IMMUNOPHARMACOLOGY

Protection from infection and disease is provided by: *the innate immune system : -a physical component: skin, mucosa; - a biochemical component: the complement; -a cellular component: neutrophils. *the adaptative immune system(cellular and humoral immunity).

1. Immunosuppressant agents:
=drugs which inhibit cellular or humoral immunity or both immune responses and have their major use in organ transplantation and autoimmune diseases.

a) CORTICOSTEROIDS
MECHANISM OF ACTION
-at

biochemical level: decrease the synthesis of PG, leukotrienes, limphokins: they inhibit major histocompatibility complex expression and IL-1,IL-2, IL-6 production so that helper Tcells are not activated; -at the cellular level: they inhibit the proliferation of T ly but B ly are less affected; at doses used for immunosuppression, they are cytotoxic to certain subsets of T cells. Continuous therapy IgG level by increasing catabolism of this class of immunoglobulins.

CLINICAL USES Prednisone: -several autoimmune diseases: *autoimmune hemolytic anemia; *idiophatic thrombocytopenic purpura; *acute glomerulonephritis; -organ transplantation(in combination). SIDE EFFECTS *adrenal suppression, *growth inhibition, *osteoporosis, *salt retention.

b)CYCLOSPORINE
It is a peptide antibiotic Mechanism of action: -it inhibits T lymphocytes proliferation, IL2 and other cytokine production. it enhances expression of an inhibitor of IL-2 which attenuates IL-2 stimulated Tcell proliferation and production of killer lymphocytes.

Clinical uses: -prevention and treatment of graft rejection reaction(! the most effective drug);It is routinely used in renal, hepatic, cardiac, bone marrow and other transplantations. *It is given orally but therapy may be started with i.v. infusion. - autoimmune diseases (early treatment of type I diabetes, asthma, severe rheumathoid arthritis, inflammatory bowel diseases, dermatomyositis) *it is often used along with corticosteroids.

c)TACROLIMUS(FK 506)
Mechanism of action: -it interferes with the synthesis of interleukins in activated T cells. ~ 100 times more potent than cyclosporine Clinical uses: - liver, kidney, pancreas, heart transplantations. ( orally as well as by i.v infusion)

d) CYTOTOXIC IMMUNOSUPPRESSANTS
1.AZATHOPRINE It is a purine antimetabolite which has more marked immunosuppressant than antitumor action. It is a prodrug and it is transformed in the body into 6- mercaptopurine which then undergoes further transformations to inhibit de novo purine synthesis and damage to DNA. Mechanism of action: -It inhibits early phases of T cells proliferation ; it has less effects on B cells.

Clinical uses: -prevention of renal and other graft rejection ; -it is used in several autoimmune diseases(progressive rheumatoid arthritis ) Side effects: -bone marrow suppression; -GI rash, skin rashes, liver dysfunction. -it increases the risk of neoplasms

2.METHOTREXATE- folate antagonist

- it markedly depresses cytokine production and cellular immunity and has antiinflammatory properties. -autoimmune diseases, like rapidly progressing rheumatoid arthritis.

3.CHLORAMBUCIL
-weak immunosuppressant -sometimes utilized in autoimmune diseases and transplant maintenance regimens.

4.CYCLOPHOSPHAMIDE
- It has more marked effect on B cells and humoral immunity Clinical uses: -bone marrow transplantation, autoimmune diseases (lupus erythematosus, thrombocytopenic purpura, hemolytic anemia). Side effects: - pancytopenia, GI distress, hemorrhagic cystitis, alopecia.

e)ANTIBODIES AS IMMUNOSUPPRESSANTS
1. Antithymocyte globulin (ATG) * It is a policlonal antibody purified from horse or rabbit immunized with human thymic lymphocytes.It binds to T lymphocytes initiating their distruction by serum complement. Uses : *bone marrow transplantation to prevent the graftversus host reaction. *in combination with cyclosporine or cytotoxic drugs (or both) for maintenance following bone marrow, heart, renal transplantations. Adverse effects: *HS reactions, (anaphylaxia and serum sickness.)

2)Muromonab CD3
* It is a murine monoclonal antibody to the T3 (CD3) antigen on the surface of human thymocytes and mature T cells; it blocks the killing action of cytotoxic T cells and probably interferes with other T cell functions. * It is used i.v. to reverse the renal allograft rejection crisis. *fever, chills, dyspnea, HS reactions.

3)Anti D immune globulin:

*It is a human Ig G preparation that contains a high titer of antibodies against Rh (D) antigen. It binds to Rh0 antigens and does not allow them to induce antibody formation in Rh negative individuals. *for prevention of postpartum formation of antibodies in Rh0-D negative women who have delivered an Rh0- D positive baby.maternal antibodies to Rh-positive cells are not produced in subsequent pregnancies and hemolytic disease of the neonate is thus averted. !! It should be administered within 72 hours of delivery.

4)I.v. Ig
*a polyclonal human Ig from a pool of thounsands of healthy donors and no specific antigen is the target of the inoculated antibody. Mechanism of action:* diminuation of helper T cells, increase in suppressor T cells, decrease in spontaneous Ig production. Clinical uses: *autoimmune diseases.

2.Immunomodulating agents(immunostimulating agents):

=stimulators of immune responses.They are used in the treatment of immune deficiency diseases, chronic infectious diseases and cancer.

a)Natural immunomodulating agents

1)THYMOSIN -is a protein hormone from the thymus gland that stimulates the maturation of pre-T cells and promotes the formation of T cells from ordinary lymphoid stem cells. Thymosin containing preparations have been used in thymic aplasia (DiGeorges syndrome). 2)THYMOPOIETIN and THYMIC HUMORAL FACTOR are other two thymus-related peptides with T cell stimulating properties.

3)CYTOKINES:
* INTERFERONS:,, : -they interact with cell receptors and increase antigen presentation ; -they increase macrophage, NK and cytotoxic T ly activation; -they inhibit cell proliferation .Interferon -1b has greater immune- enhancing actions .

They are useful in: * Interferon alfa-2a : hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma; * interferon beta-1b : relapsing multiple sclerosis ; * interferon gamma-1b :patients with chronic granulomatous disease.They also are used in hepatitis.

*INTERLEUKINS: -they stimulate T and B cells proliferation and differentiation. *TUMOR NECROSIS FACTOR it is oncostatic,proinflammatory, chemotactic () and macrophage activator().It may be useful in malignant melanoma.

*COLONY-STIMULATING FACTORS: FILGASTRIM and SARGRAMOSTIN are recombinant forms of the human colony stimulating factors GCSF and GM-CSF : they stimulate granulocyte,eosinophil production, macrophage activation. They are indicated for acceleration of marrow recovery in patients undergoing cytotoxic therapy.

4) BCG (Bacille Calmette-Gurin): it has been used for immunization against tuberculosis and as immunostimulant in cancer( bladder cancer-it activates macrophages, lymphoid cells inclusively NK lymphocytes).

5) IMMUNOGLOBULINS(IG) Ig administered in humans confer passive immunization. They are human or animal Ig (from hyperimmune donors) in varying degrees of purity.They may contain relatively high titers of antibodies directed against a specific antigen or may simply contain antibodies from all classes formed in most of the population. They are admistered i.m. or i.v.

Clinical uses: -individuals unable to form antibodies(congenital agammaglobulinemia, hipogammaglobulinemia etc); -prevention of infectious diseases (hepatitis, rubella etc.) -treatment of certain diseases normally prevented by immuniZation(tetanus). -various conditions for which active immunization is not possible (eg. Snake bite). Side effects:-pain at the site of injection;-HS reactions;-transient hypotension and pruritus.

6) NONSPECIFIC VACCINES ACTIVE IMMUNIZATION Active immunization: administration of antigen to the host to induce formation of antibodies and cell- mediated immunity.An disadvantage of active immunization is that it requires time to develop and is generally inactive at the time of specific exposure. Clinical uses: it is used to induce protection against many infectious agents.For example: protection against hepatitis B virus by administration of inactive viral antigen (i.m.).

b)Synthetic immunostimulating agents

LEVAMISOLE( antiparasitic drug). It also stimulates the maturation and proliferation of T cells.It enhances T cellmediated immune responses and restores delayed hypersensitivity. It may be useful in the immunodeficiency of Hodgkins disease and adjunctively in cancer chemotherapy.