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:

• A 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