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

COMPLEMENTS in Innate Immunity:

1. C3a, C5a chemotaxis

2. C3b opsonization

3. C5b, C6, C7, C8, C9 MAC

IMMUNOPHARMACOLOGY

IMMUNOPHARMACOLOGY0psonized bacteria Macrophage

APC

T lymphocyte

IL-2 IL-2

IFN-

Activated

MacrophageActivated

NK cells

Activated

Cytotoxic T cell

CELL-MEDIATED IMMUNITY

B lymphocyte

IL-4,IL-5

TH1

TH2

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

1. Corticosteroids2. Cyclosporine3. Sirolimus4. Tacrolimus5. Interferons6. TNF-alpha binding drugs7. Mycophenolate mofetil8. 15-Deoxyspergualin9. Thalidomide10. Glatiramer

IMMUNOPHARMACOLOGY

Immunosuppressants

IMMUNOPHARMACOLOGY

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

• 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

IMMUNOPHARMACOLOGY

Corticosteroids

• Immunosuppressive dose: 10-100 mg/day

• Adverse effects: GI bleeding adrenal suppression fluid retention diabetes proximal muscle wasting superinfections

IMMUNOPHARMACOLOGY

Corticosteroids

• 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

IMMUNOPHARMACOLOGYCyclosporin

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

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

Sirolimus (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

Interferons

• 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

IMMUNOPHARMACOLOGYTNF-α binding drugs

• 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

IMMUNOPHARMACOLOGYMycophenolate Mofetil

• Potent antimonocytic & antilymphocytic effect

• Inhibits T & B lymphocyte response

• Renal transplants; pancreas & heart transplants

IMMUNOPHARMACOLOGY15-Deoxyspergualin

• Sedative drug

• Favors TH2 over TH1

• Suppress TNF-α production

• Antiangiogenesis action: teratogenicity & anticancer

• Indications• Erythema nodosum leprosum (skin

manifestations of SLE)• Lung transplantation

IMMUNOPHARMACOLOGY

Thalidomide

• Relapsing-remitting form of multiple sclerosis

• Subcutaneous injection

• Toxicities:• Transient post-injection reaction

IMMUNOPHARMACOLOGY

Glatiramer

IMMUNOPHARMACOLOGY

CYTOTOXIC Agents:

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

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

IMMUNOPHARMACOLOGY

Azathioprine

• Prodrug of an inhibitor of pyrimidine synthesis

• Inhibits lymphoid cells

• Orally active

• RA

• Toxicities: • Headache, nausea & diarrhea• Hepatic dysfunction, renal impairment

• Teratogenic

IMMUNOPHARMACOLOGY

Leflunomide

• Most potent immunosuppressive drug

• Destroys proliferating lymphoid cells

• Autoimmune disorders: SLE

• Acquired factor XIII antibodies

• Bleeding syndromes

• Toxicities: • Pancytopenia, hemorrhagic cystitis

IMMUNOPHARMACOLOGY

Cyclophosphamide

Antibodies as Immunosuppressive Agents• Antilymphocytic antibody

• Immune Globulin IV

• Hyperimmune Immunoglobulins

• Monoclonal Antibodies

• Rho(D) Immune Globulin Micro-DosePrevention of hemolytic disease of the

newbornGiven to mother within 72 hrs after

delivery of an Rh-negative baby

IMMUNOPHARMACOLOGY

1.Muromonab- CD3

2. Palivizumab

3. Rituxumab

4.Trastuzumab

IMMUNOPHARMACOLOGYMONOCLONAL ANTIBODIES:

• T-cell specific antibody

• Renal transplantation, heart / renal

IMMUNOPHARMACOLOGY

Muromonab-CD3

•Palivizumab – RSV

•Rituximab – follicular B-cell non-hodgekins lymphma

•Trastuzumab – metastatic breast CA

IMMUNOPHARMACOLOGY

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 melanomaSoft tissue sarcoma of extremities

Interferons & IL-2 (+) effects in response to Hep B vaccine

GM-CSF Melanoma and Prostate cancer

IMMUNOPHARMACOLOGY

IMMUNOMODULATORSIMMUNOPHARMACOLOGY

LEVAMISOLE:

- antiparasitic agent

- potentiate action of fluorouracil in adjuvant therapy of Dukes class C colorectal CA

- other uses:> hodgkin’s lymphoma> RA

IMMUNOPHARMACOLOGY

IMMUNOMODULATORSIMMUNOPHARMACOLOGY

BCG (Bacille-Camille-Guarin):

- immunization against tuberculosis

- Adjuvant in intravesical therapy for SF bladder CA

IMMUNOPHARMACOLOGY

IMMUNOMODULATORSIMMUNOPHARMACOLOGY

HIV:- Inosiplex- Diethylcarbamate (DTC)

DiGeorge Syndrome of T cell deficiency - give THYMOSIN

The winds and waves are always on the side

of the ablest

navigator“The winds and waves are always on the side

of the ablest navigator”

QUIZ1. Most common adverse effect of corticosteroids2. The most potent immunosuppressive agent.3. Adverse effects of4. CYCLOPHOSPHAMIDE5. Given to mothers to prevent ‘hemolytic disease of

the newborn’ Write B if the drug inhibits B lymphocytes & its

responses; T if the drug inhibits T lymphocytes & its responses; and C if it inhibits both T & B cells:

6. Tacrolimus 9. Azathioprine7. Leflunamide 10. Cyclophosphamide8. Cyclosporin