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Presentation immunology.pptx
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- 2. Immunopotentiation • The abilityto potentiate the host immune response to control chronic infections. • 3 ways to potentiate. • Vaccination, adjuvants, lymphokines. 1: vaccination (already know)
- 3. 2: Adjuvants • Anadjuvant, by definition, is a substance when incorporated into or injected simultaneously with antigen potentiates the immune response.
- 4. Mode of actionof adjuvant • On antigen characteristics: Some adjuvants affect the way in which antigen is presented. The immune response is increased when protein antigens are precipitated by alum. • Other adjuvants prevent rapid dispersal of antigen from the local tissues. • The reservoir of antigen is available either at an extra cellular location or within macrophages.
- 5. Freund’s incomplete adjuvant •where antigen, in the aqueous phase, is emulsified with paraffin oil. Since paraffin oil can produce severe local reactions. • the use of liposomes , which are membrane bound lipid vesicles, as agents for presentation of antigen to the immune system. • Liposomes are storage vacuoles for the antigen, they also enter the macrophage and are presented in a more immunogenic manner to T cells.
- 6. • On hostimmune response: Most adjuvants, however, do not affect the antigenic characteristics but act on the host immune response. • Virtually all adjuvants stimulate macrophages, a good example is Freund’s complete adjuvant which is made from incomplete Freund’s adjuvant with the addition of killed mycobacterium or more recently, water soluble muramyldipeptide. • Such adjuvants act directly on the macrophage or via the T cell. • Besides improving antigen presentation, they enhance the accessory signals required for lymphocyte activation and proliferation.
- 7. Types of Adjuvants •Organic adjuvants: Organic adjuvants include a variety of organic molecules obtained from bacteria. Muramyldipeptide (MDP) is a bacterial peptidoglycan. MDP increases both humoral and cellular immunity.
- 8. • Synthetic adjuvants:Synthetic adjuvants that increase host immunity include levamisole and Isoprinosine. • Levamisole was initially introduced as an antihelminthic agent. It potentiates humoral and cellular immunity in a fashion that is T cell dependant. It has been used in the treatment of cancer and rheumatoid arthritis. • side effect is agranulocytosis. • Isoprinosine is a complex containing inosine, a purine precursor. It promotes T cell mitogenesis.
- 9. • Tuftsin :Tuftsin is a unique adjuvant that occurs naturally and has been synthesized as well. • It is a four amino acid peptide( threonine, lysine, proline, arginine ), homologous to a sequence in the constant region of the immunoglobulin heavy chain. • Tuftsin primarily stimulates macrophages. Since it occurs naturally it probably has a physiologic role in host defense.
- 10. 3: Lymphokines • Itincludes interferons & interleukins like IL-1, IL-2 and IFN γ, IFN β, and IFN α. • IFN α was the first to be produced in a large scale manner. IFN α has proven adjuvant properties, as assessed by reduction in tumor size, especially in lymphomas. IFN α appears to act both directly on tumor tissue and by activation of macrophages. • IFNs α, β and γ are all used therapeutically.
- 11. • Recombinant IL-2was approved in 1992 for the treatment of metastatic and inoperable renal cell carcinoma. • It has been used experimentally for malignant melanoma and HIV infection. • It appears to restore both humoral and cellular immunity in nude mice. IL-2 also appears to induce production of IFN α by T cells. • Side effects: fever, malaise, myalgia, arthralgia and fluid retention.
- 12. Immunosuppression • Immunosuppression hasbeen particularly useful is patients undergoing organ transplants and in the treatment of graft rejection, autoimmunity and allergy. Current treatment of graft rejection, autoimmunity or allergy is not antigen specific. • It is divided into 2 categories: general immunosuppression therapy & specific.
- 13. General immunosuppression therapy 1.Cytotoxicagents • Cytotoxic agents such as cyclophosphamide, chlorambucil, azathioprine and methotrexate block cell replication and preferentially kill dividing cells. • Cyclophosphamide and chlorambucil alkylate DNA in both dividing and resting cells, leading to cell death during the mitotic phase of cell division. • Azathioprine and methotrexate block DNA synthesis, killing cells that are in the S (DNA- synthesis) phase of the cell cycle.
- 14. • Cytotoxic agents,however, also suppress both humoral and cellular immunity. • Because B cells or T cells that are stimulated by antigen, go through active proliferation by cytotoxic agents. This may not be the only way that these drugs cause immunosuppression, as they are an important part of the immunosuppressive therapy given during organ transplantation.
- 15. 2.Glucocorticoids • Glucocorticoids arepotent immunosuppressive and anti inflammatory agents. • They are used regularly in the treatment of graft rejection, allergies and asthma. • The immunosuppressive effects of glucocorticoids is to reduce the levels of circulating lymphocytes and monocytes and suppress the production of IL-1 and IL-2. • Glucocorticoids have a diversity of actions and the clinical benefit seen in allergy and autoimmunity.
- 16. 3.Fungal metabolites • 1.Cyclosporineacts selectively on antigen- sensitive T cells in the G0 to G1 and blocks the transcription of lymphokine mRNA, & suppressing IL-2 production. • This effectively blocks T cell activation and proliferation. • Cyclosporine has been used successfully to prevent graft rejection and in the treatment of graft versus host disease. • Side effects: toxicity for dividing cells in the gut and bone marrow, nephrotoxic & hepatotoxic.
- 17. • 2. Tacrolimusis a macrolide that is an immunosuppressant produced by the fungus in a mechanism similar to that of cyclosporine to prevent allograft rejection. • 3. Rapamycin is structurally similar to tacrolimus and it blocks the proliferation and differentiation of activated TH cells in the G1 phase of the cell cycle.
- 18. • tacrolimus andrapamycin are 10–100 times more potent as immune suppressants than cyclosporin , and can be administered at lower doses and with fewer side effects than cyclosporin. • cyclosporin has been shown to prolong graft survival in kidney, liver, heart and heart-lung transplants. • In one study of 209 kidney transplants from cadaver donors, the 1-year survival rate was 64% among recipients receiving other immunosuppressive treatments and 80% among those receiving cyclosporin.
- 19. 4.Total Lymphoid IrradiationEliminates Lymphocytes • Because lymphocytes are extremely sensitive to x-rays , x-irradiation can be used to eliminate them in the transplant recipient just before grafting. • In total lymphoid x-irradiation, the recipient receives multiple x-ray exposures to the thymus , spleen, and lymph nodes before the transplant surgery.
- 20. • Because thebone marrow is not x-irradiated, lymphoid stem cells proliferate and renew the population of re-circulating lymphocytes. • These newly formed lymphocytes appear to be more tolerant to the antigens of the graft. Specific immunosuppression therapy
- 21. 1. Monoclonal AntibodiesCan Suppress Graft-Rejection Responses • Monoclonal antibodies to the T cell surface antigen, CD3 and the IL-2 receptor have been used for treating host rejection of allografts. Both agents have been associated with several problems. • Monoclonal antibodies directed against various surface molecules on cells of the immune system have been used successfully to suppress T-cell activity in general or to suppress the activity of subpopulations of T cells.
- 22. • A strategyto deplete immune cells involves use of a monoclonal antibody to the CD3 molecule of the TCR complex. • Injection of such monoclonal antibodies results in a rapid depletion of mature T cells from the circulation. • Another depletion strategy used to increase graft survival uses monoclonal antibodies specific for the high-affinity IL-2 receptor.
- 23. • Monoclonal-antibody therapy,which was initially employed to deplete T cells in graft recipients, also has been used to treat donors’ bone marrow before it is transplanted. • Other targets for monoclonal-antibody therapy are the cell-surface adhesion molecules. Simultaneous treatment with monoclonal antibodies to the adhesion molecules ICAM-1 and LFA-1 for 6 days after transplantation has permitted indefinite survival of cardiac grafts between allogenic mice.
- 24. 2.Blocking Co-Stimulatory Signals CanInduce Anergy • TH-cell activation requires a co-stimulatory signal in addition to the signal mediated by the T-cell receptor. • The interaction between the B7 molecule on the membrane of antigen-presenting cells and the CD28 or CTLA-4 molecule on T cells provides one such signal. • Lacking a co-stimulatory signal, antigen activated T cells become anergic.
- 25. • CD28 isexpressed on both resting and activated T cells and binds B7 with a moderate affinity; CTLA-4 is expressed at much lower levels and only on activated T cells but binds B7 with a 20-fold higher affinity. • A second pair of co-stimulatory molecules required for T-cell activation are CD40, which is present on the APC, and CD40 ligand (CD40L or CD154), which is present on the T cell.