Shanghai Jiao Tong University Types of Drugs Immunosuppressants
(important!) Immunostimulants Immunomodulators Induction of
tolerance (tolerogens) Cytokines Hematopoetic growth factors
Antibodies targeting key cell receptors/ligands
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Shanghai Jiao Tong University Simplified schematic of an immune
response Class I MHC class II/peptides APCs Protein antigens CD8 +
T cells CD4 + T cells B cells Plasma cells CD8 + cytolytic T cells
CD4 + immune cells (delayed hypersensitivity) antibody production
proliferation & differentiation IFN , IL-2 Cytokines Costim.
Mol. IL-4,-5,-6 proliferation & differentiation APC Class II
proliferation & differentiation
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Shanghai Jiao Tong University Antigen antigen presenting cell
(macrophage, dendritic cell) CD4 T helper cell primed CD4 T helper
cell CD8 T cell cytotoxic T cells plasma cells 1 2 3 4 4 IL-1 IL-2
Major steps in immune responses B cell
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Shanghai Jiao Tong University Antigen antigen presenting cell
CD4 T helper cell primed CD4 T helper cell CD8 T cell cytotoxic T
cells plasma cells 1 2 3 4 4 IL-1 IL-2 cytokines Sites of action of
immunosuppressive drugs X X X X X A B DD E C X
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Shanghai Jiao Tong University
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The cell-mediated arm of the immune response involves the
ingestion and digestion of antigen by antigen-presenting cells such
as macrophages. Activated TH cells secrete IL-2, which causes
proliferation and activation of cytotoxic T lymphocytes, and TH1
and TH2 cell subsets. TH1 cells also produce IFN- and TNF- , which
can directly activate macrophages and NK cells. The humoral
response is triggered when B lymphocytes bind antigen via their
surface immunoglobulin. They are then induced by TH2-derived IL-4
and IL-5 to proliferate and differentiate into memory cells and
antibody-secreting plasma cells. Regulatory cytokines such as IFN-
and IL-10 down-regulate TH2 and TH1 responses, respectively. Immune
response
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Shanghai Jiao Tong University Purpose of immunosuppressive
drugs Prevention of organ transplant rejection Treatment of
autoimmune diseases Multiple Sclerosis Lupus Rheumatoid Arthritis
Crohns Disease Type I Diabetes 1
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Shanghai Jiao Tong University Glucocorticoids reducing the size
and lymphoid content of the lymph nodes and spleen interfering with
the cell cycle of activated lymphoid cells lowering the effective
concentration of specific antibodies
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Shanghai Jiao Tong University
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Newton, Thorax 2000; 55:603-613 Biology of glucocorticoids
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Shanghai Jiao Tong University Newton, Thorax 2000;55:603-613
Mechanisms of Glucocorticoid Action 1.Inhibit the production of
proinflammatory cytokines 2.Promote the production of inflammatory
cytokines 3.Induce apoptosis in inflammatory cells 4. Interfere
with cytokine signals
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Shanghai Jiao Tong University Glucocorticoid-sensitive sites of
the immune response MHC Class I/peptides APCs MHC Class II/peptides
APCs Protein antigen CD8 T-cell CD4 T-cell (helper T-cells) B-cell
Plasma cell CD8 cytolytic T-cells CD4 immune cell ) (delayed
hypersensitivity) antibody production proliferation &
differentiation proliferation IL-2 IL-1 IL-1, -4,-5,-6
proliferation & differentiation GC X X X X
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Shanghai Jiao Tong University Clinical uses Autoimmune diseases
Idiopathic thrombocytopenic purpura ( ) Autoimmune hemolytic anemia
Acute glomerulonephritis Acquired factor XIII antibodies and
bleeding syndrome Organ transplantation Prevention of cell
proliferation induced by coronary stents
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Shanghai Jiao Tong University Cyclosporin isolated from the
fungus Tolypocladium inflatum ( ) isolated from a soil sample
obtained by Sandoz scientists at Hardangervidd a, Norway in
1969
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Shanghai Jiao Tong University Immunophilin ligands Cyclosporine
peptide antibiotic Cyclosporine cyclophilin complex inhibiting
cytoplasmic phosphatase, calcineurin necessary for the activation
of a T-cell-specific transcription factor
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Shanghai Jiao Tong University FK Binding protein sirolimus mTor
tacrolimus Cyclosporine cyclophilin Calcineurin Cytokine Signaling
NFAT Translocation Genes lead to T cell Activation IL-2 Targets of
Immunosuppressants
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Shanghai Jiao Tong University Mechanism of Action of Helper
T-cell blockers X X From Hardman and Limbird, The Pharmacological
Basis of Therapeutics
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Shanghai Jiao Tong University
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Clinical uses organ transplantation: Body parts: Facial, Limbs,
Organs: Heart, kidney, liver, small intestine, lung, Tissues:
Islets, hair follicles, bone, bone marrow, cornea, Cells: Stem
cells, lymphocytes
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Shanghai Jiao Tong University
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Immunological Rejection Major Histocompatibility Complex ( )
MHC Rejections: Antibody mediated T cells mediated Hyperacute
rejection e.g., Blood type mismatch Acute Graft Rejection Direct
recognition of allogeinic MHC; rejection about 10 days Chronic
rejection Take many months to years. Due to failure of
immunosuppressants
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Shanghai Jiao Tong University Clinical uses graft-versus-host
disease after hematopoietic stem cell transplantation selected
autoimmune disorders
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Shanghai Jiao Tong University Tacrolimus macrolide antibiotic
23-membered macrolide lactone discovered in 1984 from the
fermentation broth of a Japanese soil sample that contained the
bacteria Streptomyces tsukubaensis.
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Shanghai Jiao Tong University Tacrolimus binding to the
immunophilin FK-binding protein inhibiting the cytoplasmic
phosphatase, calcineurin 10-100 times more potent than cyclosporine
used in organ and stem cell transplantation
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Shanghai Jiao Tong University Sirolimus _ Structure _macrolide
similiar to tacrolimus _ Mechanism _binds to immunophilin protein
that binds to a key regulatory kinase required for T cell
activation _(new unique mechanism to inhibit T lymphocyte
activation by IL-2) _different site of action than cyclosporine and
tacrolimus
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Shanghai Jiao Tong University FK Binding protein sirolimus mTOR
tacrolimus Cyclosporine immunophilin Calcineurin Cytokine Signaling
NFAT Translocation Genes lead to T cell Activation IL-2 Targets of
Immunosuppressants
Shanghai Jiao Tong University Sirolimus _ Inhibits mammalian
target of rapamycin (mTOR) _mTOR is a protein kinase that plays
pivotal role in IL-2 receptor responses _IL-2 binds to its receptor
on T cells and leads to mTOR activation _mTOR initiates cascade of
events (including cyclin dependent kinases) that promote T
lymphocyte proliferation and differentiation _Inhibition of mTOR
blocks IL-2 dependent cell-cycle progression at G1S phase
transition
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Shanghai Jiao Tong University Mycophenolate mofetil Penicillium
glaucum inhibiting T- and B-lymphocyte responses Very often used
now alternative to cyclosporine, solid organ transplant patients
lupus nephritis, rheumatoid arthritis, and some dermatologic
disorders
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Shanghai Jiao Tong University Cytotoxic agents Azathioprine
prodrug of mercaptopurine functions as an antimetabolite
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Shanghai Jiao Tong University Cytotoxic agents Cyclophosphamide
autoimmune disorders (including systemic lupus erythematosus )
acquired factor XIII antibodies and bleeding syndrome autoimmune
hemolytic anemia antibody-induced pure red cell aplasia Wegeners
granulomatosis
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Shanghai Jiao Tong University Immunosuppressants Inhibiting T
Cell Activation Drug Glucortiocoids Cyclosporine and Tacrolimus
Sirolimus Mycophenolate Mofetil Target GRE of DNA (regulate gene
transcription, inhibit transcription) Calcineurin (inhibit the
phosphatase required for IL-2 transcription) Protein kinase
involved in cell-cycle progression (inhibits mTOR and inhbits IL-2
signaling) Inosine monophosphate dehydrogenase (inhibits de novo
guanine nucleotide synthesis)
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Shanghai Jiao Tong University Monoclonal antibody 1975,
hybridoma technology by Milstein and Kohler antibody-forming cells
fused to immortal plasmacytoma cells[ ( )] Pure and mass antibody
possible Antilymphocyte & Antithymocyte Antibodies
Muromonab-CD3 against T-cell surface proteins
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Shanghai Jiao Tong University Inhibitors of immune response
Inhibitors of immune response A- Immune Globulin (antigen
recognition) B- Corticosteroids (IL-1 production, cell
proliferation) C- Cyclosporine, Tacrolimus, (1L-2 gene expr.),
Sirolimus (IL-2 signal transduction) D- Rapamycin, Mycophenolate (T
cell prolif.), Azathioprine, Cyclophosphamide (all cell prolif.) E-
OKT3 (Muromonab-CD3) (monoclonal antibody to CD3 on T cell)
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Shanghai Jiao Tong University Immunostimulants Thymic Hormones
Improve primary immune deficiency in children Synthetic Stimulants
Levamisole stimulates phagocytosis and T cell production of
cytokines Adjuvants of bacterial origin Bacille de Calmette Guerin
(BCG, ) is viable strain of Mycobacterium bovis that enhances
macrophage activity BCG used for bladder cancer and melanomas
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Shanghai Jiao Tong University hepatitis B vaccine a small
glycoprotein, hepatitis B surface antigen (HBsAg) child's immune
system recognizes HBsAg as foreign produces antibodies when
infected with hepatitis B virus the antibodies recognize the
protein and stimulate the immune system to produce large quantities
of specific antibodies that attach to and destroy the virus and
prevent the disease.
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Shanghai Jiao Tong University vaccination a child receives
vaccination, most often before leaving the hospital after birth.
the second and third HBV immunizations are administered by the age
of 18 months, in conjunction with other routine childhood
vaccinations.