IMUNOMODULATOR

Ita Armyanti/Farmakologi
2014

1. Int J Pharm Pharm Sci, Vol 4, Suppl

1, 2012
2. GG 12ed
3. Farmakologi FK UI
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IMMUNOPHARMACOLOGY
Basic role of immune system
distinguish self and non self
2 major components of the
immune system:
INNATE (natural or non specific)
Physical skin, mucus membrane
Biochemical complement, lyzosyme
Cellular macrophages, neutrophils

ADAPTIVE (aquired or specific)

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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

TH1

IL-2

IFN-
TNF-

IL-2

TH2

IFN-
IFN-

Activated
Macrophage
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Activated
NK cells

Plasma Cells:
Activated
Cytotoxic T
cell

Memory
B Cells

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CELL-MEDIATED IMMUNITY

-IgG

- IgM

- IgA

- IgD

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. Inhibitor of lymphocyte gene
expression : glucocorticoids
2. Inhibitors of lymphocyte signaling
3. Cytotoxic agents
4. Cytokine inhibitors
5. Antibodies against specific immune
cell molecules
6. Inhibitors of immune cell adhesion
7. Tolerogens or inhibitors of immune cell
costimulation
8. miscellaneous
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Inhibitor of lymphocyte gene

expression : glucocorticoids

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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 Continuous administration:
fractional catabolic rate of IgG

Indications:
Autoimmune disorders
- autoimmune hemolytic anemia, LE
- ITP, Inflammatory Bowel Dse,, Hashimotos

Modulate allergic reactions - asthma

Organ transplantation rejection crisis
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 Immunosuppressive dose:
10-100 mg/day
Adverse effects:
GI bleeding
adrenal suppression
fluid retention
diabetes
proximal muscle wasting
superinfections
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Inhibitors of lymphocyte signaling

1. Calcineurin inhibitors
:
cyclosporine, tacrolimus
2. mTOR inhibitors
: sirolimus,
everolimus

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Cyclosporin
produced by the fungus species Beauveria nivea
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
Macrolide antibiotic produced by
Streptomyces tsukubaensis
Binds to an intracelluler protein FK506binding protein inhibits T-cell activation
10-100 times more potent than cyclosporine
Pediatric Liver transplantion & kidney
transplant
Oral or IV : t = 9-12 hrs, 99% metabolized
by CYP3A
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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CYTOTOXIC Agents:
1.
2.
3.
4.
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Azathioprine
Mycophenolate mofetil
Leflunomide
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,
Crohns 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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Mycophenolate
Inhibits a series of T & B lymphocyte
Mofetil
responses
Inhibit de novo pathway of purine synthesis
Renal & heart transplantation
Mizoribine inhibitor nucleotide synthesis
pathway; kidney transplants
Brequinar Sodium inhibitors de novo
pathway of pyrimidine synthesi; cancer &
organ transplantation
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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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Cytokine inhibitors : TNF-

inhibitors
INFLIXIMAB
Chimeric IgG1 monoclonal antibody with
human region & murine regions
Suppress generation of cytokines
Crohns disease; RA

ETANERCEPT
Chimeric protein with human regiom
Similar MOA with infliximab but shorter
half-life
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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
T-cell specific antibody IL2
I : Renal transplantation, heart /
renal

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IMMUNOPARMACOLOGY
Palivizumab RSV
Rituximab follicular B-cell
non-hodgekins lymphma
Trastuzumab metastatic
breast CA
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IMMUNOSTIMULANTS
LEVAMISOLE:
- antiparasitic agent
- potentiate action of fluorouracil
in adjuvant therapy of Dukes
class C colorectal CA
- other uses:
> hodgkins lymphoma
> RA

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 BCG (Bacille-Camille-Guarin):
- immunization against
tuberculosis
- Adjuvant in intravesical
therapy for SF bladder CA
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Interferons
Type 1: induced by viral inf.
IFN-alpha prod. by leukocytes
IFN-beta prod. by 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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15Deoxyspergual
Potent antimonocytic &
inantilymphocytic effect
Inhibits T & B lymphocyte response
Renal transplants; pancreas & heart
transplants
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Thalidomide
Sedative drug
Favors TH2 over TH1
Suppress TNF- 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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IMMUNOMODULATORS
CYTOKINES

Interferon-alpha:
- hairy cell leukemia
- chronic myelogenous leukemia
- malignant melanoma
- Kaposis sarcoma
- anticancer renal cell CA,
carcinoid syndrome, T cell leukemia
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RECOMBINANT CYTOKINES

Relapsing type multiple

sclerosis
Interferon-gamma Chronic granulomatous disease

Interferon-beta

Interleukin-2
TNF-alpha

Metastatic renal cell CA

Malignant melanoma
Malignant melanoma

Soft tissue sarcoma of

extremities
Interferons & IL-2 (+) effects in response to Hep B
vaccine
Melanoma and Prostate cancer
GM-CSF
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IMMUNOMODULATORS
HIV:
- Inosiplex
- Diethylcarbamate (DTC)
DiGeorge Syndrome of T cell
deficiency
- give THYMOSIN
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postest
Pada kasus transplantasi organ,
kortikosteroid
pilihan yang dapat diberikan adalah ?
Indikasi interferons?
Monoklonal antibodi?
Efek samping talidomide ?
MoA levamisole?
BCG?
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