IMMUNOSUPPRESSANTS.

Introduction to immune system: •Immunity: The resistance offered by the host to the harmfull effects of pathogenic microbial infection or any foreign material is called as immunity. •Immune response: the specific reactivity induced in a host by an antigenic stimulus is known as the immune response. •Antigen: molecule from a pathogen or foreign organism that provoke a specific immune response. •Antibodies: (immunoglobulines) produced in response to antigenic stimulus.

TYPES OF IMMUNITY: •INNATE/NATURAL/NATIVE: Everyone is born with innate (natural) immunity, a type of general protection.Many of the germs that affect others don't harm us. Innate immunity also includes the external barriers of the body, like the skin and mucous membranes which in preventing diseases from entering the body. •ACQUIRED: Immunity that an organism develops during its lifetime. 1. Active: Involves the lymphocytes production and develops as people are exposed to diseases(Natural) or immunized against diseases through vaccination(Artificial). 2. Passive: Immunity that is transferred in a ready-made prepared form of antibodies to the recipients.

CELLULAR AND HUMORAL IMMUNITY:

WHAT ARE IMMUNOSUPPRESSANTS?: •Agents used to dampen the immune response in Organ transplantation and Autoimmune disease. •These drugs have met with a high degree of clinical success ,however, such therapies require lifelong use and nonspecifically suppress the entire immune system, exposing patients to considerably higher risks of infection and cancer. •Immunosupressive drugs have one meaning: drugs that lowers body’s normal immune response.

Allograft rejaction: Allograft rejection is the recipient's immune response to nonself antigens expressed by donor tissues. After transplantation of organ allografts, there are two pathways of antigen presentation. In the direct pathway, recipient T cells react to intact allogeneic MHC molecules expressed on the surface of donor cells. This pathway would activate host CD4 or CD8 T cells. In contrast, donor MHC molecules (and all other proteins) shed from the graft can be taken up by host APCs and presented to recipient T cells in the context of self-MHC molecules - the indirect pathway.

IMMUNOSUPPRESSIVE DRUGS: Calcineurin inhibitors: •cyclosporine, •tacrolimus, •Sirolimus (Antiproliferative). Antiproliferative (Antimetabolite): •azathioprine, •mycophenolate(mofetil), •methotrexate. Antibodies: •muromonab, •alemtuzumab, •antithymocyte globin. Glucocorticoids: •prednisolone.

Mechanism of action: •Cyclosporine suppresses call mediated immunity. After diffusing t-cell it binds to cyclophilin (immunophilin) to form a

Adverse effects:

complex.

•Nephrotoxicity;

•This complex cause dephosphorylation of

•Hepatotoxicity;

NFATc (Nuclear Factor of Activated T-cells).

•viral infection;

•Thus NFATc cannot enter the nucleus for the

•Hypertention;

synthesis of cytokines-the primary stimulus

•hyperkalemia.

for increasing the no. of T-lymophocytes.

Therapeutic uses: •kidney, liver, heart, and other organ transplantation; •rheumatoid arthritis; •Psoriasis.

Mechanism of action: •It has same action as cyclosporin.

•The differnce is that it binds to different immunophilin,FKBP-12(FK-binding protein)

Adverse effects:

Therapeutic uses:

•Nephrotoxicity;

•Organ transplantation;

•Hyperglycemia;

•Topically in psoriasis and dermatitis.

•GIT disturbances; •Hyperkalemia.

Mechanism of action: •It binds to FKBP forming complex with m-TOR

(molecular target of rapamycin). •Blocks the progression of activated T-cells from G1 Phase to S-phase of cell cycle. •Thus inhibits the proliferation of activated T-calls. Adverse effects:

Therapeutic uses:

•Hyperlipidemia;

prophylaxis of organ transplant rejection in

•Nausea;

combination with a calcineurin inhibitor

•Headache;

and glucocorticoids.

•Diarrhea; •Leukopenia.

Mechanism of action of cyclosporin, tacrolimus and sirolimus.

Mechanism of action: •Azathioprine is cleaved to 6-mercaptopurine, which in turn is converted to additional metabolites 6-ThioIMP which is converted to 6-thio-GMP and finally to 6-thio-GTP, which is incorporated into DNA. •Inhibition of purine synthesis impairs a variety of lymphocyte functions. Adverse effects:

Therapeutic uses:

•Leukopenia;

•Acute glomeruloneritis;

•Thrombocytopenia;

•Systemic lupus erythematosus;

•GI toxicity;

•Rheumatoid arthritis.

•Risk of infection.

Mechanism of action: •It is the potent inhibitor of inosine

monophosphate dehdrogenase(IMP),crucial for purine synthesis. •Prevents the proliferation of T &B lymphocytes. Adverse effects:

Therapeutic uses:

•Nausea;

•Rheumatoid arthritis;

•Vomittig;

•In combination with prednisolone as

•Diarrhea;

alternative to cyclosporin and tacrolimus.

•Abdominal pain; •Neutropenia.

Mechanism of action: •Muromonab binds to CD3 receptor involved in antigen recognition. •Thus preventing subsequent antigen recognition. •Administration of the antibody is followed rapid depletion of T cells.

Adverse effects:

Therapeutic uses:

•Fever;

•Acute renal transplant rejection;

•Seizures;

•Steroid resistant rejection;

•Infection;

•to deplete donors T-cells prior to trasplantation.

•Cytokine release syndrome.

Mechanism of action: •The mechanism is same as muromonab the only difference is that it exerts it action through CD52 receptors. Adverse effects:

•Cytokine release syndrome;

Therapeutic uses:

•Neutropenia;

•Leukemia;

•Anaemia.

•In combination with calcineurin inhibitors and sirolimus.

Mechanism of action: •It contains cytotoxic antibodies that bind to CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44 and CD45 on the surface of human T lymphocytes . •The antibodies deplete circulating lymphocytes and block lymphocyte function

Adverse effects:

Therapeutic uses:

•glomerulonephritis

•Steroid resistant rejection;

•leukopenia

•In combination with calcineurin

•thrombocytopenia

inhibitors.

•hypotension

Mechanism of action: •It interfers with the production of various cytokines like IL-1,IL-2,interferons and TNF by inhibiting gene transcription. •Thus reduce the proliferation of T-cells. Adverse effects:

Therapeutic uses:

•Hyperlipidemia;

•Haemopoietic stem cell transplantation;

•Hyperglycemia;

•Rheumatoid arthritis;

•Hypertention;

•Systemic lupus erythmatosus;

•Osteoporosis.

•Asthma.

1. Finkel R,Clark MA,Cubeddu LX. Lippincott’s Illustrated Reviews:Pharmacology;Wolters Kluwer publications;4th edition;2009;pg no:489-498. 2. Rang HP,Dale MM,Ritter JM, Flower RJ; Rang and Dale’s Pharmacology;Churchill Livingstone publications;6th edition; 2007;pg no: 242-245. 3. Tripathi KD; Essentials of Medicinal Pharmacology; Jaypee publications; 6th edition; 2006;pg no:837-843.