Immunofarmakologi adalah bidang

biologi yang terdapat overlap antara

immunologi, patologi dan farmakologi

Pertemuan ini Imunomodulator :

Immunostimulator
Imunosupressan
Immun system
Department of Psychiatry
Tahapan utama respon imun

1- Pengenalan antigen
2- Produksi IL-1
3- Ekspresi IL-2 dan cytokine lain
4- Proliferasi dan diferensiasi
lymphocyte
 MAJOR STEPS IN IMMUNE RESPONSES
Antigen CD8 cell
IL-2
cytotoxic
1 4 T cells

2 3 primed
CD4
IL-1 IL-2 helper
antigen CD4 cell
presenting helper plasma
cell cell 4
cells
IL-2
Gangguan Imunitas &
Intervensi
Kondisi gangguan Intervensi
imun: Meningkatkan
Respon/status imun respon / status imun
rendah atau kurang Menekan respon
Respon imun imun
berlebihan /
hiperaktif
 Meningkatkan respon / status
imun
Imunoterapi aktif:
Terapi vaksin (BCG, DPT, Polio, Campak,

Hepatitis, dll)
Agen Sintetik

Levamizole Aksi utama: meningkatkan

jumlah dan aktivitas sel T; Penggunaan
utama: kanker kolorektal; Efek Samping:
agranulositosis
Thymic Hormones

Improve primary immune deficiency in children

Imunisasi adoptif
Infus: limfosit donor, limfosit T cytotoxic
(Pembangkitan ex vivo), limfosit
terinfiltrasi tumor
Imunisasi Toleransi perifer buatan
(Desensitisasi)
Imunoterapi peny gg. Autoimmun
autoantigen
Imunoterapi pd hipersensitifits /
penolakan cangkok organ
 Immunostimulatory Cytokines
Interleukins
IL-2 (enhance antitumor actions of cytotoxic T cells
and NK cells)
Colony Stimulating Factors
G-CSF (neutropenia) and GM-CSF (bone marrow
transplant patients)
Interferons (uses)
alpha (anticancer uses)
beta (relapsing type multiple sclerosis)
gamma (chronic granulomatous disease)
 Interferon Uses
Interferon Alpha (prod. by leukocytes)
(antiviral, antiproliferative)
malignant melanoma, renal cell carcinoma, hairy
cell leukemia, Kaposis sarcoma
Interferon Beta (prod. by fibroblasts)
(antiviral, antiproliferative)
relapsing type MS

Interferon Gamma (prod. by lymphocytes)

(stimulates NK cells and macrophages)
chronic granulomatous disease
Imunoterapi pasif
Seroterapi / serum terapi
Serum heterolog hiperimun
serum imunosupresif
serum agen antiinfeksi
serum antibisa
Serum homolog
serum homolog imun
serum homolog hiperimun
 Antibodi monoklonal (mAbs)
mAbs antiinfeksi organisme
mAbs antitoksik
mAbs antiplatelet
mAbs antikanker (keganasan hematologik,

tumor solid)
mAbs antihipersensitifitas tipe I
mAbs imunosupresif
mAbs imunostimulan
 Ligan imunosit
Ligan imunosupresif
Ligan imunostimulan
Sistem haptofor-toksofor
Radioimmunotherapy (RIT)
imunotoksin
TAP (Tumor Activated Prodrug)
ADEP (Antibody-directed enzyme prodrug)
delivery of scMHC class peptide
complexes
Immuno-gene therapy
 Echinacea

Phylantus niruri immunostimulator

fitofarmaka - Indonesia
 Immunostimulator
Vaccine
Antigen
Adjuvant
 Obat penekan respon imun
Obat-obat imunosupresif menghambat
fungsi dan / atau aktivasi limfosit terutama
dengan menghambat sintesis DNA
(antiproliferatif) atau produk gen spesifik
(melalui interfensi dalam signaling)
 SITES OF ACTION OF
IMMUNOSUPPRESSIVE DRUGS
Antigen CD8 cell 4
IL-2
X cytotoxic
X 1 E T cells
A C

2 X 3 primed
X D X D CD4
B IL-1 IL-2 helper
antigen CD4 cell
presenting helper 4 plasma
cell cell
X cells

cytokines
 Inhibitors of Immune Response
(site of action)
_ A- Immune Globulin (antigen recognition)
_ B- Corticosteroids (IL-1 production, cell proliferation)
_ C- OKT3 (CD3 receptor on T cell), ALG
_ D- Cyclosporine, Tacrolimus, (1L-2 gene expression
and production), Sirolimus (IL-2 signal
transduction in T cells)
_ E- Methotrexate, Cyclophosphamide, rapamycin,
mycophenolate
View
Notes
 Azathioprine

Baxiliximab
Tacrolimus Daclizumab
Sirolimus

Cyclosporin
Corticosteroid

OKT3

Mycophenolate
 Obat Imunosupressan
Cyclosporine
Tacrolimus
Sirolimus
Mycophenolate
Prednisone, Methylprednisolone
 Cyclosporine

Strukture
lipophilic cyclic peptide

Mekanisme
Menghambat trasnkripsi gen IL-2 dan ekspresi
cytokine lain (IL-3, gamma interferon)
Tempat aksi: ikatan protein yang menghambat
calcineurin (a phosphatase) yang melibatkan signal
transduction pada stimulasi antigen terhadap
reseptor sel T yang sedang berlangsung
MA
 Cyclosporine (Sandimmune)
Pharmacokinetics
Absorpsi peroral tidak lengkap
Metabolisme di hati, diekskresi dalam empedu
Pengunaan single / kombinasi dg prednisone dan
azathioprine (atau obat anti kanker lain)
Adverse Effects
nephrotoxicity, hepatotoxicity, hirsutism,
neurotoxicity
Interaksi obat: induksi dan inhibisi enzim cytochrome
P450
 Cyclosporine (Neoral)
Pharmacokinetics
microemulsion of cyclosporine
(capsules and oral solution)
improved oral absorption
60% oral availability vs 30% for
Sandimmune
terminal half-life approx. 8.4 hours vs 19
hours for Sandimmune
 Tacrolimus
Strukture
macrolide (structure like erythromycin)

Mekanisme
Sama dg cyclosporine kecuali ikatan pada protein
yang berbeda dalam menghambat calcineurin (suatu
enzim phosphatase dalam transkripsi gen IL-2,
gamma interferon and other cytokines)

MA
 Tacrolimus
Bioavailability
Pemberian infus IV atau peroral
Digunakan bersamaan dg kortikosteroids

Adverse Effects
nephrotoxicity, meningkatkan resiko
lymphoma, hypersensitivity, hyperglycemia,
tremor, headache
 Sirolimus
Sirolimus (Rapamune)
Struktur
Structure
macrolide similiar to tacrolimus
macrolide similiar to tacrolimus
Mekanisme
Mekanisme
Mechanism
Berikatan dg protein imunofilin yg berikatan pada
binds
kunci to immunophilin
pengaturan protein
kinase that binds pada
dan diperlukan to a key
regulatory
aktivasi selkinase
T required for T cell activation
(new
(new unique
unique mechanism
mechanism toto inhibit
inhibit T
T lymphocyte
lymphocyte
activation
activation by
by IL-2)
IL-2)
different
site yang
Tempat aksi of action than dengan
berbeda cyclosporine and
cyclosporine dan
tacrolimus
tacrolimus
MA
 Sirolimus
Target of rapamycin (TOR) berperan penting pd
jalur pengenalan antigen untuk memperkuat
respon immune mengikuti (urutan) pengenalan
anitgen, aktivasi T cells synthesize dan pelepasan
IL-2 serta proinflammatory cytokines IL-2 lain
yang berikatan pada sel T dan menunjuk aktivasi
TOR yang mengawali kejadian cascade
 Consequences of TOR
Konsekuensi aksi TORAction

Proliferasi
Lymphocyte dan
celldiferensiasi
proliferation &
differentiation
Sel T

T cells
Sel B
B cells
Produksi Antibodi
Antibody

Proliferasiproduction
sel mesenkimal
Mesenchymal
Sel otot polos cell proliferation
pembuluh darah
Vascular smooth muscle cells
Sel Endothelial
Endothelial
Fibroblasts cells
Fibroblasts
 Properties of TOR Inhibitors
Sifat Inhibitor TOR seperti
such as Sirolimus (Rapamune)
Sirolimus
Selective blockade of cytokine signal

transduction
Selective menghambat transduksi signal
Inhibition
cytokine of cell division and proliferation
Potent and effective
Menghambat immunosuppression
proliferasi dan pembagian sel
Imunosupresi potensial dan efektif
Mempunyai sinergi yang kuat dengan
immunosuppressants lain
 Sirolimus
other theoretical actions include
blockade of B cell Ig synthesis
inhibition of antibody-dependent cellular toxicity
inhibition of lymphocyte activated killer cells
inhibition of natural killer cells
inhibition of immune and nonimmune cell
proliferation (via inhibition of growth factor
signalling)
 Mycophenolate Mofetil
Adverse Effects
diarrhea, leukopenia and CMV infections
increased incidence of lymphomas and other
malignancies

MA
 New Immunosuppressants
_ Mizoribine (investigational)
_ Inhibitor of purine nucleotide synthesis
_ Brequinar (investigational)
_ Inhibitor of de nove pyrimidine synthesis
_ 15-Deoxyspergualin (investigational)
_ Antimonocytic that decreases MHC antigen
expression
_ Pimecrolimus (Elidel)
_ Calcineurin inhibitor like cyclosporine
_ Approved for topical treatment of eczema
Antibodies Used for Acute Rejection
of Organ Transplants
OKT3 (Muromonab-CD3) MA

monoclonal antibody to CD3 on T cell

inhibits cytotoxic T killer cell function
opsonizes circulating T lymphocytes and enhances
their removal
used to prevent or reverse acute graft rejection

Antilymphocyte Globulin
polyclonal antibody similiar to OKT3

Antithymocyte Globulin-Rabbit
used to treat acute renal transplant rejection
 Antithymocyte Globulin-Rabbit
(Thymoglobulin)
Rabbit gamma immune globulin preparation
Composed of antibodies to variety of T cell
markers
Mechanisms
removal of T cells from circulation
modulation of T cell activation, homing and
cytotoxicity
decreases cytokine induced reactions
 Adverse Effects of Antibody Preps
_ Reaksi hipersensitif meliputi kedinginan, febris,
thrombocytopenia, erythema, pruritis. Untuk
membatasi efek tersebut pemberian antibodi Anti-
OKT3, hanya diberikan melalui infus IV selama 7-
14 hari
 Sediaan antibodi yang lain
Rh(D) Immune Globulin
Untuk ibu Rh (neg.) setelah melahirkan bayi
Rh(pos.)
Abciximab
Untuk reseptor permukaan pada aktivasi platelet
untuk mencegah restenosis setelah coronary
angioplasty
Rituximab
Untuk CD20 pada sel pre-B dan sel B mature pada
terapi non-hodgkins lymphoma
 Antibodi reseptor IL-2
Basiliximab (Simulect)
Chimeric murine monoclonal antibody against
human IL-2 receptor alpha subunit of activated T to
block T cell
Blocks activation and inhibits clonal expansion of T
cells
Used to induce immunosuppression and to prolong
organ transplants in combination with
immunosuppressants

MA
 Other IL-2 Receptor Antibodies
Daclizumab (Zenapax)
a humanized immunoglobulin similar to Basiliximab
which blocks IL-2 receptor
Formed by splicing complementary portions of light and
heavy chain variable regions of murine antibody into
human-derived Fab framework and fusing the Fab to the
Fc portion of human IgG

MA
Corticosteroids
Prednisone used most often orally
Methylprednisolone used parenterally
Numerous available preparations
 Corticosteroid Actions
Inhibition of IL-1 and TNF gene expression and synthesis
Decreased activation of T lymphocytes by decreasing IL-1
release
Decreased activation of T lymphocytes by decreasing IL-1
release
Decreased neutrophil functions esp chemotaxis
Decreased antibody production (high doses)
Decreased release of kinins and proinflammatory eicosanoids
(prostaglandins and leukotrienes)
 Corticosteroid
Immunosuppression
_ Decreased cell-mediated immune
reactions that mediate rejection of organ
transplants
_ Mechanism involves decreased activation of
T lymphocytes by inhibition of IL-1 synthesis
by macrophages and decresed lymphocyte
mobilization out of lymphoid organs

MA
 Corticosteroid Adverse Reactions
_ All commonly occur because high doses used for
immunosuppression
_ Suppression of HPA function
_ Hypertension
_ Weight gain, hyperglycemia
_ Euphoric personality changes
_ Cataracts
 Antimetabolites
Immunosuppresion by inhibition of
lymphocyte proliferation and cause bone
marrow suppression
Azathioprine
Cyclophosphamide

MA
 Cytokine Inhibitors
_ TNF inhibitors (disease modifiers to treat
rheumatoid arthritis)
_ Etanercept (Enbrel)
_ Recombinant version of TNF receptor

_ Infliximab (Remicade)
_ Chimeric human/murine anti-TNF monoclonal
antibody
_ Anakinra (Kineret)
_ Human IL-1 receptor antagonist
_ Disease modifier agent for Rheumatoid
arthritis
Immunosupressive
 Reference:
Textbook of Immunopharmacology
Website: Immunotherapy
Wassalamualaikum Wr. Wb.