Question

Choose an Immunosuppressive drug from ones that currently being used for kidney transplants.

Walk the audience through the pathway that your Immunosuppressive drug is targeting

Describe how Immunosuppressive drug inhibits this pathway, provide a mechanism if applicable.

Explain how inhibiting this pathway leads to the down regulation of the immune system.

Answer 1

Drug: Cyclosporine

Major Histocompatibilty Complex (MHC)

The antigens responsible for rejection of genetically disparate tissues are called histocompatibility antigens; they are products of histocompatibility genes. Histocompatibility antigens are encoded on more than 40 loci, but the loci responsible for the most vigorous allograft rejection reactions are on the major histocompatibility complex (MHC).

The MHC molecules are divided into 2 classes. The class I molecules are normally expressed on all nucleated cells, whereas the class II molecules are expressed only on the professional antigen-presenting cells (APCs), such as dendritic cells, activated macrophages, and B cells. The physiological function of the MHC molecules is to present antigenic peptides to T cells, since the T lymphocytes only recognize an antigen when it is presented in a complex with an MHC molecule. The class I molecules are responsible for presenting antigenic peptides from within the cell (eg, antigens from intracellular viruses, tumor antigens, self-antigens) to CD8 T cells. The class II molecules present extracellular antigens such as extracellular bacteria to CD4 T cells. The immune response to a transplanted organ consists of both cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms.

Generation of humoral and cell- mediated immune response and sites of action of immunosuppressant drugs

In humoral immune response, the antigen (Ag) is processed by macrophages or other antigen presenting cells (APC), coupled with class II major histocompatibility complex (MHC) and presented to the CD4 helper T-cells which are activated by interleukin-I (IL-I), proliferate and secrete cytokines. These in turn promote proliferation and differentiation of antigen activated B cells into antibody (Ab) secreting plasma cells. Antibodies finally finally bind and inactivate the antigen.

In cell mediated immunity, foreign antigen is processed and presented to CD4 helper T cell which elaborate IL-2 and other cytokines that in turn stimulate proliferation and maturation of precursor cytotoxic lymphocytes (CTL) that have been activated by antigen presented with class I MHC. The mature CTL (killer cells) recognize cells carrying the antigen and lyse them.

1. Glucocorticoids inhibit MHC expression and IL-1, IL-2, IL-6 production so that helper T cells are not activated.
2. Cytotoxic drugs block proliferation and differentiation of T and B cells
3. Immunosuppressive drug inhibit antigen stimulated activation and proliferation of helper T cells as well as expression of IL-2 and other cytokines by them.
4. Antibodies like muromunab CD3, antithymocyte globulin specifically bind to helper T cells, prevent their response and deplete them.

Immunosuppressive mechanism of cyclosporine

The CD4 molecule associated with T cell receptor on helper T cells anchors the MHC II carrying the antigen peptide so that it is able to activate the T cell receptor. Stimulation of T cell receptor phosphorylates phospho lipase c (PLc), which hydrolysis phosphatidyl inositol bisphosphate (PIP2) to generate diacyl glycerol (DAG) and IP3. While DAG activates protein kinase C (PKc) to produce MAPkinase dependent and other actions, IP3 releases intracellular Ca2+. After binding to calmodulin (CAM) this Ca2+ activates a membrane associated serine/ threonine phosphatase called calcineurin which dephosphorylates regulatory protein nuclear factor activated T cell (NFAT), permitting its intranuclear migration and transcription of cytokine genes leading to production of IL-2 along with other interleukins, GM-CSF, TNF-alpha, interferon etc. IL-2 is the major cytokine for T cell multiplication and differentiation. Cyclosporine enters target cells and binds to cyclophilin, an immunophilin class of protein. The complex then binds to and inactivates calcineurin, thus response of the helper T cell to antigenic stimulation fails. Cyclosporine also enhances expression of transforming growth factor beta (TGF beta), an inhibitor of IL-2 which attenuates IL-2 stimulated T cell proliferation and production of killer lymphocytes.