Immunosuppressants

• Immune Response


  Defensive body mechanisms against pathogenic invasion or injury
• Types of immune response

  • Innate
  • Adaptive
• Innate immune response


  • First line of defense against pathogens
  • Consists of mechanical, biochemical, and cellular components
• Components of the innate immune response

  • Mechanical
  • Biochemical
  • Cellular
• Mechanical components


  • Skin/epidermis
  • Mucus
• Biochemical components


  • Antimicrobial peptides and proteins (e.g., defensins)
  • Complement
  • Enzymes (e.g., lysozyme, acid hydrolases)
  • Interferons
  • Acidic pH
  • Free radicals (e.g., hydrogen peroxide, superoxide anions)
• Cellular components


  • Neutrophils
  • Monocytes
  • Macrophages
  • Natural killer cells
  • Natural killer-T cells
• The adaptive immune system is mobilized by cues from the innate response when the innate processes are incapable of coping with an infection
• Adaptive immune response


  • Respond to a variety of antigens in a specific manner
  • Discriminate between foreign (“nonself”) antigens and self antigens
  • Respond to previously encountered antigens with a memory response
• Antibodies


  Effectors of humoral immunity
• T lymphocytes


  Effectors of cell-mediated immunity
• Immune responses can become defective or overactive
• Types of agents used in immune response

  • Immunostimulants
  • Immunosuppressants
• Immunostimulants


  • Used when the immune system is compromised
• Immunosuppressants


  • Used in immune overactivity or to prevent transplant rejection
• Immunosuppressive agents


  • Glucocorticoids
  • Calcineurin inhibitors
  • Antiproliferative/antimetabolic agents
  • Biologics (antibodies)
• Drugs


  • Prednisolone
  • Prednisone
  • Methylprednisolone
  • Deflazacort
  • Dexamethasone
  • Betamethasone
• Prednisolone


  Intermediate acting, drug of choice for systemic anti-inflammatory and immunosuppressive effects
• Prednisone


  Prodrug, intermediate acting, inactive until converted to prednisolone
• Methylprednisolone


  Intermediate acting, anti-inflammatory and immunosuppressive
• Deflazacort


  Prodrug, short acting, must be converted by plasma esterases into active metabolite
• Dexamethasone


  Long acting, anti-inflammatory and immunosuppressive, used especially where water retention is undesirable
• Betamethasone


  Long acting, anti-inflammatory and immunosuppressive, used especially when water retention is undesirable
• Glucocorticoids


  • Multiple mechanisms involved in the suppression of inflammation
• Actions on inflammatory cells

  • Decreased egress of neutrophils
  • Reduced activation of neutrophils, macrophages, and mast cells
  • Decreased overall activation of T-helper (Th) cells
  • Decreased fibroblast function
  • Reduced activity of osteoblasts
• Effects of glucocorticoids


  • Decreased generation of many cytokines
  • Reduction in the concentration of complement components
  • Decreased generation of induced nitric oxide
  • Decreased histamine release
  • Decreased IgG production
  • Increased synthesis of anti-inflammatory factors
• Clinical uses of glucocorticoids


  • Prevent and treat transplant rejection
  • Reverse acute transplant rejection
  • Treat autoimmune disorders
  • Limit allergic reactions
  • Treat inflammatory diseases
  • Certain forms of cancer
• Unwanted effects of glucocorticoids


  • Suppression of the response to infection or injury
  • Cushing’s syndrome
  • Osteoporosis
  • Hyperglycaemia
  • Muscle wasting and proximal muscle weakness
• In children, inhibition of growth may occur if treatment is continued for more than 6 months
• CNS effects of glucocorticoids

  • Euphoria
  • Depression
  • Psychosis
• Other effects of glucocorticoids

  • Glaucoma
  • Raised intracranial pressure
  • Increased incidence of cataracts
• Sudden withdrawal after prolonged therapy may result in acute adrenal insufficiency
• Careful procedures for phased withdrawal should be followed
• Recovery of full adrenal function usually takes about 2 months, although it can take 18 months or more
• Calcineurin inhibitors


  • Ciclosporin
  • Tacrolimus
• Cyclosporine


  A peptide antibiotic that blocks T cell activation
• Cyclosporine is produced by the fungus Beauveria nivea
• Cyclosporine


  • Lipophilic and highly hydrophobic
  • Formulated for clinical administration using castor oil or other strategies
• Uses of cyclosporine


  • Human organ transplantation
  • Graft-versus-host disease
  • Treatment of selected autoimmune disorders
• Cyclosporine-cyclophilin complex


  • Inhibits calcineurin necessary for T-cell activation