This document discusses various immunopharmacology drugs and their uses. It covers immunosuppressive antibodies including monoclonal antibodies used for transplantation, cancer, and autoimmune diseases. It also discusses immunosuppressive drugs classified as immunophilin ligands or cytotoxic agents that are used for transplantation and graft-versus-host disease. Common drugs discussed include cyclosporine, tacrolimus, sirolimus, mycophenolate, azathioprine, and cyclophosphamide.

2. Immunopharmacology
By
M.H.Farjoo M.D. , Ph.D.
Shahid Beheshti University of Medical Science

3. Immunopharmacology
 Classification
 Immunosuppressive Antibodies
 Hypersensitivity & Drug allergy
 Clinical Uses
 Transplantation
 GVHD
 Cytokines
 Cytokine Inhibitors
 Desensitization to Drugs
 Drug Pictures

7. Classification
 Immunophilin Ligands:
 Cyclosporine
 Tacrolimus (FK 506)
 Sirolimus
 Mycophenolate mofetil (MMF)
 Thalidomide
 Cytotoxic Agents:
 Azathioprine
 Cyclophosphamide
 Other cytotoxic agents

8. Cyclosporine
 Cyclosporine is a peptide antibiotic that blocks T cell
activation.
 It binds to cyclophilin, a member of a class of
intracellular proteins called immunophilins.
 Cyclosporine and cyclophilin form a complex that
inhibits calcineurin.
 calcineurin is a phosphatase necessary for the
activation of a T-cell-specific transcription factor.
 This transcription factor, NF-AT, is involved in the
synthesis of interleukins (eg, IL-2) by activated T cells.

11. Cyclosporine Cont,d
 There is interpatient variability in bioavailability
which requires individual patient dosage
adjustments.
 Cyclosporine has efficacy in human organ
transplantation and in the treatment of GVHD.
 Toxicities are numerous: nephrotoxicity,
hypertension, liver dysfunction and seizures.

12. Cyclosporine Cont,d
 Tumors may arise after cyclosporine treatment
because the drug induces TGF-β.
 Cyclosporine has been used for transplants of
the kidney, pancreas, liver and heart.
 Cyclosporine with methotrexate, is a standard
prophylactic regimen to prevent GVHD
allogeneic transplants.

13. Tacrolimus (FK 506)
 Tacrolimus is 10-100 times more potent than
cyclosporine in inhibiting immune responses.
 Tacrolimus is utilized for the same indications
as cyclosporine.
 Its toxic effects are similar to those of
cyclosporine.

14. Sirolimus
 Sirolimus (rapamycin) is derived from Streptomyces
hygroscopicus
 It binds FK506-binding protein, resulting in an active
complex that blocks the molecular target of
rapamycin (mTOR).
 The mTOR is a key component in cell growth and
proliferation, angiogenesis, and metabolism.
 Thus, blockade of mTOR can lead to inhibition of
interleukin-driven T-cell proliferation.

17. Sirolimus
 Sirolimus is synergistic with cyclosporine.
 Sirolimus has been used to prevent rejection of solid
organ allografts.
 Toxicities includes: profound myelosuppression
(especially thrombocytopenia), hepatotoxicity,
diarrhea, hypertriglyceridemia, and headache

18. Mycophenolate mofetil (MMF)
 MMF is a derivative of mycophenolic acid, isolated
from the mold Penicillium glaucum.
 MMF inhibits T- and B-lymphocyte responses by
inhibition of purines synthesis.
 It is used in solid organ transplant for refractory
rejection.
 It is also used in combination with tacrolimus to
prevent GVHD.
 Toxicities include: GI disturbances, hypertension and
reversible myelosuppression.

19. Thalidomide
 Thalidomide inhibits angiogenesis and has anti-
inflammatory and immunomodulatory effects.
 Thalidomide is used in multiple myeloma and when
combined with dexamethasone, the response rates are
90%.
 The adverse effect profile of thalidomide is extensive.
The most important toxicity is teratogenesis.
 Thrombosis is sufficiently frequent that most patients
are placed on warfarin.

20. Azathioprine
 Azathioprine is a prodrug of mercaptopurine and
functions as an antimetabolite.
 These agents are prototypes of the antimetabolite group
of cytotoxic immunosuppressive drugs.
 Azathioprine and mercaptopurine interfere with purine
metabolism at steps required for lymphoid cell
proliferation.

22. Azathioprine Cont,d
 Drug inactivation depends on xanthine oxidase so the
dose should be reduced in patients receiving
allopurinol.
 It may cause hepatic dysfunction (very high ALP,
mild jaundice) particularly in preexisting hepatic
dysfunction.

24. Azathioprine Cont,d
 Cellular immunity as well as serum antibody
responses can be blocked by Azathioprine.
 Azathioprine and mercaptopurine are benefitial in
maintaining renal allografts.
 The chief toxic effect of azathioprine and
mercaptopurine is bone marrow suppression.

25. Cyclophosphamide
 Cyclophosphamide destroys proliferating lymphoid
cells.
 Large doses of cyclophosphamide may causes
pancytopenia and hemorrhagic cystitis.

26. Other cytotoxic agents
 Hydroxychloroquine (antimalarial agent) decreases T-
cell activation, used for rheumatoid arthritis and SLE.
 Methotrexate is used in rheumatoid arthritis.

29. Immunosuppressive Antibodies
 Hybridomas: consist of antibody-forming cells fused to
plasmacytoma cells.
 Hybrid cells produce the required antibody and can be
subcloned for antibody production.
 Humanization involves replacing most of the murine antibody
with human regions while keeping only the variable regions
intact.
 Chimeric mouse-human antibodies have less complete
replacement of the murine components.
 the suffix "-umab" or "-zumab" is used for humanized
antibodies, and "-imab" or "-ximab" for chimeric products.

30. 1) Immunisation of a mouse
(2) Isolation of B cells from the spleen
(3) Cultivation of myeloma cells
(4) Fusion of myeloma and B cells
(5) Separation of cell lines

31. (6) Screening of suitable cell lines
(7) in vitro (a) or in vivo (b) multiplication
(8) Harvesting

32. Sketches of mouse (top left), chimeric (top right) and
humanized (bottom left) monoclonal antibodies.
Human parts in brown, non-human parts in blue

33. Immunosuppressive Antibodies Cont,d
 Consist of:
 Monoclonal antibodies (MABS)
 Antilymphocyte & antithymocyte antibodies
 Immune globulin intravenous (IGIV)
 Hyperimmune immunoglobulins
 Rho (D) immune globulin

35. Monoclonal Antibodies (MABs)
 Indications of MABs:
 Antitumor
 Delivery of Isotopes to Tumors
 Immunosuppressants and Anti-Inflammatory
 Anti-TNF-α MABs
 Other Immunosuppressant MABs
 Antiplatelet

36. Antitumor MABs.
 Alemtuzumab (Campath, Lemtrada)
 Bevacizumab (Avastin)
 Cetuximab (Erbitux)
 Ofatumumab (Not in Iran)
 Panitumumab (Not in Iran)
 Rituximab (Rituxan, MabThera and Zytux)
 Trastuzumab (Herceptin)

37. Antitumor MABs
 Alemtuzumab is used in chronic lymphocytic leukemia.
 It may cause pancytopenia (risk of infection).
 Bevacizumab binds to VEGF and inhibits angiogenesis in
tumors.
 It is used for metastatic colorectal cancer, non-small cell lung
cancer, and metastatic kidney cancer.
 Since it is antiangiogenic, it should NOT be used until patients
heal from surgery.
 Side effects are hemorrhage, GI perforations, and wound
healing problems.

38.  Cetuximab targets EGFR and inhibits tumor cell
growth by decreases in growth factor production, and
increased apoptosis.
 It is used in EGFR-positive metastatic colorectal
cancer and head and neck cancer.
 Rituximab is used for B-cell non-Hodgkin’s
lymphoma, chronic lymphocytic leukemia,
rheumatoid arthritis.
 It induces apoptosis in the malignant lymphoma cells.
Antitumor MABs

39. Antitumor MABs
 Trastuzumab (Herceptin) is a recombinant DNA-
derived, humanized monoclonal antibody.
 It is used for breast cancer and gastric adenocarcinoma.
 It induces remission in 15–20% of breast cancer
patients, and increases 1-year survival.

40. MABs Used to Deliver Isotopes to Tumors
 Arcitumomab (Not in Iran)
 Capromab pendetide (Not in Iran)
 Ibritumomab (Zevalin)
 Tositumomab

41. MABs Used to Deliver Isotopes to Tumors
 Ibritumomab is labeled with isotopic yttrium and is
used in non-Hodgkin’s lymphoma.
 Tositumomab is labeled with iodine 131 and is used
in non-Hodgkin’s lymphoma.
 Toxicities include severe cytopenias.

42.  Anti-TNF-α MABs
 Adalimumab (Humira)
 Certolizumab pegol (Not in Iran)
 Etanercept (Enbrel)
 Golimumab (Not in Iran)
 Infliximab (Remicade)
 Other Immunosuppressant MABs
 Basiliximab and Daclizumab
 Natalizumab
 Omalizumab
MABs Used as Immunosuppressants and
Anti-Inflammatory Agents.

43.  They bind TNF-α, a proinflammatory cytokine.
 This suppresses downstream inflammatory cytokines
(IL-1, IL-6) involved in leukocyte activation.
 An increased risk of infection or reactivation of TB,
hepatitis B, and invasive systemic fungi is common to
all of them.
 Risk of malignancies (eg. lymphoma) is increased.
Anti-TNF-α MABs

44.  Adalimumab, Etanercept and Infliximab are used
in rheumatoid arthritis, ankylosing spondylitis, and
psoriatic arthritis.
 Infliximab is also used for Crohn’s disease and
ulcerative colitis.
Anti-TNF-α MABs

45.  Basiliximab and Daclizumab are IL-2 antagonists,
and are therefore immunosuppressive.
 They are used for prophylaxis of rejection in renal
transplant patients.
 Natalizumab inhibits the adhesion of leukocytes to
their receptor.
 It is used in multiple sclerosis and Crohn’s disease.
 Omalizumab is an anti-IgE antibody used in allergic
asthma when inhaled corticosteroids are ineffective.
Other Immunosuppressant MABs

46.  Abciximab binds to the activated platelets and
prevents their aggregation.
 It is used in percutaneous coronary intervention for
the prevention of cardiac ischemic complications
Antiplatelet MAB

48. Antilymphocyte & Antithymocyte Antibodies
 Antilymphocyte globulin (ALG) and antithymocyte
globulin (ATG) are used in transplantation.
 The antiserum is obtained by immunization of horses
or sheep with human lymphoid cells.
 They play a definite role in the management of solid
organ and bone marrow transplantation.

49. Immune Globulin Intravenous (IGIV)
 Immunoglobulin (IgG) is prepared from pools of
thousands of healthy donors.
 No specific antigen is the target of the "therapeutic
antibody.“
 Its precise mechanism of action is still controversial
 One expects that the pool of different antibodies will
have a normalizing effect upon the patient's immune
networks.
 IGIV is effective in immunoglobulin deficiencies,
autoimmune disorders, HIV disease and bone marrow
transplants.

50. Hyperimmune Immunoglobulins
 Hyperimmune immunoglobulin are IGIVs with high
titers of antibodies against viruses or toxins.
 Hyperimmune IGIVs are available for hepatitis B
virus, rabies, tetanus, and digoxin overdose.
 Intravenous administration of the hyperimmune
globulins reduces risk or severity of infection.

51. Rho(D) Immune Globulin
 Rho(D) immune globulin is a concentrated (15%)
solution of human IgG.
 Sensitization of Rh-negative mothers to the D antigen
occurs usually at the time of birth of an Rho(D)-
positive infant.
 In subsequent pregnancies, maternal antibody is
transferred to the fetus during the third trimester,
leading to erythroblastosis fetalis.

52. Rho(D) Immune Globulin Cont,d
 If an Rho(D) antibody is injected to the mother within
24-72 hours after the birth of an Rh-positive infant, the
process is stopped.
 Treatment is also often advised in miscarriages, ectopic
pregnancies, or abortions.

53. Hypersensitivity & Drug allergy
 Hypersensitivity can be classified as antibody-
mediated or cell-mediated.
 Three types of hypersensitivity are antibody-mediated
(types I-III), while the fourth is cell-mediated (type
IV).
 Hypersensitivity occurs in two phases: the
sensitization phase and the effector phase.
 Sensitization occurs upon initial encounter with an
antigen; the effector phase involves immunologic
memory.

54. Hypersensitivity & Drug allergy Cont’d
 Type I hypersensitivity results from cross-linking of
membrane-bound IgE on basophils or mast cells by
antigen.
 Type II hypersensitivity results from the formation of
Ag-Ab complexes (blood transfusion reaction).
 Subsequent administration of the drug can lead to
anaphylaxis (type I hypersensitivity).

55. Type II Reactions to Drugs
 Examples include:
 SLE following hydralazine or procainamide.
 "lupoid hepatitis" due to cathartic sensitivity.
 Autoimmune hemolytic anemia by methyldopa.
 Thrombocytopenic purpura due to quinidine.
 Agranulocytosis due to a variety of drugs.

56. Type II Reactions to Drugs Cont’d
 Autoimmune reactions to drugs subside within
several months after the drug is withdrawn.
 Immunosuppressive therapy is warranted only
when the autoimmune response is unusually
severe.

57. Hypersensitivity & Drug allergy Cont’d
 Type III hypersensitivity (Serum sickness) is due to the
complement activation by Immune complexes.
 In type III hypersensitivity, clinical symptoms occur 3 to
4 days after exposure to the antigen.
 Type IV delayed-type hypersensitivity (DTH) occur 2-3
days after exposure to the antigen.
 DTH induces a local inflammatory response that causes
tissue damage by antigen-nonspecific cells, especially
macrophages.

59. Type III Reactions to Drugs
 Type II and type III hypersensitivities often overlap.
 The clinical features include: urticarial and
erythematous skin eruptions, arthralgia,
glomerulonephritis, edema and fever.
 The reactions last 6-12 days and subside once the
offending drug is eliminated.

60. Type III Reactions to Drugs Cont’d
 Glucocorticoids are useful in attenuating severe
serum sickness reactions to drugs.
 In severe cases plasmapheresis can be used to remove
the offending drug and immune complexes.
 The sulfonamides, penicillin, thiouracil, iodides and
anticonvulsants all may initiate immune angiitis.
 Stevens-Johnson syndrome is associated with
sulfonamide therapy.

61. Hypersensitivity & Drug allergy Cont’d
 In some drug reactions, several hypersensitivity
responses may present simultaneously.
 Some reactions to drugs may be mistakenly classified
as allergic when they are actually genetic deficiency
or idiosyncratic.
 Two examples are:
 Hemolysis due to primaquine in G6PD deficiency
 Aplastic anemia caused by chloramphenicol.

62. Transplantation
 Four types of rejection can occur in a solid
organ transplant recipient:
 Hyperacute: is due to preformed antibodies, (anti-
blood group antibodies), occurs within hours,
cannot be stopped with immunosuppressives.
 Accelerated: is mediated by both antibodies and T
cells, immunosuppressive drugs cannot stop it.

65. Transplantation Cont,d
 Acute: Occurs within days to months and involves
cellular immunity. Reversal of rejection is usually
possible.
 Chronic: Occurs after months or years and is
characterized by fibrosis of the vasculature of the
transplanted organ. It is treated as acute rejection.

68. Organ Immunopharmacologic Agents Used Response
Renal Cyclosporine, azathioprine, prednisone, ALG,
tacrolimus, basiliximab,3 daclizumab,3 sirolimus
Very good
Heart
Cyclosporine, azathioprine, prednisone, ALG,
tacrolimus, basiliximab, daclizumab, sirolimus
Good
Liver
Cyclosporine, prednisone, azathioprine,
tacrolimus, sirolimus
Fair
Bone marrow
Cyclosporine, cyclophosphamide, prednisone,
methotrexate, ALG
Good
Organ transplantation outcome

70. GVHD
 Graft-versus-host disease (GVHD) is very common,
occurring in the majority of patients who receive an
allogeneic transplant.
 GVHD occurs as donor T cells fail to recognize the
patient's skin, liver, and gut (usually) as self.
 Acute GVHD occurs within the first 100 days, and is
manifested as a skin rash, severe diarrhea, or
hepatotoxicity.

71. GVHD Cont,d
 Patients generally progress to chronic GVHD (after
100 days) and require therapy for variable periods
thereafter.
 Patients generally can stop immunosuppression as
GVHD resolves (1-2 years after their transplant).

72. Cytokines
 The cytokines are a large and heterogeneous group of
proteins with diverse functions.
 Some play numerous roles in the function of the
immune system and in the control of hematopoiesis.
 Cytokines have antiproliferative, antimicrobial, and
antitumor effects.

74. The cytokines
Cytokine Properties
Interferon-a (IFN-α) Antiviral, oncostatic, activates NK cells
Interferon-b (IFN-β) Antiviral, oncostatic, activates NK cells
Interferon-γ (IFN-γ)
Antiviral, oncostatic, secreted by and activates or up-
regulates TH1 cells, NK cells, CTLs, and macrophages
Interleukin 1 to 32 (IL-1 to
32)
Variable functions
Tumor necrosis factor-α
(TNF-α)
Oncostatic, macrophage activation, proinflammatory
Tumor necrosis factor-β
(TNF-β)
Oncostatic, proinflammatory, chemotactic
Granulocyte colony-
stimulating factor
Granulocyte production
Granulocyte-macrophage
colony stimulating factor
Granulocyte, monocyte, eosinophil production
Macrophage colony-
stimulating factor
Monocyte production, activation
Erythropoietin (epoetin,
EPO)
Red blood cell production
Thrombopoietin (TPO) Platelet production

77. Cytokines Cont,d
 Interferons (IFNs), are cytokines that are grouped into
three families: IFN-α, IFN-β and IFN-γ.
 The IFN-α and IFN-β families are type I that act on
the same receptor. IFN- γ, a type II acts on a separate
receptor.
 IFNs, particularly IFN-γ, display immune-enhancing
properties.

78. Cytokines Cont,d
 IFNs also inhibit cell proliferation. In this respect, IFN-
α and IFN-β are more potent than IFN-γ.
 IFN-α is approved for the treatment of several
neoplasms and for use in hepatitis B and C.
 Toxicities of IFNs, which include fever, depression and
myelosuppression can severely restrict their clinical
use.

79. Cytokines Cont,d
 Cancer therapy by TNF-α has been disappointing due to
dose-limiting toxicities.
 One exception is intra-arterial high-dose TNF-α for
malignant melanoma and soft tissue sarcoma.
 In these settings, response rates >80% have been noted.
 The more recently discovered cytokines have been
classified as interleukins (ILs) and numbered in the
order of their discovery.

81. Cytokine Inhibitors
 Cytokine inhibitors are used when cytokines are
involved in the pathogenesis (septic shock).
 Anakinra (not yet in Iran) is an IL-1 receptor
antagonist, stemming the cascade of cytokines
released.
 Anakinra is used in rheumatoid arthritis untreated by
other antirheumatic drugs.

82. Desensitization to Drugs
 When certain drugs (penicillin, insulin) must be used
even in the presence of known allergic sensitivity.
 It is done by starting with very small doses and
increasing the dose within hours to the full dose.
 This practice must be performed under direct medical
supervision, as anaphylaxis may occur before
desensitization.
 Patient is only desensitized during administration of
the drug.

87. anti D immunoglobulin

89. Infliximab

90. Omalizumab

91. Hepatitis B Immune Globulin

92. Hepatitis B Immune Globulin

93. Hepatitis B Vaccine

94. Hepatitis B Vaccine

96. Influenza Vaccine

97. Pneumococcal Vaccine

98. Tetanus Immune Globulin

99. Lena delta in Russia (NASA satellite)
170 Km.

100. Summary
In English

101. Thank you
Any question?