• Headache, nausea & diarrhea
• Hepatic dysfunction, renal impairment
• Teratogenic
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Cyclophosphamide
• Most potent immunosuppressive drug
• Destroys proliferating lymphoid cells
• Autoimmune disorders: SLE
• Acquired factor XIII antibodies
• Bleeding syndromes
• Toxicities:
• Pancytopenia, hemorrhagic cystitis
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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
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MONOCLONAL ANTIBODIES:

1.Muromonab- CD3

2. Palivizumab

3. Rituxumab

4.Trastuzumab
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Muromonab-CD3

• A T-cell specific antibody

• Renal transplantation, heart /

renal
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• Palivizumab – RSV

• Rituximab – follicular B-cell

non-hodgekins lymphma

• Trastuzumab – metastatic
breast CA
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 melanoma
Soft tissue sarcoma of
extremities
Interferons & IL-2 (+) effects in response to Hep B
vaccine
GM-CSF Melanoma and Prostate cancer
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IMMUNOMODULATORS
 LEVAMISOLE:

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

BCG (Bacille-Camille-Guarin):

- immunization against
tuberculosis

- Adjuvant in intravesical
therapy for SF bladder CA
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IMMUNOMODULATORS

HIV:
- Inosiplex
- Diethylcarbamate (DTC)

DiGeorge Syndrome of T cell

deficiency
- give THYMOSIN