IMMUNOPHARMACOLOGY

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IMMUNOPHARMACOLOGY

• Ma. Janetth B. Serrano, M.D., DPBA

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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

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IMMUNOPHARMACOLOGY

• COMPLEMENTS in Innate Immunity
• 1. C3a, C5a ? chemotaxis
• 2. C3b ? opsonization
• 3. C5b, C6, C7, C8, C9 ? MAC

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IMMUNOPHARMACOLOGY
0psonized bacteria
Macrophage
APC
B lymphocyte
T lymphocyte
IL-4,IL-5
IL-2
IL-2
TH1
TH2
IFN-? TNF-?
IFN-?

• Plasma Cells
• IgG - IgM
• IgA - IgD

IFN-?
Activated Macrophage
Activated Cytotoxic T cell
Activated NK cells
Memory B Cells
CELL-MEDIATED IMMUNITY
HUMORAL IMMUNITY
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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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IMMUNOPHARMACOLOGY

• ABNORMAL IMMUNE RESPONSES
• HYPERSENSITIVITY
• AUTOIMMUNITY
• IMMUNODEFICIENCY

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Immunosuppressants
IMMUNOPHARMACOLOGY

• 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

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Corticosteroids
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

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IMMUNOPHARMACOLOGY
Corticosteroids

• 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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IMMUNOPHARMACOLOGY
Corticosteroids

• Immunosuppressive dose
• 10-100 mg/day
• Adverse effects
• GI bleeding
• adrenal suppression
• fluid retention
• diabetes
• proximal muscle wasting
• superinfections

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IMMUNOPHARMACOLOGY
Cyclosporin

• 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
IMMUNOPHARMACOLOGY

• 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

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IMMUNOPHARMACOLOGY
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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IMMUNOPHARMACOLOGY
Interferons

• 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

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IMMUNOPHARMACOLOGY
TNF-a binding drugs

• 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

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IMMUNOPHARMACOLOGY
Mycophenolate Mofetil

• 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

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IMMUNOPHARMACOLOGY
15-Deoxyspergualin

• Potent antimonocytic antilymphocytic effect
• Inhibits T B lymphocyte response
• Renal transplants pancreas heart transplants

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IMMUNOPHARMACOLOGY
Thalidomide

• Sedative drug
• Favors TH2 over TH1
• Suppress TNF-a production
• Antiangiogenesis action teratogenicity
  anticancer
• Indications
• Erythema nodosum leprosum (skin manifestations of
  SLE)
• Lung transplantation

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IMMUNOPHARMACOLOGY
Glatiramer

• Relapsing-remitting form of multiple sclerosis
• Subcutaneous injection
• Toxicities
• Transient post-injection reaction

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IMMUNOPHARMACOLOGY
CYTOTOXIC Agents

• 1. Azathioprine
• 2. Leflunomide
• 3. Cyclophosphamide

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IMMUNOPHARMACOLOGY
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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IMMUNOPHARMACOLOGY
Azathioprine

• Renal allograft, AGN, SLE(renal), RA, Crohns
  disease
• Prednisone-resistant antibody-mediated ITP
• Autoimmune hemolytic anemia
• Toxicities
• Bone marrow suppression
• GI disturbances NV, diarrhea
• Skin rashes, drug fever, hepatic dysfunction

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IMMUNOPHARMACOLOGY
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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IMMUNOPHARMACOLOGY
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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Antibodies as Immunosuppressive Agents
IMMUNOPHARMACOLOGY

• 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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IMMUNOPHARMACOLOGY
MONOCLONAL ANTIBODIES

• 1.Muromonab- CD3
• 2. Palivizumab
• 3. Rituxumab
• 4.Trastuzumab

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IMMUNOPHARMACOLOGY
Muromonab-CD3

• A T-cell specific antibody
• Renal transplantation, heart / renal

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IMMUNOPHARMACOLOGY

• Palivizumab RSV
• Rituximab follicular B-cell non-hodgekins
  lymphma
• Trastuzumab metastatic breast CA

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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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IMMUNOMODULATORS

• 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
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IMMUNOPHARMACOLOGY
IMMUNOPHARMACOLOGY
IMMUNOMODULATORS

• LEVAMISOLE
• - antiparasitic agent
• - potentiate action of fluorouracil in adjuvant
  therapy of Dukes class C colorectal CA
• - other uses
• gt hodgkins lymphoma
• gt RA

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IMMUNOPHARMACOLOGY
IMMUNOPHARMACOLOGY
IMMUNOMODULATORS

• BCG (Bacille-Camille-Guarin)
• - immunization against tuberculosis
• - Adjuvant in intravesical therapy for SF
  bladder CA

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IMMUNOPHARMACOLOGY
IMMUNOPHARMACOLOGY
IMMUNOMODULATORS

• HIV
• - Inosiplex
• - Diethylcarbamate (DTC)
• DiGeorge Syndrome of T cell deficiency
• - give THYMOSIN