Immunopharmacology

Course: Pharmacology & Therapeutics-

IIB
Course Code: PHARM-508
Prepared & Presented by:
Dr. Ishrat Imran
Head, Department of Pharmacology,
FoP, HU
 Immune system
Is responsible to protect the host from harmful
foreign molecules.
Immune System Overview
Two types of Immune Response
◦ Non-specific (Basically just recognizes
foreign vs native)
 Barriers
 Inflammation
 Phagocytes
 All types of White Blood Cells (Leukocytes)
 Dendritic Cells
 Macrophages
 Neutrophils
Immune System Overview
Specific (Adaptive) Response
◦ Lymphocytes (also types of white blood cells)
 B Lymphocytes (B Cells)
 Produced in bone marrow
 Humoral Response
 Before Infection/Infiltration
 T Lymphocytes (T Cells)
 Start in bone marrow, but mature in Thymus
 Cell Mediated Response
 Helper T Cells
 Cytotoxic T Cells
Once activated, T Cells and B Cells
differentiate and divide
◦ Causes cytokine and lymphokine release
B-Cells
Have membrane-bound antibodies on cell
surface
◦ Variable and specific for each B-Cell
Make antibodies
Activation:
◦ Antigen must bind to sites
◦ Stimulation by Helper T-Cells
T-Cells
Helper T Cells
◦ Respond to nearly all antigens,
◦ Produce CD4, which helps bind to class II MHC
complexes on antigen presenting cells
Cytolytic T Cells
◦ Main response towards infected and cancerous cells
◦ Produce CD8 protein, binds transplanted tissue,
infected cells, cancer cells
◦ Secrets proteins that cause cell death
T-Regulatory Cells (Tregs)
◦ Suppress the activation of the immune system to help
maintain homeostasis
Immunomodulators
 Agentsthat modulate the immune system play an
important role in:

1. Preventing the rejection of organ or tissue grafts

2. In the treatment of certain diseases that arise from

dysregulation of the immune response.
 Autoimmune diseases.
 Immunodeficiency diseases.
 Indications

◦ First line therapy for solid organ allografts &

haematopoietic stem cell transplantation.

◦ Autoimmune diseases as refractory rheumatoid

arthritis, systemic lupus erythematosus (SLE),
asthma.

◦ Acute or chronic rejection of solid organ

allografts.
Solid Organ and Bone Marrow
transplantation
• Four types of rejection can occur in a solid organ transplant
recipient: hyper-acute, accelerated, acute, and chronic.

 Transplant of organ introduces foreign tissue to the body

 The body’s immune system sees this foreign tissue, thinks it’s
bad and start producing lymphokines including IL-2

 The lymphokines then activates the immune system even

further, leading to a nasty cycle of foreign tissue destruction
rejection
Transplant Rejection agents complexity
• Many problems exist in currently approved
regimens:
1. Treatments are often very complex.
2. low patient compliance.
3. Therapeutic margins can be very narrow.
4. Pharmacokinetic interaction potential is high
and causes problems.

Unfortunately, these agents also have the potential

to cause disease and to increase the risk of
infection and malignancies.
12
Classification
• Glucocorticoids
•Prednisolone
Anti-metabolites
Calcineurin inhibitors ◦ Azathioprine
◦ Ciclosporin A ◦ Mycophenolates
◦ Tacrolimus ◦ Leflunomide

IL-2 receptor ‘mabs’ m-TOR inhibitors

◦ Basiliximab ◦ Sirolimus
◦ Daclizumab
 Cytokines

Cytokines are soluble, antigen-nonspecific

signaling proteins that bind to cell surface
receptors on a variety of cells. They are important
in modulation of immunity & inflammation.

Cytokines include
◦ Interleukins,
◦ Interferons (IFNs),
◦ Tumor Necrosis Factors (TNFs),
◦ Transforming Growth Factors (TGFs)
◦ Colony-stimulating factors (CSFs).
 Inhibitors of cytokine gene expression

Corticosteroids
◦ Prednisone
◦ Prednisolone
◦ Methylprednisolone
◦ Dexamethasone

They have both anti-inflammatory action

and immunosuppressant effects.
Immunosuppression –
Glucocorticoids
Usually co-administered with other
suppressive agents to treat auto-immune
disorders or treatment of transplant
rejection
Exact mechanism not elucidated
Very broad anti-inflammatory effects
Downregulate IL-1 and IL-6
Cause apoptosis in activated cells
Immunosuppression –
Glucocorticoids
Side Effects
◦ Toxic
◦ Causes increased infection risk
◦ Poor wound healing
◦ Hyperglycemia
◦ Hypertension
Immunosuppression –
Glucocorticoids

Prednisone
Dexamethasone

Cortisol
 Immunosuppression –
Calcineurin Inhibitors
◦ Calcineurin (CaN) is a calcium and calmodulin
dependent serine/threonine protein phosphatase. It
activates the T cells of the immune system (Cell
medixated immunity)
◦ Calcineurin – protein phosphatase that activates T
Cells by dephosphorylating transcription factors,
including NFAT (nuclear factor of activated T cells).
◦ Blocks T Cell proliferation
 Decreased immune response
Immunosuppression –
Calcineurin Inhibitors

Tacrolimus
a.k.a. FK-506
Cyclosporin A
 Immunosuppression –
Anti-proliferative and Anti-Metabolic Drugs

mTOR (mechanistic target of rapamycin)

sometime also called FRAP1, is a kinase.
It is dysregulated in human diseases, such as
diabetes, obesity, depression, and certain cancers
mTOR inhibitors block immune cell proliferation,
reducing the immune response
Immunosuppression –
Anti-proliferative and Anti-Metabolic Drugs

Sirolimus Everolimus
Immunosuppression –
Anti-proliferative and Anti-Metabolic Drugs
◦ Azathioprine
 Purine anti-metabolite

Tioguanine
Azathioprine Mercaptopurine

Guanine
Immunosuppression –
Anti-proliferative and Anti-Metabolic Drugs
◦ Mycophenolate Mofentil
◦ Hydrolyzed to mycophenolic acid
 IMPDH inhibitor (inosine monophosphate
dehydrogenase enzyme
 Important in biosynthesis of guanine
 Good alternative to azathioprine when toxicity is an
issue

Mycophenolic acid
Immunosuppression –
Monoclonal Antibodies
Anti-CD3 Antibodies
Muromonab-CD3
◦ Binds to chain of CD3, which is involved in T-cell
antigen recognition, signaling, and proliferation
◦ Administration of mAb followed by depletion of
T cells from bloodstream and lymphoid organs
◦ Lack of IL-2 production
◦ Reduction of multiple cytokines

Used to treat organ transplant rejection

Immunosuppression –
Monoclonal Antibodies
Anti-IL-2 Receptor [Anti-CD25]
Antibodies
Daclizumab and Basiliximab
Exact mechanism not understood
Binds to IL-2 receptor on surface of
activated T cells
◦ No effect on resting T cells
◦ Stops current response
Immunosuppression –
Monoclonal Antibodies
 Monoclonal antibodies
Basiliximab and Daclizumab
 Obtained by replacing murine amino acid sequences
with human ones.
 Basiliximab is a chimeric human-mouse IgG (25%
murine, 75% human protein).
 Daclizumab is a humanized IgG (90% human
protein).
 Have less antigenicity & longer half lives than murine
antibodies
 Basiliximab is more potent than Daclizumab.
Immunosuppression –
Other Agents
Others include
◦ Alemtuzumab (mAb) – targets CD52, causes
lympholysis by inducing apoptosis of targeted
cells
◦ IL-1 Inhibition
◦ Alefacept – protein, interferes with T-cell
activation
General targets of Immunosuppressants
muromunab
 INTERFERONS

Three families:
Type I IFNs ( IFN-α, β ):
Acid-stable proteins; act on same target cell receptor
Induced by viral infections
Leukocyte produces IFN-α
Fibroblasts & endothelial cells produce IFN-β
Type II IFN (IFN-γ):
Acid-labile;
acts on separate target cell receptors
Produced by Activated T-lymphocytes.
 Interferon Effects

IFN- γ : Immune Enhancing

◦ Increased antigen presentations with macrophage,
natural killer cell, cytotoxic T-lymphocyte
activation
IFN- α, β :
◦ effective in inhibiting cellular proliferation
(more effective than IFN- γ in this regard)
 USES OF INTERFERON

◦ Treatment of certain infections e.g. Hepatitis C

(IFN- α ).
◦ Autoimmune diseases e.g. Rheumatoid arthritis.
◦ Certain forms of cancer e.g. melanoma, renal cell
carcinoma.
◦ Multiple sclerosis (IFN- β): reduced rate of
exacerbation.
◦ Fever, chills, myelosuppression.
 THALIDOMIDE
 A sedative drug.
 Teratogenic (Class-X).
 Can be given orally.
 Has immunomodulatory actions
 Inhibits TNF-α
 Reduces phagocytosis by neutrophils
 Increases IL-10 production
 USES OF THALIDOMIDE

 Myeloma
 Rheumatoid arthritis
 Graft versus host disease.
 Leprosy reactions
 Treatment of skin manifestations of lupus
erythematosus
Immunostimulants
Thalidomide
◦ Teratogenetic
◦ BUT is useful to treat erythema nodosum
leprosum and multiple myeloma

Thalidomide
Immunostimulants
Immunostimulants are applicable during
infections, immunodeficiency, and cancer
Levamisole
◦ Restores depressed immune function of B and
T Cells, monocytes, and macrophages
◦ Causes agranulocytosis
◦ Removed from market in 2005

Levamisole