What is IMMUNITY? The word immunity is derived from the Latin word immunes which means “exempt from”. Immunity is usually defined as a state of relative resistance to an infection. Substances capable of stimulating immune mechanism are called as antigens.
There are 2 types of immunity: Active immunity. Passive immunity.
Theimportant components of immune system include: Granulocytes Complement synthesis and antibody formation Cellular immunity Mucocutaneous barriers
NEUTROPHILS are synthesized from GRANULOCYTES, as the total granulocyte count falls below 1000 cells /mm3, the rate of bacterial infection increases. The common org. affecting this are E.coli, Pseudomonas aeruginosa, Klebsiella, Pneumonia and stapylococcus aureus. The chances of fungal viral and protozal infection is also very high.
When the defect in this system is there the increase in infection rate is seen. Such effects usually occur through the chronic treatment with chemotherapeutic agents.
Itprovides protection against fungal bacterial, viral and protozal infections. Certain drugs, neoplastic diseases and organ transplantation procedures paralyzes cellular immunity.
They prohibit pathogenic organisms to take entry into the internal vital organs. However these barriers are damaged by a no. of medical devices, procedures, or chemotherapy. This leads to easy access of pathogens to the internal organs resulting into infectious state.
(A) ANTI-HISTAMINIC AGENTS: Histamine- binding lymphocytes have immunosuppressive activities. By inhibiting their activation , antihistaminic agents improve cell mediated immune response.
IT is the non-narcotic analgesic agent that relives pain sensation b inhibiting prostaglandin biosynthesis. This leads to significant improvement in the functioning of t-lymphocytes. Useful in coccidiomycosis and mycobacterial infections.
Chemically it is the complex of inosine and an organic salt. It enhances t-cell proliferation, phagocyotsis and chemo taxis through unknown mechanism. Initially it was found as an anti-viral agent.
IT improves chemotactic responses and immune mechanisms in patients with diseases associated with immunodeficiency. It probably acts by inducing the release of c-GMP.
Onlytwo lymphokines known as IL-1, IL-2 were found to stimulate the patient immunity.
These are the polypeptides isolated from the epithelial cells of thymus gland. They induce formation of mature T- cells by unknown mechanism. This are given usually in saline i.m. in doses between 0.5mg/kg and 1.0 mg/kg /day for 2-3 weeks and then reduced to 1-3 doses per week.
Thisis low molecular weight peptide (m.w. less than 6000 Daltons) isolated from blood leucocytes of the patient with delayed hypersensitivity. it has stimulant effect of cell mediated immunity. it may be used in treatment of immunodeficiency syndrome like chronic mucotaneius candidacies, in treatment of recurrent herpes simplex conditions
Depending upon the suppressant and stimulate effects exerted by these drugs on immune system they are categorized as: (1) IMMUNOSUPPRESSANTS (2) IMMUNO ENHANCERS.
Phases of immune Suppressants EnhancersresponseAntigen recognisation Corticosteriods. BCG vaccine.and processing Cyclophosphamide C. Parvum cytimun TetramisoleAmplification. L- Asparaginase Concanavalin A. Corticosteroids. Tetramisole. Cyclophosphamide. Cytimum. 5-fluorouracilAntibody formation Corticosteroids. Lipopolysaccaride. Cyclophosphamide Tetramisole. Cyclosporin A cytimun
Phases of immune Suppressants. enhancers.responseImmune affector Corticosteroids C. parvum.response Cylcophosphamide tetramisole Cyclosporin A Cytarabine Cytimun Methotrexate.
During organ transplantation, certain complex antigens or allograts activate the cytotoxic lymphocytes. Their activation results to the development of cellular immunity rejects organ transplants. Immunosuppressive agent beneficial effects in such condition suppressing the cellular immunity.
Most of these agents are primarily used as anti- neoplastic agents. On the basis of the mechanism of action, immunosuppressant can be classified as:
Alkylatingcorticosteroids antimetabolites agents Antibodies and antibiotics enzymes miscellaneous agents
They all possess anti allergic and anti- inflammatory and immunosuppressive activities. T- lymphocytes are most susceptible to the action of corticosteroids resulting into lymphopenia. They also effect humoral immune responses by inhibiting antibody synthesis.
Adverse effect: High doses cause Osteoporosis, hyperglycemia, ulcer formation and increased susceptibility for fungal infections . DOSE: 2-10 mg/kg per day for few weeks. Adverse effect can be reduced by usig combination of other cytotoxic agents and lowering the dose.
This kill components of immune response of body. They give immunosuppressive action to the rapidly proliferation cells in the marrow and exert cytotoxic effects to the lymphocytes by alkylating their nucleic acid. EXAMPLES: CYLCOPHOSPHAMIDE,CYTIMUN.
CYCLOPHOSPHAMIDE: It is a nitrogen mustard and have broad spectrum of antineoplastic and immune suppressive activities. More effective suppressor of humoral immune mechanisms. It exerts cyotoxic action on both T-cells and B-cells. DOSE: 2 mg/kg per day.
Usuallyused in combination with corticosteroids in treatment of several autoimmune diseases, including Wegener’s granulomatosis. Childhood nephrosis, idiopathic thrombocytopenia purpura and severe rheumatoid arthrititis.
CYTIMUM: It is analog of cylophosphamide having better therapeutic index. It is specifically effective against B-cells.
These drugs act by exerting cyotoxic effects on rapidly proliferating cells like those of bone marrow, myeloid tissues, gonadal tissues and g.i. tract. METHOTREXATE, 6- MERCAPTOPURINE, AND AZATHIOPRINE are extensively studied drugs which are more toxic to S-phase when DNA synthesis is occurring.
AZATHIOPRINE: It is imidazole derivative of 6- mercaptopurine having anti-rheumatic activity along with cytotoxic effect. It is orally effective and having plasma half life of about 16 hours. It is the most effective suppressant of phase-II of immune responses.
Xanthine oxidase enzyme converts much of the drug in liver and RBC to 6-thiouric acid, thioionisic acid and various other metabolized. Thioinosic acid competitively inhibit synthesis of inosinic acid. This result in inhibition of DNA synthesis. thus upon the metabolized activation, this suppresses both mediated and humoral immune responses and depresses antibody proliferative responses.
AZATHIOPRINE is used orally in the treatment of acute glomerunephritis, systemic lupus erythematosus, temporalcranial arteritis. It is also used in management of organ transplantation and delay hypersentizing reactions. DOSE: 2-5 mg/kg per day.
METHOTREXATE: It is an orally active folic acid analog having anti neoplastic and antipsoratic and mild immune suppressant activity. It has a plasma half-life 7.2-9.0 hours. It acts by inhibiting folate metabolism and affects phase-II of immune responses. It is used to treat severe psorasis, dermatomcosotis and rheumatoid arthritis and also used in organ transplantation procedure. Other drug include chlorambucil, mercaptopurine, thioguanine, azarbine, cytarabine.
CYCLOSPORIN A is he example for this having immunosuppressive. It is the cyclic activity and is isolated from the soil fungus, Tolypolacadofium inflatum. It spefically inhibit generation of effectors T-lymphocytes without expressing effect of suppressor lymphocytes and B-cells activity. It impairs proflirative response of T-cells of antigens.
Once T-cells are stimulated by antigens they synthesized interculin -2 that’s start growth promoting effects on T- lymphocytes. Cyclosporine has low activity profile. A.E.: gumhypertropy, tremor. Neurasthesia, depressive psychosis and benign breast tumours. It has plasma half life of 10-27 hours.
USED in organ transplantation in patients having liver, kidney, pancreas disorder and heart transplantation. It also expands its effects in the treatment of immune diseases of rheumatic arthritis. DOSE: adult oral dose is 10-20 mg/kg per day. i.v. 50 mg diluted intranasal saline may be given by slow infusion.
L-ASPARAGINASE is the drug of choice in treatment of acute lymphoblastic leukaemia. It has half life of about 11-23 hours. this enzyme is usually given i.v. or i.m. When combined with methotrexate it lowers down the adverse effect and intensifies its activity.
EXAMPLE: ANTITHYMOCYTE GLOBULIN (ATG) ATG is used alone or in combination with azathioprine and corticosteroids in the prevention of the renal allograft rejection in the dose of 1-5 mg/kg per day. However in some patients , allergic reactions has been reported to occur to leading to serum sickness and nephritis.
(A) ADENOSINE DEAMINASE INHIBOTORS; Examples are erythro-9-(2-hydroxy-3- nonyl) adenine hydrochloride and 2- deoxy- coformycin.(pentastatin). Former one have effect on T-lympohcytes while pentastatin is used as antimetabolite.
(B) BREDININ: It is an imidazole nucleoside having antimetabolite antineoplastic activity and is used as an immunosuppressant in human kidney transplantation. (C) CYCLOIMMUNE: It is analog of cyclosporine, undergoing clinical trials and showing activity for organ transplantation.
(D) NIRIDAZOLE: It is an orally active nitrothiazole derivative having anthelmintic activity, anti bacterial and immunosuppressive activities. It is used to suppress cell- mediated immunity response.
This category of the drugs is used to overcome immunodeficiency or immunosupreesion arising as a result of either inherited or acquired disorders of immune system. Examples of inherited disorders: Agammaglobulinemia and Severe combined immune deficiency syndrome (SCIDS). Causes: chemotherapy. Radiation or viral infection may cause immunosupreesion.
Examples of this category include : (a) BCG Vaccine: It is used as immunological enhancer to stimulate intact immune system (i.e. a non- specific immunoenhancer.) of the body. BCG and its methanol extracted residue (MER) contain muramyl dipeptide as an active immunostimulant ingredient.
T-lymphocytes are principle target cells for the action of BCG vaccine. It causes stimulation of macrophage function, phagocytic activity, lysosomal enzyme activity and chemotaxis mechanisms . It induces the production of lymphocyte-activity factor resulting of phase I of immune response. Because of its activity against tumour antigen it is beneficial in treatment of lung and breast cancer, acute lympholytic and myelogeneous leukaemia. It is available as unlyophilized, live or killed lyophilized form. Administration as oral, i.v., i.p., i.d. , intralesional.
Levamisole is orally active S(-) isomer of tetramisole. It is used as immunostimulant in the therapy of certain infections, r.a., and immunosuppressive conditions It mainly acts by raising c-GMP levels through interaction with thymopoietien receptor sites. this leads to decrease in metabolic inactivation of c- GMP accompanied with increased breakdown of c- AMP. The increase in c-GMP level induces lymphocyte proliferation and augmentation of chemotactic responses. This reflects into increased antibody production, lymphokine production, increased phagocytosis.
Tetramisole is used in treatment of: (1)certain chronic and recurrent bacterial infections (2) certain diseases with immunodeficiency like chronic granulomatous syndrome, job’s syndrme etc. (3) autoimmune diseases like r.a., crohn’s disease, SLE.