introduction to immune system: immunity: the resistance offered by the host to the harmfull effects...
TRANSCRIPT
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.
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.
Cyclosporin:Mechanism of action:
•Cyclosporine suppresses call mediated
immunity. After diffusing t-cell it binds to
cyclophilin (immunophilin) to form a
complex.
•This complex cause dephosphorylation of
NFATc (Nuclear Factor of Activated T-cells).
•Thus NFATc cannot enter the nucleus for the
synthesis of cytokines-the primary stimulus
for increasing the no. of T-lymophocytes.
Adverse effects:
•Nephrotoxicity;
•Hepatotoxicity;
•viral infection;
•Hypertention;
•hyperkalemia.
Therapeutic uses:
•kidney, liver, heart, and other organ
transplantation;
•rheumatoid arthritis;
•Psoriasis.
Tacrolimus: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:
•Nephrotoxicity;
•Hyperglycemia;
•GIT disturbances;
•Hyperkalemia.
Therapeutic uses:
•Organ transplantation;
•Topically in psoriasis and dermatitis.
Sirolimus:
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:
•Hyperlipidemia;
•Nausea;
•Headache;
•Diarrhea;
•Leukopenia.
Therapeutic uses:
prophylaxis of organ transplant rejection in
combination with a calcineurin inhibitor
and glucocorticoids.
Azathioprine:Mechanism of action:
•Azathioprine is cleaved to 6-mercaptopurine, which
in turn is converted to additional metabolites 6-Thio-
IMP 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:
•Leukopenia;
•Thrombocytopenia;
•GI toxicity;
•Risk of infection.
Therapeutic uses:
•Acute glomeruloneritis;
•Systemic lupus erythematosus;
•Rheumatoid arthritis.
Mycophenolate mofetil (MMF):
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:
•Nausea;
•Vomittig;
•Diarrhea;
•Abdominal pain;
•Neutropenia.
Therapeutic uses:
•Rheumatoid arthritis;
•In combination with prednisolone as
alternative to cyclosporin and tacrolimus.
Muromonab: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:
•Fever;
•Seizures;
•Infection;
•Cytokine release syndrome.
Therapeutic uses:
•Acute renal transplant rejection;
•Steroid resistant rejection;
•to deplete donors T-cells prior to trasplantation.
Alemtuzumab: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;
•Neutropenia;
•Anaemia.
Therapeutic uses:
•Leukemia;
•In combination with calcineurin
inhibitors and sirolimus.
Antithymocyte globulins: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:
•glomerulonephritis
•leukopenia
•thrombocytopenia
•hypotension
Therapeutic uses:
•Steroid resistant rejection;
•In combination with calcineurin
inhibitors.
Prednisolone: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:
•Hyperlipidemia;
•Hyperglycemia;
•Hypertention;
•Osteoporosis.
Therapeutic uses:
•Haemopoietic stem cell transplantation;
•Rheumatoid arthritis;
•Systemic lupus erythmatosus;
•Asthma.
References: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.