IMMUNOLOGY
Immunology
Immunological agents: Produce immunityPrevent or modify infectious disease.
Immunity
Active immunity Develop antibodies Natural and species specific Acquired by introduction of antigen
Passive immunity Transfer of antibodies from donor to recipient
Vaccines
Dead microorganisms- Primary course followed by booster. Live attenuated microorganismsMore potent Lifelong immunity (except typhoid & polio) Stimulate production of antibodies Prophylactic use
Vaccines
B.C.G. – the only live bacterial vaccine Bacterial vaccines- Toxoids Inactivated vaccines. Viral vaccines
Vaccines
ToxoidsToxins of microorganisms+ formalin Loss of toxicity and Reduced antigenicity Nucleic acid vaccines D.N.A. Vaccines- safer, stable,heat resistant genetically engineered Antisera- Diphtheria, tetanus
Immune Human Sera
Immunoglobulins- Gamma globulins high antibody titre
Monoclonal Antibodies
Single clone of B cells Monospecific and homogenous Recombinant D.N.A. technique Specifically block- T lymphocytes, B lymphocytes, T.N.F.alpha Interleukins
Monoclonal Antibodies
Therapeutic Uses: Immunosuppressant- Renal transplant Autoimmune disease Antiviral agent Diagnostic - Immunoassay
What are Immunosuppressants??
Immunosuppressive drugs or immunosuppressants are drugs which are capable of inhibiting the body's immune system. Useful in preventing the rejection of transplanted organs and tissues. Useful to treat autoimmune disorders.
Useful to treat some other non-autoimmune inflammatory diseases.
General Principles of Immunosuppression
Primary immune responses are more easily suppressed than secondary (memory) Different immunosuppressants have different effects on different immune reactions Suppression is more likely achieved if therapy begins before exposure to the immunogen
Anti-inflammatory and Immunosuppressive Drugs
Nonsteroid anti-inflammatory drugs: Aspirin, Vioxxx (no longer used), and Celebrex. Work through COX1/2 (cylooxygeneases, which are involved in the synthesis of prostaglandins) Antihistamines: Blockers of histamine receptors: Allegra, Claritin, Clarinex, Benadryl
*Steroid hormones: Glucocorticoid derivatives: prednisone, dexamethasone, and hydrocortisone *Lymphocyte specific immunosuppressants: Cyclosoprine, FK506, rapamycin, FTY720, specific antibodies and receptors (bioactive). Cytotoxic agents: cyclophosphamide
Simplified Schematic of an Immune Response
CD8+ T cells
Class I
proliferation & differentiation
CD8+ cytolytic T cells
APC
Class II
CD4+ T cells
Cytokines Costim. Mol.
proliferation & differentiation CD4+ immune cells
(delayed hypersensitivity)
IL-4,-5,-6
Protein antigens
B cells
proliferation & differentiation
Plasma cells antibody production
MHC class II/peptides APCs
T-cell Activation Blockers:
Cyclosporine, Tacrolimus (FK506), and Sirolimus (Rapamycin)
Glucocorticoid effects related to immunosuppression
Reduced immune cell content of lymph nodes, spleen and blood
lymphopenia, monocytopenia, eosinopenia, but neutrophilia
Interference with APC, T-cell and macrophage functions
Immunophilins
Cyclophilin is a peptidyl-prolyl cis-trans-isomerase which catalyzes the cis-trans isomerization of proline imidic peptide bonds.
Helps protein folding.
FKBPs are also known to participate in many cellular processes such as cell signaling, protein transport (such as Notch) and transcription.
Use of Glucocorticoid as Immunosuppressants
Most widely used effective anti-inflammatory drugs Used with other immunophilin inhibitors to prevent transplant rejection and GVHD natural glucocorticoids not used due to mineralocorticoid activity
Prednisone and prednisolone are used orally at moderate
to high doses; Very high doses of methylprednisolone used i.v. during acute organ rejection Used before and after anti-thymocyte Abs to inhibit allergic reactions
Classification of Immunosuppressants
Immunosuppressants can be classified as follows:Glucocorticoids Specific T-cell inhibitors Cytotoxic drugs
Antibodies
Other drugs
Currently Used Immunosuppressants
Category Alkyl Agent Antimetabolic Agent Steroids Biological Agents Fungus Products Chinese Medicine Drugs
Cyclophosphamide
Azathioprin (Aza) Predenisone,Prednisolone, Dexamethasone, etc ALG (anti-lymphocyte globulins), ATG (anti-thymocyte globulins), OKT3 CsA FK506 Rapamicin，Cellcept (mycophenolate mofetil )
Ideal Immunosuppressant
Strongly Immunosuppressive Specific, No Overall Immunosuppression Anti-infection ability Low Toxicity for Vital Organs Low cost Long in vivo bioactivity Easy to use
Immunosuppressants
Antimetabolites- Azathioprine Nucleotide synthesis inhibitorsMethotrexate Specific suppressants of certain immune responses- cyclosporine Highly selective monoclonal antibodies Inhibit unwanted reactions due to immune responses- glucocoticoids, thalidomide
Help on the Way
Adult bone-marrow-derived mesenchymal stem cells are immunosuppressive We postulate that mesenchymal stem cells have a potent immunosuppressive effect in vivo.
Lancet. 2004 May 1;363:1439-41.
Immunosuppressants
General suppression of immune responsesAzathioprine, methotrexate. Cytotoxic agents Interfere with the dividing lymphoid cell Not specific Affect other dividing cells Increased susceptibility to infection Uses: Organ transplants
Glucocorticoids
GLUCOCORTICOIDS BLOCK
Specific T-cell inhibitors
Calcineurin (CN) is a protein phosphatase also known as protein phosphatase2B (PP2B).
Calcineurin is responsible for activating the transcription of interleukin 2 (IL-2), that stimulates the growth and differentiation of T cell response. Calcineurin is inhibited by cyclosporin and tacrolimus (FK506) - these drugs are known as calcineurin inhibitors.
Cytotoxic drugs
They are also known as antiproliferative drugs.
They are classified as follows:1. Alkylating agents 2. Antimetabolites include: Folic acid analogues , such as methotrexate.
Purine analogues such as azathioprine, Mycophenolate Mofetil (MMF).
Alkylating agents
Cyclophosphamide
The drug is chemically related to nitrogen mustard and gets transformed into active metabolites like aldophosphamide & phosphoramide when metabolised in liver by enzyme P-450.
In small doses prevents systemic lupus erythematosus, autoimmune hemolytic anemias, Wegener's granulomatosis and other immune diseases.
Other drugs
Interferons:- IFN-β suppresses the production of Th1 cytokines and the activation of monocytes.It is used to treat multiple sclerosis. Opioids:- Prolonged use of opioids may cause immunosuppression of both innate and adaptive immunity. Myriocin(Thermozymocidin) has been reported being 10 to 100 times more potent than Cyclosporin.
Immunosuppressants
Suppress immunity Autoimmune diseasee.g. Rheumatoid arthritis Prevention of graft rejection General suppression of all immune responsesSusceptibility to infections
Newer immunosuppressants
Leflunomide and Malononitriloamides (MNA)
Leflunomide suppresses T cell and B cell proliferation.
MNA inhibits protein tyrosine kinases & Dihydroorotate dehydrogenase (DHODH), a critical enzyme for the de novo pyrimidine synthesis which are essential for activated lymphocytes for proliferation. Phase I and II trials in rheumatoid arthritis.
Specific Suppressants
Cyclosporin: Blocks early stage in activation of cytotoxic T lymphocyte Toxicity- Nephrotoxicity, Hypertension Increased susceptibility to infection Leukopenia Uses: Prophylaxis and treatment of graft rejection in organ transplant Autoimmune disease
Immunostimulants and Immunomodultors
Enhance immunological and nonspecific host defences Mech. Of action: Increase humoral antibody response Enhance phagocytic activity of macrophages Modify cell mediated immune response
Immunostimulants and Immunomodultors
Amantidine B.C.G. Vaccine- Leukemia Thalidomide-Terratogenic Anti-inflammatory Immunomodulatory Antiangeogenesis Uses- AIDS & cancer pts.
Immunostimulants and Immunomodultors
LevamisoleModulates cell mediated immune responses Enhanced phagocytic activity of macrophages Toxicity- Thrombocytopenia,agranulocytosis Interferons
Summary
Immunosuppressants are primary line of therapy for cases of graft rejection & certain autoimmune disorders. The disadvantage is that, these drugs are nonselective & do not distinguish between normal & abnormal immune responses. Hence at present they are used in combination with mAB’s to increase the selectivity & the potency of the drugs. Presently some focus is also on the usage of stem cells for immunosuppressive therapy.