Transcript IMMUNOMODULATORS

IMMUNOMODULATORS
Prof. Mervat Hesham
The Immune Response - why
and how ?
 Discriminate: Self / Non self
 Destroy:
 Infectious invaders
 Dysregulated self (cancers)
 Immunity:
 Innate, Natural
 Adaptive, Learned
• Innate immune response
– first line of defense against an antigenic insult.
Includes
 defenses like physical (skin),
 Biochemical (complement, lysozyme,
interferons)
 cellular components (neutrophils, monocytes,
macrophages).
• Adaptive immune response
a) Humoral immunity - Antibody production –
killing extracellular organisms.
b) Cell mediated immunity – cytotoxic / killer T
cells – killing virus and tumour cells.
Who are involved ?
 Innate
 Complement
 Granulocytes
 Adaptive:
 B and T
lymphocytes
 Monocytes/macroph  B: antibodies
ages
 T : helper,
 NK cells
cytolytic,
suppressor.
 Mast cells
 Basophils
ABNORMAL IMMUNE
RESPONSE
• Hypersensitivity reactions
Type 1 – Anaphylactic shock
Type 2 – mismatched blood transfusion
Type 3 – Serum Sickness, glomerulonephritis
and arthritis.
Type 4 – TB, leishmaniasis.
Autoimmunity
– Autoimmune diseases arise
when the body mounts an immune response
against itself as a result of failure to distinguish
self tissues and cells from foreign antigens.
Rheumatoid Arthritis, S.L.E, Type 1 Diabetes
Mellitus, Multiple Sclerosis etc….
• Immunodeficiency Diseases
a) Congenital – Di George’s syndrome, SCID due
to ADA deficiency.
b) Extrinsic – HIV causing AIDS.
IMMUNOMODULATORS
DEFINITION
Immunomodulators are drugs which
either suppress the immune system –
Immunosuppressants
or
stimulate the immune system –
Immunostimulants
immunosuppressant
Immunosuppressants
 Glucocorticoids - Prednisolone.
 Calcineurin inhibitors
 Cyclosporine
 Tacrolimus
 Antiproliferative / antimetabolic agents
 Sirolimus
 Everolimus
 Azathioprine
 Mycophenolate Mofetil
 Others – methotrexate, cyclophosphamide,
thalidomide and chlorambucil , Interferon
 Antibodies
 Antithymocyte globulin
 Anti CD3 monoclonal antibody
Muromonab
 Anti IL-2 receptor antibody –
 Daclizumab, basiliximab
 Anti TNF alpha – infliximab, etanercept

Immunosuppressants
 Organ transplantation
 Autoimmune diseases
Problem
Life long use
Infection, cancers
Nephrotoxicity
Diabetogenic
Glucocorticoids
 Induce redistribution of lymphocytes –
decrease in peripheral blood lymphocyte
counts
 Intracellular receptors – regulate gene
transcription
 Down regulation of IL-1, IL-6
 Inhibition of T cell proliferation
 Neutrophils, Monocytes display poor
chemotaxis
 Broad anti-inflammatory effects on multiple
components of cellular immunity
USES - Glucocorticoids
 Transplant rejection
 GVH – BM transplantation
 Autoimmune diseases – RA, SLE,
Hematological conditions
 Psoriasis
 Inflammatory Bowel Disease, Eye conditions
Toxicity
 Growth retardation
 Avascular Necrosis of Bone
 Risk of Infection
 Poor wound healing
 Cataract
 Hyperglycemia
 Hypertension
CALCINEURIN INHIBITORS
• Calcineurin (CN)
is a protein phosphatase
activates the T cells of the immune system and
can be blocked by drugs.
Cyclosporine –
 – bind to the cytosolic protein cyclophilin (an
immunophilin) of immunocompetent
lymphocytes, especially T-lymphocytes. This
complex of ciclosporin and cyclophilin inhibits
the phosphatase calcineurin, which under normal
circumstances induces the transcription of
interleukin-2.
 The drug also inhibits lymphokine production
and interleukin release, leading to a reduced
function of effector T-cells.
Uses
 Organ transplantation: Kidney, Liver,
Heart
 Rheumatoid arthritis, IBD, uveitis
 Psoriasis
 Aplastic anemia
 Skin Conditions- Atopic dermatitis,
Alopecia Areata, Pemphigus vulgaris,
Lichen planus, Pyoderma gangrenosum
Toxicity : Cyclosporine
 Renal dysfunction
 Tremor
 Hirsuitism
 Hypertension
 Hyperlipidemia
 Gum hyperplasia
 Hyperuricemia – worsens gout
 Calcineurin inhibitors + Glucocorticoids =
Diabetogenic
Tacrolimus ( FK 506, Prograf )
– It binds to the immunophilin FKBP1A,
followed by the binding of the complex to
calcineurin and the inhibition of its
phosphatase activity. In this way, it prevents
the cell from transitioning from the G0 into G1
phase of the cell cycle. Tacrolimus is more
potent than ciclosporin and has less
pronounced side-effects.
Use
-Prophylaxis of solid-organ allograft rejection
–Topical preparation available for use in atopic
dermatitis and psoriasis.
Toxicity - Tacrolimus
 Nephrotoxicity
 Neurotoxicity-Tremor, headache, motor
disturbances, seizures
 GI Complaints
 Hypertension
 Hyperglycemia
 Risk of tumors, infections
Sirolimus (rapamycin, trade
name Rapamune)
 Contrary to ciclosporin and tacrolimus, drugs
that affect the first phase of T lymphocyte
activation, sirolimus affects the second one(
namely signal transduction and lymphocyte
clonal proliferation).
 It binds to FKBP1A like tacrolimus, however
the complex does not inhibit calcineurin but
another protein, mTOR (mammalian target of
rapamycin ).
 It indirectly inhibits several T lymphocyte-
specific kinases and phosphatases, hence
preventing their transition from G1 to S
phase of the cell cycle.
 Sirolimus prevents B cell differentiation into
plasma cells,
 reducing production of IgM, IgG, and IgA
antibodies.
CELL CYCLE
Sirolimus
Uses
 Prophylaxis of organ transplant rejection
with other drugs
Toxicity
 Increase in serum cholesterol, Triglycerides
 Anemia
 Thrombocytopenia
 Hypokalemia
 Fever
 GI effects
 Risk of infection, tumors
Azathioprine (Imuran )
 the main immunosuppressive cytotoxic
substance. It is nonenzymatically cleaved to
mercaptopurine, that acts as a purine
analogue and an inhibitor of DNA synthesis.
 By preventing the clonal expansion of
lymphocytes in the induction phase of the
immune response, it affects both the cell
and the humoral immunity.
Uses
 Prevention of organ transplant rejection
 Rheumatoid arthritis
Toxicity - Azathioprine
 Bone marrow suppression- leukopenia,
thrombocytopenia, anemia
 Increased susceptibility to infection
 Hepatotoxicity
 Alopecia
 GI toxicity
 Drug interaction: Allopurinol
Mycophenolate Mofetil
 Prodrug  Mycophenolic acid
 Inhibits IMPDH – enzyme in guanine
synthesis (Inosine monophosphate
dehydrogenase (IMPDH) is a major target for both
antitumor and immunosuppresive drug design.)
 T, B cells are highly dependent on this pathway
for cell proliferation
 Selectively inhibits lymphocyte proliferation,
function , Antibody formation, cellular
adhesion, migration
Uses - Mycophenolate Mofetil
 Prophylaxis of transplant rejection
 Combination: Glucocorticoids
Calcineurin Inhibitors
 Toxicity
 GI, Hematological
 Diarrhea, Leucopenia
 Risk of Infection
Drug Interaction
 Decreased absorption when co-
administered with antacids
 Acyclovir, Gancyclovir compete with
mycophenolate for tubular
secretion
Antibodies
 Against lymphocyte
cell-surface antigens
 Polyclonal /
Monoclonal
Antibodies
 Antithymocyte Globulin
 Monoclonal antibodies
 Anti-CD3 Monoclonal antibody (Muromonab-CD3)
 Anti-IL-2 Receptor antibody (Daclizumab,
Basiliximab)
 Campath-1H (Alemtuzumab)
 Anti-TNF Agents
 Infliximab
 Etanercept
 Adalimumab
 LFA-1 Inhibitor (lymphocyte function associated)
 Efalizumab
Anti-thymocyte Globulin
 Purified gamma globulin from serum of
rabbits immunized with human thymocytes
 Cytotoxic to lymphocytes & block
lymphocyte function
Uses
 Induction of immunosuppression –
transplantation
 Treatment of acute transplant rejection
Toxicity
 Hypersensitivity
 Risk of infection, Malignancy
Anti-CD3 Monoclonal Antibody
(Muromonab-CD3 )
 Binds to CD3, a component of T-cell
receptor complex involved in
 antigen recognition
 cell signaling & proliferation
Uses
 Treatment of acute organ transplant
rejection
Toxicity
 “Cytokine release syndrome”
High fever, Chills, Headache, Tremor,
myalgia, arthralgia, weakness
 Prevention: Steroids
Cytokine release syndrome
 is a common immediate complication occurring
with the use of anti-T cell antibody infusions such
as ATG, OKT3
 The pathogenesis is that the antibodies bind to
the T cell receptor, activating the T cells before
they are destroyed. The cytokines released by the
activated T cells produce a type of systemic
inflammatory response similar to that found in
severe infection characterised by hypotension,
pyrexia and rigors.
 the cytokine release syndrome is effectively a type
of non-infective fever.
Anti-IL-2 Receptor Antibodies
(Daclizumab and Basiliximab )
 Bind to IL-2 receptor on surface of activated T
cells  Block IL-2 mediated T-cell activation
Uses
 Prophylaxis of Acute organ rejection
Toxicity
 Anaphylaxis, Opportunistic Infections
Anti-TNF Agents
 TNF – Cytokine at site of
inflammation
 Infliximab
 Etanercept
 Adalimumab
Infliximab
Uses
 Rheumatoid arthritis
 Chron’s disease – fistulae
 Psoriasis
 Psoriatic arthritis
 Ankylosing spondylosis
Toxicity
 Infusion reaction – fever, urticaria,
hypotension, dyspnoea
 Opportunistic infections – TB, RTI, UTI
Etanercept
 Fusion protein produced through
expression of recombinant DNA.
 Ligand binding portion of Human TNF-α
receptor fused to Fc portion of human
IgG1
Uses
 Rheumatoid arthritis
Adalimumab
Recombinant human anti-TNF mAb
Uses :
moderate to severely active crohn’s disease
LFA-1 Inhibitor - Efalizumab
 Monoclonal Ab Targeting Lymphocyte
Function Associated Antigen
 Blocks T-cell Adhesion, Activation,
Trafficking
Uses
 Organ transplantation
 Psoriasis
SUMMARY
Glucocorticoids
– Lympholytic activity, antiinflammatory
property.
• Used as 1st line immunosuppressive therapy
in solid and heamatopoietic stem cell
transplant, ITP, RA etc….
• Sirolimus
– inhibits protein kinase and inhibits T cell
response to IL-2.
– Blocks cell cycle progression
Thalidomide – inhibits angiogenesis, reduces
phagocytosis, enhances cell mediated immunity
– Increases levels of IL-10.
– Used in multiple myeloma, graft versus host
disease, myelodysplastic syndrome, colon
and prostrate Cancer.
• Mycophenolate Mofetil – mycophenolic acid
– Inhibits inosine monophosphate
dehydrogenase which is a key enzyme in
guanine nucleotide synthesis.
– Used in steroid refractory GVHD, RA, SLE.
Leflunomide – it inhibits pyrimidine synthesis.
Used in RA.
• Cyclophosphamide – alkylating agent which
destroys proliferating lymphoid cells. Used in
SLE, autoimmune haemolytic anaemia,
multiple sclerosis, Wegener’s granulomatosis.
• Muromonab CD3 – T cell receptor complex
( blocks Ag recognition ).
– Used in steroid resistant rejection.
• Daclizumab, Basiliximab – IL-2 receptor
(blocks IL-2 mediated T cell activation ).
– Used in acute organ rejection in renal
transplant patients.
Azathioprine ( Mercaptopurine )
– interferes with purine nucleic acid
metabolism and incorporates false
nucleotide.
–Used in Renal allograft, RA, SLE, ITP, Crohn’s
disease, glomerulonephritis
Interferons
- IFN alpha- immune enhancing action melanoma.
– IFN beta - multiple sclerosis
– IFN gamma - chronic granulomatous disease.
Immunostimulants
Immunostimulants
USES:
immunodeficiency disorders
Chronic infections
 cancer
specific Immunostimulants
 Levamisole
 Thalidomide
 BCG
 Recombinant Cytokines
Interferons
Interleukin-2
 Other drugs
– inosiplex, azimexon, imexon, thymosin,
methylinosine monophosphate
 Immunization
Vaccines , Immune Globulin , Rho (D) Immune
Globulin
Levamisole
 Antihelminthic
 Restores depressed immune function of B, T
cells, Monocytes, Macrophages
USES:
 Adjuvant therapy with 5FU in colon cancer
 Used to treat immunodeficiency associated
with Hodgkins disease.
Toxicity
 Agranulocytosis
Thalidomide
 Birth defect
 Contraindicated in women with
childbearing potential
 Enhanced T-cell production of cytokines –
IL-2, IFN-γ
 NK cell-mediated cytotoxicity against tumor
cells
USE:
 Multiple myeloma
Bacillus Calmette-Guerin
 Live, attenuated culture of BCG strain of
Mycobacterium Bovis
 It causes activation of macrophages to make
them more effective killer cells.
 used as intravesical therapy for superficial
bladder cancer.
Adverse Effects
 Hypersensitivity
 Shock
 Chills
Interferons
 Antiviral
 Immunomodulatory activity
 Bind to cell surface receptors – initiate
intracellular events
 Enzyme induction
 Inhibition of cell proliferation
 Enhancement of immune activities
 Increased Phagocytosis
Interferon alfa-2b
 Hairy cell leukemia
 Malignant melanoma
 Kaposi sarcoma
 Hepatitis B
Adverse reactions
 Flu-like symptoms – fever, chills, headache
 CVS- hypotension, Arrhythmia
 CNS- depression, confusion
Interleukin-2 (aldesleukin)
 Proliferation of cellular immunity –
Lymphocytosis, eosinophilia, release of
multiple cytokines – TNF, IL-1, IFN-γ
Uses
 Metastatic renal cell carcinoma
 Melanoma
Toxicity
 Cardiovascular: capillary leak syndrome,
Hypotension
Capillary leak syndrome
 (systemic capillary leak syndrome or Clarkson
syndrome)
 A rare medical condition where the number
and size of the pores in the capillaries are
increased which leads to a leakage of fluid
from the blood to the interstitial fluid,
resulting in dangerously low blood pressure
(hypotension), edema and multiple organ
failure due to limited perfusion.
Immunization
Active – Stimulation with an
Antigen
Passive – Preformed antibody
Active immunization
Vaccines
 Administration of antigen as a whole, killed
organism, or a specific protein or peptide
constituent of an organism
 Booster doses
 Anticancer vaccines:
Vaccinating patients with autologous antigen
presenting cells (APC) expressing tumorassociated antigens (TAA)
Immune Globulin
Indications
 Individual is deficient in antibodies –
immunodeficiency
 Individual is exposed to an agent, inadequate
time for active immunization
 Rabies
 Hepatitis B
Nonspecific immunoglobulins
Antibody-deficiency disorders
Specific immune globulins
High titers of desired antibody
Hepatitis B, Rabies, Tetanus
Rho (D) Immune Globulin
 Antibodies against Rh(D)
antigen on the surface of
RBC
 prevent the immunological
condition known as Rhesus
disease (or hemolytic
disease of newborn).
 treating chronic idiopathic
thrombocytopenic purpura
in Rh-positive patients who
have not been
splenectomized