Professional Documents
Culture Documents
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
Major Steps in Immune
Responses
1. Antigen recognition
2. IL-1 production
3. IL-2 and other cytokine expression
4. lymphocyte proliferation &
differentiation
Antigen
antigen
presenting
cell
(macrophage,
dendritic cell)
CD4
T helper
cell
primed
CD4
T helper
cell
CD8 T cell
cytotoxic
T cells
plasma
cells
1
2
3
4
4
IL-1
IL-2
IL-2
IL-2
MAJOR STEPS IN IMMUNE RESPONSES
B cell
Antigen
antigen
presenting
cell
CD4
T helper
cell
primed
CD4
T helper
cell
CD8 T cell
cytotoxic
T cells
plasma
cells
1
2
3
4
4
IL-1
IL-2
IL-2
cytokines
SITES OF ACTION OF
IMMUNOSUPPRESSIVE DRUGS
X
X
X
X
X
A
B
D D
E
C
X
IMMUNOPHARMACOLOGY
0psonized
bacteria
Macrophage
APC
T lymphocyte
IL-2 IL-2
IFN-
Activated
Macrophage
Activated
NK cells
Activated
Cytotoxic T
cell
CELL-MEDIATED IMMUNITY
B lymphocyte
IL-4,IL-5
TH
1
TH
2
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
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
IMMUNOPHARMACOLOGY
IMMUNOPHARMACOLOGY
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,, Hashimotos
Modulate allergic reactions - asthma
Organ transplantation rejection crisis
IMMUNOPHARMACOLOGY
Immunosuppressive dose:
10-100 mg/day
Adverse effects:
GI bleeding
adrenal suppression
fluid retention
diabetes
proximal muscle wasting
superinfections
IMMUNOPHARMACOLOGY
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
IMMUNOPHARMACOLOGY
Binds to FK-binding protein inhibits T-cell
activation
10-100 times more potent than cyclosporine
Liver & kidney transplant
Oral or IV : t = 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
(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
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
RA
IMMUNOPHARMACOLOGY
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
IMMUNOPHARMACOLOGY
Potent antimonocytic & antilymphocytic
effect
Inhibits T & B lymphocyte response
Renal transplants; pancreas & heart
transplants
IMMUNOPHARMACOLOGY
Sedative drug
Favors TH2 over TH1
Suppress TNF- production
Antiangiogenesis action: teratogenicity &
anticancer
Indications
Erythema nodosum leprosum (skin
manifestations of SLE)
Lung transplantation
IMMUNOPHARMACOLOGY
Relapsing-remitting form of multiple sclerosis
Subcutaneous injection
Toxicities:
Transient post-injection reaction
IMMUNOPHARMACOLOGY
IMMUNOPHARMACOLOGY
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
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
IMMUNOPHARMACOLOGY
Prodrug of an inhibitor of pyrimidine synthesis
Inhibits lymphoid cells
Orally active
RA
Toxicities:
Headache, nausea & diarrhea
Hepatic dysfunction, renal impairment
Teratogenic
IMMUNOPHARMACOLOGY
Most potent immunosuppressive drug
Destroys proliferating lymphoid cells
Autoimmune disorders: SLE
Acquired factor XIII antibodies
Bleeding syndromes
Toxicities:
Pancytopenia, hemorrhagic cystitis
IMMUNOPHARMACOLOGY
Antibodies as Immunosuppressive Agents
Antilymphocytic antibody
Immune Globulin IV
Hyperimmune Immunoglobulins
Monoclonal Antibodies
Rh
o
(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
IMMUNOPHARMACOLOGY
1.Muromonab- CD3
2. Palivizumab
3. Rituxumab
4.Trastuzumab
IMMUNOPHARMACOLOGY
MONOCLONAL ANTIBODIES:
A T-cell specific antibody
Renal transplantation, heart / renal
IMMUNOPHARMACOLOGY
Palivizumab RSV
Rituximab follicular B-cell
non-hodgekins lymphma
Trastuzumab metastatic
breast CA
IMMUNOPHARMACOLOGY
Sites of Action of Immunosuppressants Inhibiting
T Cell Activation
Drug
Glucortiocoids
Cyclosporine and
Tacrolimus
Sirolimus
Mycophenolate Mofetil
Target
GRE of DNA (regulate gene
transcription, inhibit transcription)
Calcineurin (inhibit the phosphatase
required for IL-2 transcription)
Protein kinase involved in cell-cycle
progression (inhibits mTOR and
inhbits IL-2 signaling)
Inosine monophosphate
dehydrogenase (inhibits de novo
guanine nucleotide synthesis)
Inhibitors of Immune Response
(site of action)
A. Immune Globulin (antigen recognition)
B. Corticosteroids (IL-1 production, cell
proliferation)
C. OKT3 ,ATG (T cell receptors/surface prot.)
D. Cyclosporine, Tacrolimus, (1L-2 gene expr.),
Sirolimus (IL-2 signal transduction)
E. Rapamycin, Mycophenolate (T cell prolif.),
Azathioprine,Cyclophosphamide (all cell prolif.)
View
Notes
CYTOKINES
Interferon-alpha:
- hairy cell leukemia
- chronic myelogenous leukemia
- malignant melanoma
- Kaposis sarcoma
- anticancer renal cell CA,
carcinoid syndrome, T cell leukemia
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
IMMUNOPHARMACOLOGY IMMUNOPHARMACOLOGY
LEVAMISOLE:
- antiparasitic agent
- potentiate action of fluorouracil
in adjuvant therapy of Dukes
class C colorectal CA
- other uses:
> hodgkins lymphoma
> RA
IMMUNOPHARMACOLOGY IMMUNOPHARMACOLOGY
BCG (Bacille-Camille-Guarin):
- immunization against
tuberculosis
- Adjuvant in intravesical
therapy for SF bladder CA
IMMUNOPHARMACOLOGY IMMUNOPHARMACOLOGY
HIV:
- Inosiplex
- Diethylcarbamate (DTC)
DiGeorge Syndrome of T cell
deficiency
- give THYMOSIN