1. IMMUNOSUPPRESSANTS
PRESENTED BY
B.DEVADATHA
M.SCII BMB
DEPT .OF BMB
B. Devadatha
(123680029)
M. Sc. IInd Year BMB

2. 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

3. 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

4. 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

5. 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

6. 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 Tcells)


7. 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

8. 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


9. 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

10. 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

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

12. 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

13. 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 enzymes
Renal impairment
Teratogenicity
Cardiovascular effects

14. 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

15. 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)

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

23. 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

24. 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

25. 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

27. 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