IMMUNOPHARMACOLOGY

1.         Drugs used in Clinical Immunology

2.            Cyclosporine A (CsA)

a.            Mechanism of action:

i.          CsA binds to ubiquitous cytosolic cyclophilin.

ii.            CsA/cyclophilin complex binds and inhibits calcineurin.

iii.         this prevents the translocation of transcription factors of IL-2, IL-3 and IFN-g.

iv.            cytokine gene transcription and synthesis are inhibited.

v.         inhibits primarily T cell proliferation.

b.         It is a fat-soluble cyclic endocapeptide natural product from Tolypocladium Inflatum.

c.            Pharmacokinetics:

i.            cyclosporine is given orally on a daily basis in a dosage of 7.5-25mg/kg.

ii.          it is slowly and incompletely absorbed (20-50%) after oral administration.

iii.         it has an elimination half-life of 24 hours and is excreted in the bile.

d.         Clinical efficacy:

i.          it is effective in human organ transplantation, in the treatment of graft-versus-host syndrome after bone marrow transplantation, and in the treatment of selected autoimmune disorders.

ii.          it is also useful in treatment of uveitis, rheumatoid arthritis, and the early treatment of type I diabetes.

e.         Side-effects:

i.            nephrotoxicity

ii.            hyperglycemia and hyperlipidemia

iii.            transient liver dysfunction.

iv.         GI problem / hypertension / gingival hypertrophy.

v.            osteoporosis / hirsutism.

3.            Tacrolimus (FK 506)

a.         FK 506 is an immunosuppressant macrolide antibiotic produced by Streptomyces tsukubaensis.

b.         It is not chemically related to cyclosporine but their mechanism of actions are very similar.

c.            Pharmacokinetics:

i.          it can be administered orally or intravenously.

ii.          after oral intake, peak concentrations are reached after 1-4 hours.

iii.         the half-life of the intravenous form is 9-12 hours.

iv.         the drug is metabolized primarily by P450 enzymes in the liver.

d.         On a weight basis, FK 506 is 10-100 times more potent than cyclosporine in inhibiting immune responses.

e.         Its toxic effects are similar to those of cyclosporine.

4.            Sirolimus (Rapamycin)

a.         It binds to a FKBP complex which in turn binds and inhibits sirolimus effector protein.

b.         The complex inhibits:

i.            activation of 70 kDa S6 kinase

ii.          gene transcription of c-myb.

iii.         kinase activity of cd2/cyclin E

c.         The end result is a growth arrest from G1 to S phase.

d.         It also inhibits cytokine-mediated proliferation of T and B cells.

5.            Azathioprine

a.         It is an imidazolyl derivative of 6-mercaptopurine.

b.         It is well absorbed from the gastrointestinal tract.

c.         Its mechanism of action stems from interference with nucleic acid metabolism thereby limiting the proliferating of T lymphocytes.

d.            Precaution of use:

i.          as drug is excreted by kidney, an increase in toxicity may occur in anephric or anuric patients.

ii.          patients who are on allopurinol should reduce dosage of azathioprine to prevent excessive toxicity.

e.         Clinical use:

i.            maintaining renal allografts and in transplantation of other organs.

ii.            management of acute glomerulonephritis and in renal component of systemic lupus erythematosus.

f.          Side effects:

i.          bone marrow depression, usually manifest as leukopenia, anemia.

ii.          skin rashes, drug fever, nausea, vomiting and diarrhea.

iii.         hepatic dysfunction and mild jaundice.

6.         15-Deoxyspergualin

a.         It was isolated from Bacillus laterosporus.

b.         It has potent antimonocytic effects, including decreasing MHC antigen expression and inhibition of free radical generation.

c.         It also has antilymphocytic effects, inhibiting antibody production after immunization as well as cytotoxic cell generation during mixed lymphocyte reactions.

d.         It has been successful in the treatment of acute rejection in renal transplantation.

e.         Its main side effect is bone marrow depression.

7.            Antilymphocyte and Antithymocyte antibodies

a.            Antilymphocyte globulin (ALG) antithymocyte globulin (ATG) are used clinically in transplantation programs.

b.         The antiserum is usually obtained by immunization of large animals with human lymphoid cells or by the hybridoma technique for monoclonal antibody generation.

c.            Antilymphocytic antibody acts primarily on the small, long-lived peripheral lymphocytes that circulate between the blood and lymph.

d.         ALG binds to surface of T cells and induce immunosuppression by:

i.            antibodies raised against T-cell surface proteins.

ii.            opsonization and complement-dependent cytotoxicity.

iii.            antibody-dependent cell-mediated cytotoxicity.

iv.            depletion / inactivation of T lymphocytes.

e.            Management of Transplants:

i.          ALG and monoclonal antibodies can be used in the induction of immunosuppression, in the treatment of initial rejections, or in the treatment of steroid-resistant rejections.

ii.          after transplantation of an organ, ALG is often administered first on a daily basis and subsequently less so together with azathioprine and prednisolone.

iii.         it reduces the dosage requirements for the other immunosuppressive drugs and improves survival in patients who receive kidneys from unrelated or cadaver donors.

iv.         the recipient is treated with ALG in large doses for 7-10 days prior to transplantation of bone marrow cells from the donor.

v.         residual ALG destroys T cells in the donor marrow graft and the probability of severe graft-versus-host syndrome is reduced.

f.          Side effects:

i.          local pain and erythema often occur at the injection site.

ii.            anaphylactic reaction / serum sickness.

iii.            complexes of host antibodies with horse ALG may precipitate and localize in the glomerulus of the transplant kidney.

iv.         risk of CMV and EBV infections.

g:          OKT3:

i.          murine monoclonal antibody directed against CD3 molecule on the surface of human thymocytes and mature T cells can also be useful in the treatment of renal transplant rejection.

ii.          OKT3 blocks both killing by cytotoxic T cells and the generation of other T cell functions.

iii.         side effects are anaphylaxis and serum sickness with increased risk of infection and malignancy.

8.         Rh(D) Immune Globulin

a.         It is used in preventing Rh hemolytic disease of the newborn.

b.         The technique is based on the observation that a primary antibody response to a foreign antigen can be blocked if specific antibody to that antigen is administered passively at the time of exposure to antigen.

c.            Sensitization of Rh-negative mothers to the D antigen occurs usually at the time of birth of an Rh(D)-positive infant, when fetal red cells may lead into the mother’s bloodstream.

d.         If an injection of Rh(D) antibody is administered to the mother within 72 hours after the birth of an Rh-positive baby, the mother’s own antibody response to the foreign Rh(D)-positive cells is suppressed.

9.         Use of Immunosuppressant Agents

10.            Immunomodulating Agents

a.         These agents are used to increase the immunoresponsiveness of patients who have either selective or generalized immunodeficiency.

b.         The major potential uses are in immunodeficiency disorders such as AIDS, chronic infectious disease and cancer.

c.         At present, all but two of the immunostimulating or immunomodulating agents (BCG and levamisole) are classified as investigational drugs.

d.            Thymosin and thymic peptides:

i.          it is a group of protein hormones synthesized by the epithelium of thymus.

ii.          it appears to convey T cell specificity to uncommitted lymphoid stem cells.

iii.         in vitro treatment of lymphocytes with thymosin increases the number of cells that manifest T cell surface markers and function.

e.            Cytokines:

i.          IFN-a is used in various neoplasms, including hairy cell leukemia and Kaposi’s sarcoma and has anticancer activity against malignant melanoma, renal cell carcinoma and T cell leukemia.

ii.          IFN-b reduce the severity of multiple sclerosis over a period of 2 years.

iii.         IFN-g is used in the treatment of chronic granulomatous disease.

iii.         IL-2 is used in the treatment of metastatic renal cell carcinoma.

iv.            cytokine inhibitors are used for the treatment of inflammatory diseases and septic shock.

f.            Levamisole:

i.          it increases the magnitude of T cell-mediated immunity.

ii.          it potentiates the action of fluorouracil in adjuvant therapy of colorectal cancer.

g.         BCG:

i.          it is employed as a nonspecific adjuvant or immunostimulant in cancer therapy but is successful only in bladder cancer.

ii.          acts in part via activation of macrophages to make them more effective killer cells.