PRESENTED BY

B.DEVADATHA

M.SCII BMB

DEPT .OF BMB

IMMUNOSUPPRESSANTS

B. Devadatha(123680029)

M. Sc. IInd Year BMB

INTRODUCTION Immunosuppression involves an act that reduces the activation or

efficacy of the immune system

Immunosuppressants are used to control severe manifestations of allergic, autoimmune and transplant-related diseases

Now over 80 autoimmune diseases and several common allergic conditions in which immunosuppressant's are used

Prevent the rejection of transplanted organs and tissues

Treatment of autoimmune diseases or diseases that are most likely of autoimmune origin

Treatment of some other non-autoimmune inflammatory diseases

CLASSIFICATION OF IMMUNOSUPPRESSANTS

1.PHYSICAL IMMUNOSUPRESSANTS

Includes Total Lymphoid Irradiation, Plasmapheresis, thoracic duct drainage

Inhibits Cell division ,cell activation, Antibody production

2.CHEMICAL IMMUNOSUPPRESSANTS:

I. Corticosteroids

II. Cytostatics

III. Antibodies

IV. Drugs acting on Immunophilins

3.BIOLOGICAL IMMUNOSUPPRESSANTS:

interferon's, interleukins, colony-stimulating factors, monoclonal antibodies

PHYSICAL IMMUNOSUPPRESSANTS Total Lymphoid Irradiation (TLI ):

Fractionated irradiation focused on Lymphoid tissues, with shielding of Bone marrow, Lungs ,Non lymphoid tissues

Induces formation of large granular Lymphocytes lacking T,B & Macrophage markers which non specifically suppresses Ag –specific cytolytic arm of Allogenic immune reactions

TLI can induce true Transplantation tolerance to Renal allografts in humans

UV-B light is absorbed by skin Urocanic acid & undergoes isomerization to Cis form which induces suppression through effect on Dendritic APC

Adverse Effects: Myelosuppression

Skin changes

Nausea and vomiting

PHYSICAL IMMUNOSUPPRESSANTS Plasmapheresis:

removing plasma hemocomponent that is circulating with pathogens and replacing it with a suitable solution

Useful adjunct to chemotherapy for removing circulating immunoglobulins or immunoglobulin components in multiple myeloma and other dysproteinemias

Rapidly removes pathogenic antibody Must be combined with B lymphotoxic drug to prevent

rebound (e.g. cyclophosphamide, steroids) Combination with IVIg very powerful Risks include cardiovascular instability

PHYSICAL IMMUNOSUPPRESSANTS

Thoracic duct drainage: Woodruff demonstrated that synergism of

thoracic-duct drainage with lymphoid-depleting modality, antilymphocyte serum

effective and safe in decreasing the immunologic response of the recipient of renal transplants from genetically related donors

Lymphocytapheresis using TDD is very selective for removing lymphocytes (especially helper T-cells)

CHEMICAL IMMUNOSUPRESSANTS

• Corticosteroids: Prednisone , Prednisolone

Dexamethasone,Methylpredinsolone They have both anti-inflammatory action and

immunosuppressant effects

Mechanism of action: bind to glucocorticoid receptors and the complex interacts with

DNA to inhibit gene transcription of inflammatory genes

stimulates migration of T cells from intravascular tissue to lymph nodes

Inhibit mitosis of lymphocytes

Reduce size and lymphoid content of the lymph node and spleen

Inhibit the production of inflammatory mediators, including PAF, leukotrienes, prostaglandins, histamine and bradykinin

Decrease production of cytokines IL-1, IL-2, interferon, TNF

Corticosteroids

Dosage: Maintenance up to 20 mg/day; treatment of rejection 200 mg/day for 3 dats or 3 days

Adverse Effects: Sodium and fluid retention, Muscle weakness, Steroid myopathy, Loss of muscle mass and osteoporosis, Peptic ulcer with possible perforation and

hemorrhage; Pancreatitis, impaired wound healing, thin fragile skin Increased tendency to diabetes mellitus Hypertension

Cytostatics Cytostatics inhibit cell division

In immunotherapy, they are used in smaller doses than in the treatment of malignant diseases.

They affect the proliferation of both T cells and B cells.

Due to their highest effectiveness, purine analogs are most frequently administered.

It includes the following: Alkylating agents; Antimetabolites

ALKYLATING AGENTS:

The alkylating agents used in immunotherapy are nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others

In small doses, it is very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias,Wegener's granulomatosis and other immune diseases

Cyclophosphamide

Cyclophosphamide is an alkylating agent. It is a widely used as a cytotoxic agent.

It is given orally as well as intravenously with efficacy

Mechanism of action: suppress bone marrow function

It is inactive in parent form, and must be activated to cytotoxic form by liver CYT450 liver microsomal system to 4‐Hydroxycyclophamide and Aldophosphamide. 4‐Hydroxycyclophamide and Aldophosphamide are delivered to the dividing normal and tumor cells.

Aldophosphamide is converted into acrolein and phosphoramide mustard.They crosslink DNAs resulting in inhibition of DNA synthesis

Side effects: Usually large Doses of cyclophosphamide is associated with ‐

a. Pancytopenia

b. Hemorrhagic cystitis

c. Nausea and vomiting

d. Cardiac toxicity

e. Electrolyte imbalances

ANTIMETABOLITES

Includes folic acid analogues, such as methotrexate; purine analogues such as azathioprine and mercaptopurine pyrimidine analogues; protein synthesis inhibitors

Azathioprine : Prodrug that releases 6-mercaptopurine Mechanism of Action: Converts 6-mercaptopurine to tissue inhibitor of metalloproteinase, which

is converted to thioguanine nucleotides that interfere with DNA synthesis; thioguanine derivatives may inhibit purine synthesis

Uses: a. Used for graft rejectionMycophenolate mofetil

b. Normally used in combination with corticosteroids. Side effects: Bone marrow suppression (leukopenia, anemia), Skin rashes,nausea Liver toxicity ,macrocytosis

Azathioprine

Mycophenolate mofetil Mycophenolic acid from penicillium molds

Mechanism of Action:

Prevents T- and B-cell proliferation by inhibition of de novo purine synthesis by inhibition of inosine monophosphate dehydrogenase

Dosage 1 to 2 g/day in divided doses

CLINICAL USE:

Solid organ transplants for refractory rejection.

Steroid-refractory hematopoietic stem cell transplant patients.

Combined with prednisone as alternative to CSA or tacrolimus.

Rheumatoid arthritis, & dermatologic disorders.

Adverse Effects:

Leukopenia, neutropenia.

Lymphoma

GIT toxicity

Leflunomide Pyrimidine synthesis inhibitor

Active metabolite undergoes enterohepatic circulation

Arava oral administration as tablets containing 10, 20, or 100 mg

Mechanism of Action:

Dihydroorotate dehydrogenase inhibitor

antiproliferative activity

CLINICAL USE:

rheumatoid arthritis

Organ transplant

Adverse Effects:Elevation of liver enzymesRenal impairmentTeratogenicityCardiovascular effects

Methotrexate

a folic acid antagonist

Mechanism of Action:

Inhibits dihydrofolate reductase required for folic acid activation (tetrahydrofolic)

Inhibition of DNA, RNA &protein synthesis

Interferes with T cell replication.

Rheumatoid arthritis & psoriasis and Crohn disease

Adverse effects

Nausea-vomiting-diarrhea

Alopecia

Bone marrow depression

Pulmonary fibrosis

Renal & hepatic disorders

Antibodies

block T cell surface molecules involved in signaling immunoglobulins

They are of two types:

Polyclonal antibodies & Monoclonal antibodies

Polyclonal antibodies:

obtained from plasma or serum of horses hyper-immunized with human lymphocytes.

Inhibit T lymphocytes and cause their lysis, which is both complement mediated cytolysis and cell-mediated opsonization followed by removal of reticuloendothelial cells from the circulation in the spleen and liver.

• Antithymocyte globulin (ATG)• Antilymphocyte globulin (ATGAM)

Polyclonal antibodies

Mechanism of Action:

agents contain antibodies specific for many common T cell antigens including CD2, CD3, CD4, CD8, CD11a, CD18

Blocks T-cell membrane proteins (CD2,CD3, CD45, and so forth), causing altered function, lysis, and prolonged T-cell depletion

CLINICAL USE: Combined with cyclosporine for bone marrow

transplantation. To treat acute allograft rejection. Steroid-resistant rejection. Adverse Effects:

Leukopenia ,Thrombocytopenia

serum sickness

muscle pain

lymphopenia

Monoclonal antibodies Monoclonal antibodies are antigen-specific immunosuppressants that will

reduce immune response to alloantigens of the graft while preserving the response to alloantigens to unrelated antigens

Early rejection prophylaxis and treatment of rejection.

Muromonab-CD3 (OKT3):

Directed against CD3 component of T-cell–receptor

signal-transduction complex

Mechanism of Action:

Binds to CD3 associated with T-cell receptor,leading to initial activation and cytokine release, followed by blockade of function, lysis, and T-cell depletion

Adverse Effects: Severe cytokine-release syndrome, pulmonary edema, acute renal

failure, gastrointestinal disturbances, changes in central nervous system

Alemtuzumab Humanized monoclonal antibody against CD52

Approved for use in B-cell chronic lymphocytic leukemia

Mechanism of Action:

Binds to CD52 on all B and T cells, most monocytes, macrophages, and natural killer cells, causing cell lysis and prolonged depletion

Efficacy: effective as induction therapy for the prevention of acute rejection in

kidney, liver, pancreas, intestinal, and lung transplants

Adverse Effects:

pancytopenia, neutropenia, thrombocytopenia, and lymphopenia

hypotension, fever, shortness of breath

Basiliximab and Daclizumab

Basiliximab is a chimeric human-mouse IgG

(25% murine, 75% human protein). Daclizumab is a humanized IgG (90% human protein). Mechanism of Action:

Binds to and blocks the interleukin-2–Receptor a chain (CD25 antigen) on activated T cells, depleting them and inhibiting interleukin-2–induced T-cell activation

Efficacy:

Both basiliximab and daclizumab are approved for use in kidney transplantation in combination with cyclosporine and corticosteroids

Adverse Effects:

Hypersensitivity reactions (uncommon)

gastrointestinal disorders

Drugs acting on Immunophilins

Cyclosporine: 11-amino-acid cyclic peptide from Tolypocladium inflatum

Mechanism of Action:

Binds to cyclophilin intracellular protein receptors

complex inhibits calcineurin phosphatase and T-cell activation

CLINICAL USE:

Kidney, liver, heart organ transplantation used in combination with azathioprine and corticosteroids

Adverse Effects: Nephrotoxicity, hemolytic–uremic syndrome, hypertension

neurotoxicity, gum hyperplasia

skin changes ,hirsutism,

post-transplantation diabetes mellitus

hyperlipidemia

Tacrolimus (FK506) Macrolide antibiotic From Streptomyces tsukubaensis

Mechanism of Action:

Binds to FK-binding protein 12; inhibits synthesis and release of IL-2

CLINICAL USE: Organ and stem cell transplantation Prevention of rejection of liver and kidney transplants (with

glucocorticoids). TAC is 10 – 100 times more potent than CsA in inhibiting

immune responses

Toxic effects :

lower incidence of hypertension, hyperlipidemia, skin changes, hirsutism, and gum hyperplasia

higher incidence of post-transplantation diabetes mellitus and neurotoxicity

Sirolimus (Rapamycin)

Triene macrolide antibiotic from Streptomyces hygroscopicus from

Easter Island

Mechanism of Action:

Binds to FKBP12; complex inhibits target of rapamycin and interleukin-2–driven T-cell proliferation

Blocks the progression of activated T cells from G1 to S phase of cell cycle

Efficacy:

approved for the prophylaxis of rejection in kidney transplant patients

treatment of variety of tumors including small cell lung cancer, pancreatic cancer, leukemia ,lymphoma, rhabdomyosarcoma, neuroblastoma

Adverse Effects:

Hyperlipidemia, increased toxicity of calcineurin inhibitors,

thrombocytopenia, delayed wound healing,

delayed graft function

New Immunosuppressive Drugs

derived from myriocin, a fungus-derived sphingosine analogue

Mechanism of Action:

Works as an antagonist for sphingosine-1-phosphate receptors on lymphocytes, enhancing homing to lymphoid tissues and preventing egress, causing lymphopenia

• Prescribed for– Renal transplant– Multiple sclerosis

• Side effect– Reversible first-dose bradycardia, potentiated by general

anesthetics and beta-blockers– nausea, vomiting, diarrhea, increased liver-enzyme

New Immunosuppressive Drugs Etanercept (Enbrel)

Recombinant DNA drug binds TNF (tumor necrosis factor) in the circulation and

in the joint, preventing interaction with cell surface TNF receptors thereby reducing TNF activity

Subcutaneous injection Side effects Susceptibility to opportunistic infection

ISA 247 novel isomeric cyclosporine A analog mixture a

calcineurin inhibitor. treatment of psoriasis and prevention of organ rejection

after transplantation

REFERENCE TEXT BOOKS:

JANEWAY’S Immunobiology 7th ed

Kuby Immunology.6th ed

Ivan Roitt Essential Immunology 11th ed

WEBSITES & JOURNALS

Immunosuppression after Liver Transplantation http://gft.sagepub.com

www.accesspharmacy.com.proxy.lib.umich.edu/popup.aspx?aID=7996230&print=yes 1/

The new england journal Of medicine www.nejm.org

Erasmus Journal of Medicine • vol 1 - nr 2 - January 2011

Ultraviolet A Radiation: Its Role in Immunosuppression and Carcinogenesis

Current Concepts of Immunosuppression and Side Effects Anand Khurana and Daniel C. Brennan

Pancreas-Kidney Transplantation: Drugs (http:/ / www. pancreas-kidney. com/ drugs. html), a brief history of immunosuppressive drugs. Accessed on 21 August 2005

Immunosuppressants, Pharmacologic profile (http:/ / www. drugguide. com/ classification_articles/ immunosuppressants. htm). Drugguide.com. Accessed on 21 August 2005