Immunopharmacology 2003

Immunopharmacology
DR SANJITA DAS
Prof and HOD, Pharmacology
NIET Pharmacy Institute, Greater Noida

Immunopharmacology Drugs
Objectives:
• Know the mechanisms, clinical uses, and adverse effects
associated with:
Cyclosporine
Sirolimus
Prednisone
Cyclophosphamide
Methotrexate
Mycophenolate Mofetil
• Know the mechanism and clinical uses of antibodies as
immunosuppressants

Outline:
I. Purpose of Immunosuppressive Drugs
II. Organ transplant rejection
 Cellular basis for rejection
 Molecular basis for rejection
 Mechanism of action of immunosuppressive
drugs
III. Antibodies as immunosuppressants

I. Purpose of Immunosuppressive Drugs
•Prevention of organ transplant rejection
•Treatment of autoimmune diseases
Multiple Sclerosis
Lupus
Rheumatoid Arthritis
Crohn’s Disease
Type I Diabetes

The dream of transplants
The 3rd Century,
Saints Cosmas and Damian

Relationships between Donor and
Recipient
Syngeneic - between genetically identical individuals, usually the
same individual, identical twins or isogenic strains
Allogeneic - from one individual to another of the same species
Xenogeneic - between individuals of different species.

Immunological Rejection
Major Histocompatibility Complex (MHC) is the major concern.
Rejections:
Antibody mediated
T cells mediated
Hyperacute rejection
e.g., Blood type mismatch
Acute Graft Rejection
Direct recognition of allogenic MHC; rejection about 10 days
Chronic rejection
Take many months to years. Due to failure of immunosuppressants

II. Organ transplant rejection
Cellular basis for rejection:
(Figures modified from Lechler et al., (2005) Nature Medicine, 11, 605-613)
IL2 = T cell growth factor
1.Antigen presenting cell
(APC) activates T Cells
2.T cells produce Interleukin
2 (IL2)
3.IL2 stimulates the
proliferation of T cells and
the production of additional
cytokines that stimulate the
proliferation of multiple
types of immune cells: T
cells, B cells, macrophages,
…
4.Activated immune cells
attack transplanted organ
(allograft)
1.
2.
3.
4.

Molecular basis for rejection
(Steps 1 and 2 - T cell activation and IL2 production):
Calcineurin
NFAT = Nuclear Factor of Activated T cells
IL-2 mRNA
IL-2 Protein:
NFAT PO3
NFAT
Nucleus
IL-1
[Ca2+]

(Step 3 - IL2 stimulation of T cell proliferation):
IL2
Receptor
mTOR
T Cell
T Cell
Cell Proliferation
T Cell
T Cell
Cytokine Production
Activation of multiple types of immune cells

(Steps 1 and 2 - T cell activation and IL2 production):
Calcineurin
NFAT PO3
NFAT
NFAT = Nuclear Factor of Activated T cells
IL-2 mRNA
IL-2 Protein:
Nucleus
IL-1
Tacrolimus(FK506)/FKBP
Cyclosporine/Cyclophilin
TPrednisone
[Ca2+]

(Step 3 - IL2 stimulation of T cell proliferation):
IL2
Receptor
mTOR
T Cell
T Cell
Cell Proliferation
T Cell
T Cell
Cytokine Production
Activation of multiple types of immune cells
T
Anti-IL-2 T
Anti-IL-2
receptor
Sirolimus(rapamycin)/
FKBP
Cyclophosphamide
Methotrexate
Mycophenolate Mofetil

Cyclosporine- Inhibits Calcineurin; Adverse
effects: nephrotoxicity, hepatotoxicity, neurotoxicity
Sirolimus- Inhibits mTOR; Adverse effects:
hyperlipidemia
Prednisone- Inhibits cytokine production;
Adverse effects: Insomnia, hypomania, ulcers
Signaling inhibitors:
Corticosteroid:
Prednisone
Cyclophosphamide
Methotrexate
(IL-2)
(Figure modified from Briffa and Morris, (1997) Eur. Respir. J., 10, 2630-2637)
Summary of Immunosuppressant Drugs:

Cyclophosphamide
Methotrexate
Mycophenolate Mofetil; Adverse effects:
proliferation-associated toxicities (myelosuppression)
Proliferation Inhibitors:
Prednisone
Cyclophosphamide
Methotrexate
(IL-2)
(Figure modified from Briffa and Morris, (1997) Eur. Respir. J., 10, 2630-2637)

Anti-inflammatory and Immunosuppressive Drugs
Nonsteroid anti-inflammatory drugs: Aspirin, Vioxxx (no longer
used), and Celebrex. Work through COX1/2
(cylooxygeneases, which are involved in the
synthesis of prostaglandins)
Antihistamines: Blockers of histamine receptors: Allegra,
Claritin, Clarinex, Benadryl
*Steroid hormones: Glucocorticoid derivatives: prednisone,
dexamethasone, and hydrocortisone
*Lymphocyte specific immunosuppressants: Cyclosoprine, FK506,
rapamycin, FTY720, specific antibodies
and receptors (bioactive).
Cytotoxic agents: cyclophosphamide

Simplified Schematic of an Immune Response
Class I
MHC class II/peptides
APCs
Protein antigens
CD8+ T cells
CD4+ T cells
B cells Plasma cells
CD8+ cytolytic T cells
CD4+ immune cells
(delayed hypersensitivity)
antibody
production
proliferation &
differentiation
Cytokines
Costim. Mol.
IL-4,-5,-6
proliferation &
differentiation
APC
Class II
proliferation &
differentiation

© 2003 by LIPPINCOTT WILLIAMS & WILKINS
Fundamental Immunology
TCR Costimulation

FKBP
Rapamycin
mTor
FK506 Cyclosporine
Cyclophilin
Calcineurin
Cytokine Signaling NFAT Translocation
Genes lead to T cell Activation
Targets of Immunosuppressants

Mechanism of Action of
Helper T-cell blockers
X
X
From Hardman and Limbird, The Pharmacological Basis of Therapeutics

Cyclophilin is a peptidyl-prolyl cis-trans-isomerase which catalyzes the cis-trans
isomerization of proline imidic peptide bonds. Helps protein folding.
FKBPs are also known to participate in many cellular processes such as cell
signaling, protein transport (such as Notch) and transcription.
Immunophilins

Newton, Thorax 2000;55:603-613
Mechanisms of Glucocorticoid Action
1. Inhibit the production of
proinflammatory cytokines
2. Promote the production of
inflammatory cytokines
3. Induce apoptosis in
inflammatory cells
4. Interfere with cytokine signals

Glucocorticoid-sensitive sites of
the immune response
MHC Class I/peptides
APCs
MHC Class II/peptides
APCs
Protein antigen
CD8 T-cell
CD4 T-cell
(helper T-cells)
B-cell Plasma cell
CD8 cytolytic T-cells
CD4 immune cell
(delayed hypersensitivity)
antibody
production
proliferation &
differentiation
proliferation
IL-1
IL-1, -4,-5,-6
proliferation &
differentiation
GC
X
X
GC
X
X

Use of Glucocorticoid as Immunosuppressants
• Most widely used effective anti-inflammatory drugs
• Used with other immunophilin inhibitors to prevent transplant
rejection and GVHD
– natural glucocorticoids not used due to mineralocorticoid activity
• Prednisone and prednisolone are used orally at moderate to high
doses; Very high doses of methylprednisolone used i.v. during acute
organ rejection
• Used before and after anti-thymocyte Abs to inhibit allergic reactions

General Principles of Immunosuppression
• Primary immune responses are more easily
suppressed than secondary (memory)
• Different immunosuppressants have
different effects on different immune
reactions
• Suppression is more likely achieved if
therapy begins before exposure to the
immunogen

Uses of Calcineurin inhibitors
(TCR activation blockers)
• Cyclosporine commonly used with prednisone
and other immunosuppressants to prevent
allograft rejections in renal, hepatic and cardiac
transplants, and in RA and psoriasis
– use is delayed posttransplantation due to
neurotoxicity concerns
• FK506 (Tacrolimus) is approved for
prevention of solid-organ allograft rejection,
and eczema (topical)
– Treatment begins prior to surgery, and is
maintained well afterwards

Glucocorticoid effects related to immunosuppression
• Reduced immune cell content of lymph nodes, spleen and
blood
– lymphopenia, monocytopenia, eosinopenia, but
neutrophilia
• Interference with APC, T-cell and macrophage functions

Sirolimus (Rapamycin, Rapamune):
a new T-cell blocker
• different mechanism of action
– blocks mTOR kinase
• similar poor bioavailability as cyclosporine and tacrolimus, much
longer half-life; 62 h v. 18 and 12 h
• same metabolism (CYP3A) and potential drug interactions
• used for prophylaxis of organ transplant rejection in combination
with a calcineurin inhibitor and glucocorticoids
• toxicities include:
– hyperlipidemia, lymphocoele, anemia, leukopenia,
thrombocytopenia, fever, GI effects, hyper- or
hypokalemia

Toxicity of Glucocorticoids
• Major side effects are common due to high
doses necessary for suppression
– Cushings syndrome
– glucose intolerance
– infections
– bone dissolution
– muscle wasting

Cytotoxic Agents as immunosuppressants
• Antineoplastic drugs will also prevent clonal expansion of T- and
B-cells
– azathioprine (prodrug of nucleotide anti-
metabolite)
– mycophenolate mofetil
• becomes MPA; inhibits IMP dehydrogenase
– cyclophosphamide (DNA alkylating agent)
– methotrexate (inhibits dihydrofolate reductase)

Uses of cytotoxic agents
• Azathioprine; with cyclosporine and/or prednisone for organ
transplant rejection and severe RA
• Mycophenolate mofetil; with cyclosporine and prednisone for
renal transplants
• Cyclophosphamide; for BMT
• Methotrexate; GVHD prophylaxis

Bioactive Immunosuppressants
• Anti-thymocyte antibodies
– 3 types available
• all derived from non-human sources
• Rh(D) immune globulin
• OKT3, OKT4, Anti-CD20, anti-TNF, anti-ICAMs, and
CTLA4-Ig
• Repeated blood transfusion; transfusion of apoptotic cells

III. Antibodies as immunosupressants
Antibody Molecule
Constant Fragment-Fc
Antigen Binding Sites
•Proteins produced by B
cells (plasma cells)
•Function by binding to
antigens and neutralizing
them through several
mechanisms

Clinically Useful Antibodies:
• Muromonab-CD3 (OKT-3)
– Binds CD3 on the surface of T cells and
inhibits T cell function; Used to treat acute
transplant rejection
• Anti-IL-2 receptor antibodies (Daclizumab)
– Blocks IL-2 receptor activation, thus blocking T
cell activation; Used to treat acute transplant
rejection

•Rh(D) immune globulin
Background: Rh(D) negativemother will generate antibodies
to Rh(D) antigen on the erythrocytes of an Rh(D) positive
newborn. The mother will be exposed to the newborn
erythrocytes shortly after giving birth.
If the mother is given Rh(D) immune globulin shortly after
giving birth (within 72 h), it will lyse the erythrocytes from
the baby before the mother generates an immune response.
A subsequent Rh(D) positive baby will be protected from
hemolytic disease.
[Will not work once the mother has developed
Rh(D)antibodies.]

Ideal Immunosuppressant
• Strongly Immunosuppressive
• Specific, No Overall Immunosuppression
• Anti-infection ability
• Low Toxicity for Vital Organs
• Low cost
• Long in vivo bioactivity
• Easy to use

Immunopharmacology 2003

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