IMMUNOMODULATORS
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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