Introduction to immunopharmacology, immunomodulators, immunostimulants and Immunosuppressants

1. Introduction to immunopharmacology,
immunomodulators, immunostimulants and
Immunosuppressants
UNIT-1 Chemotherapy and Immunopharmacology (PC- 660)
2 Credits
Priyansha Singh
B. Pharm, M.S. (Pharm.)- Pharmacology & Toxicology

2. Immunopharmacology is the study of the
effects of the drugs modifying immune
mechanism in body.
It is the ability of the living body or the process to fight various
types of microorganisms, toxins or tumour cells that tend to damage
the tissue and organs.
Immune mechanism ?

3. Immunology
And
Immune system

4. • Immunology
• Study of the components and function of the immune system
• Immune System
• Molecules, cells, tissues and organs which provide non-specific and
specific protection against
• Microorganisms
• Microbial toxins
• Tumor cells
• Crucial to human survival
Specificity
Recognition of self
Memory
Salient features

5. Immunity
• First line of defense
• Anatomic barriers (Skin, mucous
membranes)
• Physiological barriers (temperature,
pH)
• Phagocytic Barriers (cells that eat
invaders)
• Inflammatory barriers (redness,
swelling, heat and pain)
• Second line of defense
• Antigen specificity
• Diversity
• Immunological memory
• Self/non-self recognition
Innate (non-specific) immunity Adaptive (specific) immunity
Components of immune system
• Humoral immunity - Antibody
production – killing extracellular
organisms.
• Cell mediated immunity –
cytotoxic / killer T cells – killing
virus and tumour cells.

6. Humoral and cellular immunity

7. Origin of cells of the immune system
Derived from common progenitor
cell in bone marrow
Pluripotent hematopoietic
stem cell
Progenitor Stem Cells
Erythroid lineage
Erythrocytes and
Megakaryocytes
Myeloid lineage
Monocyte/macrophage,
dendritic cells, PMN’s,
mast cells
Lymphoid lineage
Small and large
lymphocytes

8. Cells of innate and adaptive immunity
Myeloid Lineage
•Neutrophil
• Principal phagocytic cell of innate immunity
•Eosinophil
• Principal defender against parasites
•Basophil
• Functions similar to eosinophils and mast cells
• Referred to as
• Polymorphonuclear leukocytes (PMN’s)
• Nuclei are multilobed (2 to 5)
• Granulocytes
• Cytoplasmic granules

9. • Monocytes
• Leukocytes with bean-shaped or
brain-like convoluted nuclei
• Circulate in blood with half life of 8
hours
• Precursors of tissue macrophages
• Macrophages
• Mononuclear phagocytic cells in
tissue
• Derive from blood monocytes
• Participate in innate and adaptive
immunity
Cells of innate and adaptive immunity
Myeloid Lineage

10. •Dendritic cells
• Cells with dendriform (star shaped)
morphology
• Interdigitating reticular cells
(synonym)
• Capture and present antigens to T
lymphocytes
•Mast cells
• Located in mucous membrane and
connective tissue throughout body
• Major effector cell in allergy
• Modulation of initial immune
response
Cells of innate and adaptive immunity
Myeloid Lineage

11. •Large lymphocytes (large granular lymphocytes)
• Natural killer (NK) cells (CD16, CD56)
• Innate immunity to viruses and other intracellular pathogens
• Participate in antibody-dependent cell-mediated cytotoxicity (ADCC)
•Small lymphocytes
• B cells (CD19)
• T cells (CD3, CD4 or CD8)
• Adaptive immunity
Cells of innate and adaptive immunity
Lymphoid Lineage

12. Lymphocytes originate in bone marrow
Lymphoid tissues and organs
• Primary
• Development and maturation of lymphocytes
• Bone Marrow (B cells) and thymus gland (T cells)
• Secondary
• Mature lymphocytes meet pathogens
• Spleen, adenoids, tonsils, appendix, lymph nodes, Peyer’s patches,
mucosa-associated lymphoid tissue (MALT)
Lymphocytes, lymphoid tissues and organs

13. Secondary lymphoid tissues associated
with mucous membranes
Primary portals of entry for pathogens
• Respiratory tract
• Gastrointestinal tract
Secondary lymphoid tissues
• Bronchial-associated lymphoid
tissue (BALT)
• Gut-associated lymphoid tissues
(GALT)
Tonsils, adenoids, appendix,
Peyer’s patches
Pathogens are directly transferred
across mucosa by “M” cells

14. The innate immune response
• Mediated (initiated) by
phagocytes, NK cells and
soluble proteins
• Phagocytes
• Cells specialized in the
process of phagocytosis
• Macrophages
• Reside in tissues and
recruit neutrophils
• Neutrophils
• Enter infected tissues
in large numbers
• Recognize common
molecules of bacterial cell
surface using a few surface
receptors
• Phagocytosis
• Capture, engulfment and
breakdown of bacterial
pathogen

15. • Inflammatory response enhances phagocytosis through acute phase proteins
• Mannose-binding lectin (MBL)
• Binds to bacterial surface with particular spatial arrangement of mannose or fucose
• C-reactive protein (CRP)
• Binds to phosphorylcholine on bacterial surface
• Complement
• Set of proteins which bind to bacterial surface
• Inflammatory response
• Accumulation of fluid and cells at infection site (swelling, redness, heat and pain)
The innate immune response

16. Naturally acquired immunity
Active
• Antigens enter body naturally with response of
Innate and adaptive immune systems
• Provides long term protection
Passive
• Antibodies pass from mother to
Fetus across placenta
Infant in breast milk
• Provides immediate short term protection

17. Active
•Antigens enter body through vaccination with response of
Innate and adaptive immune systems
•Provides long term protection
Passive
•Antibodies from immune individuals injected into body
•Referred to as
Immune serum globulins (ISG)
Immune globulins (IG)
Gamma globulins
•Provides immediate short-term protection
Artificially acquired immunity

18. The adaptive immune response
• Creates millions of different B and T cells for specific antibody-mediated and cell-
mediated immunity
• Antibody-Mediated Immunity (AMI)
• Involves B lymphocytes, plasma cells and antibodies
• Humoral immunity
• Name derives from antibodies found in body fluids (humors - old medical term)
• Cell-Mediated Immunity (CMI)
• Involves T lymphocytes, antigen-presenting cells and MHC (major
histocompatibility complex) molecules
• Cellular immunity

19. Antigens?
 A substance that when introduced into the body, stimulates
the production of an antibody.
 An antigen is an organic compound - protein,
polysaccharide or glycolipid.
 Antigens include:
 Toxins
 Bacteria
 Foreign blood cells
 Microorganisms
 Allergens

20. Antibody?
 They are gamma globulins or immunoglobulin's
produced in the serum on exposure to antigen.
 Chemically they are glycoprotein's containing two
heavy chains and two light chains joined together by
disulfide bonds.
 It has 2 parts
 Fab
 Fc
 There are 5 types of Antibodies: IgG ,IgM , IgA , IgE , IgD

21. Immunopharmacology is the study of the effects of
the drugs modifying immune mechanism in body.
 Hypersensitivity disorders or allergies
 Autoimmunity or autoimmune disorders
 Primary or secondary immunodeficiencies:
These disorders are characterized by immune system not capable of
mounting a normal immune response
 Immunoproliferative disorders:
Malignancies of the immune system (multiple myeloma,
lymphoma, leukemia, etc)
What happens to the immune system?

22.  Allergy is one of the consequences of immunological response involving antigen-antibody
reaction.
 It is the increased reactivity to foreign antigen by the normal immune system. Hence, it is
also called hypersensitivity.
 Two French scientists, Paul Portier and Charles Richet, were the first to recognize and
describe hypersensitivities.
 There are multiple types of hypersensitivity reactions.
 Immediate hypersensitivity reactions result in symptoms that manifest themselves
within very short time periods after the immune stimulus.
 Other types of hypersensitivity reactions take hours or days to manifest themselves, and
are referred to as delayed- type hypersensitivity (DTH) reactions.
Hypersensitivity disorders or allergies
Immediate hypersensitivity reactions result from antibody-antigen
reactions, whereas DTH is caused by T-cell reactions.

23. Hypersensitivity disorders or allergies
P. G. H. Gell and R. R. A. Coombs, proposed a classification scheme to
discriminate among the various types of hypersensitivity.
1-Type I - Immediate
(atopic, or anaphylactic)
2-Type II – Cytotoxic
hypersensitivity
3-Type III - Immune complex
hypersensitivity
4-Type IV – Cell-mediated or
Delayed type hypersensitivity

24. Hypersensitivity disorders or allergies
Type I hypersensitivity reactions are mediated by IgE antibodies and
include many of the most common allergies to respiratory allergens, such
as pollen and dust mites.
Type II hypersensitivity reactions result from the binding of IgG or IgM
to the surface of host cells, which are then destroyed by complement- or
cell-mediated mechanisms.
In type III hypersensitivity reactions, antigen-antibody complexes
deposited on host cells induce complement fixation and an ensuing
inflammatory response.
Type lV hypersensitivity reactions result from inappropriate T-cell
activation.
Humoral
Cell
mediated

25. Type Immune mechanism Typical example
I. Anaphylactic type. Allergen(Ag) cross-links Ab release of vasoactive
amines and other mediators from basophils and
mast cells recruitment of other inflammatory cells.
Anaphylaxis, some forms of bronchial
asthma.
II. Antibody to fixed
tissue antigen.
IgG or IgM binds to Ag on cell surface phagocytosis
of target cell or lysis of target cell by complement
or Ab dependent cell-mediated cytotoxicity(ADCC).
Autoimmune haemolytic anaemia,
transfusion reactions, hemolytic
disease of the newborn
(erythroblastosis foetalis in humans).
III. Immune complex
disease.
Ag-Ab complexes activate complement attract
neutrophils release of lysosomal enzymes, oxygen
free radicals, etc.
Arthus reaction, serum sickness,
certain forms of acute
glomerulonephritis.
IV. Cell-mediated
(delayed)
hypersensitivity.
Sensitized T-lymphocyte release of cytokines and
T-cell-mediated cytotoxicity.
Tuberculin reaction, TB, contact
dermatitis, transplant rejection.
Hypersensitivity disorders or allergies

26.  Auto-immune disorders occur when the immune system can not distinguish between self
antigen and foreign antigen and reacts against self-antigen.
Auto-immune disorders
 By activation of self reactive T & B lymphocytes that produce cell-mediated response
directly against self-antigen and lead to killing of body’s own cells.
 Eg. Rheumatoid arthritis
Myasthenia gravis
Ulcerative anemia etc
 It may be organ specific – autoimmune response directed against particular disease like
thyroid in Hashimoto.s thyroiditis, or nonorgan-specific – against widespread antigens
such as cell nuclear antigens in Lupus.
Mechanism:
 The development of autoimmune disease
depends on a combination of genetic and
environmental factors like hormones,
diet, toxins, drugs and infections.

27. Immunosuppressants
Therapies in immunopharmacology
Immunostimulants or Immunoenhancers
Immunomodulators
 Natural or synthetic substances
that help regulate or
normalize the immune system
 They correct immune systems
out of balance, i.e., strengthen
weak immune systems or
moderate over reactive immune
systems.
 Agents that are envisaged to enhance
body’s resistance against infections
 They enhance the basal levels of immune
response, especially in
immunodeficiency
 Agents that suppress the immune system
 Used for the control of pathological immune
response in autoimmune disease or
hypersensitivity

29. Specific immunostimulants
Immunostimulants
Non-specific immunostimulants
 Provide antigenic specificity in
immune response, such as vaccines
or any antigen.
 They act irrespective of antigenic
specificity to augment immune
response of other antigen or stimulate
components of the immune system
without antigenic specificity, such as
adjuvants
Immunostimulants or Immunoenhancers

30. Immunostimulants or Immunoenhancers
 The agents are:
Cytokines
• Immunoregulatory proteins synthesized within lymphoreticular cells
• Cytokines mediate their effects through receptors on relevant target cells
• They have antiproliferative, antimicrobial, & antitumor effects.
• Most cytokines (TNFα, IFN-ɣ, IL2, granulocyte colony-stimulating factor "G- CSF", &
granulocyte-macrophage colony-stimulating factor "GM-CSF"), have very short serum
t1/2 (minutes).
Interferons (INFs):
Type II IFN, acid-labile protein, includes IFN-ɣ that acts on a separate receptor on target cells
& usually it is product of activated T- lymphocytes.
Proteins having antiviral, immunomodulatory, & antiproliferative activities.
.
Type I IFNs,
acid-stable proteins, include IFN-α & IFN-β that act on the same receptor on target cells &
usually induced by viral infections, with leukocytes producing IFN-α while fibroblasts &
epithelial cells produce IFN-β.

31. Immunostimulants or Immunoenhancers
 IFNs:
 ↑expression of MHC molecules on cell surfaces; where all three types of IFNs induce
MHC class I molecules, only IFN-ɣ induces class II expression.
 In glial cells, IFN-β antagonizes this effect & may ↓antigen presentation within the
nervous system.
 IFN-ɣ: display immune-enhancing properties include ↑antigen presentation & macrophage,
NK cell, & cytotoxic T-lymphocyte activation
 IFN-α & IFN-β (more potent than IFN-ɣ), inhibit cell proliferation.
Interferons (INFs):
Cytokines
Mechanisms of actions
 IFN-α approved for several neoplasms include, hairy cell leukemia, chronic myelogenous leukemia,
malignant melanoma, & Kaposi's sarcoma. Also for hepatitis B & C infections, & shown anticancer
activity in renal cell carcinoma, carcinoid syndrome, & T- cell leukemia.
 IFN-β approved for relapsing-type multiple sclerosis.
 IFN-ɣ approved for treatment of chronic granulomatous disease.
Uses:

32. Immunostimulants or Immunoenhancers
 Cytokines
T-cell growth factor or IL2
MOA:
 Binds to IL2 receptor on surface of responsive cell inducing proliferation of T- cytotoxic cell
& B –cell
 Stimulate macrophage activity, & increase toxicity of NK –cells.
Uses:
 Used for metastatic melanoma & renal cell carcinoma
Colony stimulating factors - Granulocyte-macrophage colony-stimulating factor
"GM-CSF"
 Recombinant Cytokines
 Recombinant IL2, which promotes
production of cytotoxic T –cells &
activates NK –cells.
 Used in renal cell carcinoma &
lymphoma.
 Recombinant IL1 receptor antagonist that
prevents IL1 from binding to its receptor,
stemming the cascade of cytokines released if IL1
were to bind to the IL1-Rc.
 Approved for RA in adult pt who have failed
treatment with DMARDs (disease- modifying anti-
rheumatic drugs).
Aldesleukin
Used to rescue BM graft failure & to help graft recovery after autologous BM transplant.
In prophylaxis of cancer chemotherapy induced neutropenia.
Anakinra

33. Immunostimulants or Immunoenhancers
 Bacillus Calmette-Guerin (BCG) vaccine
• Available as attenuated strain of Mycobacterium bovis , the active
component is muramyl dipeptide.
• It is not only used for tuberculosis but also in leukaemia
• Stimulates macrophages and this macrophages produce cytotoxicity
against neoplastic cells and also increase phagocytic activity
 Lipopolysaccharides:
• This agents increase antibody production and produce the characteristic
biological activities of endotoxin from gram-positive bacteria
 Anthelminthes: Levamisole
• It increases the breakdown of c-AMP and decreases the breakdown of c-
GMP so produce the cytotoxicity and phagocytosis
 Thalidomide
 Isoprinosine
 Immunocynin

34.  Immunophilin ligands: (selective inhibitors of
cytokine production & function)
e.g. Cyclosporine, Tacrolimus, & Sirolimus
 Cytotoxic agents: (immunosuppressant
antimetabolites & alkylating agents)
e.g. Methotrexate "MTX", Azathioprine "AZT",
Mycophenolate mofetil, Leflunomide, Cyclophosphamide.
Also others like hydroxychloroquine, Cytarabine,
Pentostatin, Vincristine, & Vinblastine
 Corticosteroids:
e.g. Prednisone & its derivatives
 Immunosuppressive antibodies:
• Immunoglubin based:
e.g. Anti-lymphocyte & anti-thymocyte antibodies
• Immunosuppressive mAbs:
e.g. anti-TNFα (adalimumab, etanrecept, infliximab),
IL2-Rc antagonists (daclizumab, basiliximab), IL6-Rc
antagonist (tocilizumab "atlizumab"), & CD-
antagonists (alefacept, muromonab, efalizumab,
abatacept)
Immunosuppressants
MOA: Inhibit antigen stimulated activation and
proliferation of a helper T cells as well as expression
of IL-2 and other cytokines by them.
MOA: Cytotoxic drugs block proliferation and
differentiation of T and B cells.
MOA: Inhibit MHC expression and IL-I. IL –II. IL-6
production so that Helper T cells are not activated.
MOA: They specifically bind to helper T cells and
prevent their response and deplete them.

35.  Organ transplantation (suppress rejection of transplanted
organ or tissue)
e.g. kidney, heart, liver, & bone marrow
 Autoimmune diseases
e.g. Idiopathic thrombocytopenic purpura, autoimmune
hemolytic anemia, acute glomerulonephritis, hemolytic
disease of newborn (erythroblastosis fetalis), & RA
 Prevention of cell proliferation
e.g. Coronary stents
Immunosuppressants
Clinical uses of immunosuppressive agents:

36. COVID-19 – The actual fate
Viral infection &
replication
Host inflammatory response
 Cytokine storm
 Viral evasion of cellular immune responses
SARS-CoV-2
infection
What we know?
What we do not know?
What we should know?
How to predict Covid progression & severity?
Systemic pro- inflammatory cytokines – IL-6 (<7.0 pg/ml)
Biomarkers – Ferritin (13-150 ng/ml)
Degree of D-dimer causes venous thromboembolism (<0.50
mg/ml FEU)
C-reactive protein (CRP) (<0.50 mg/dL)
Lactate dehydrogenase (LDH) (135-214 U/L)
Chance
Of
survival?
Rapid deterioration & worsening respiratory
symptoms requiring hospital admission
predictors

37. Anti-cytokines: Interleukin (IL)-1
IL-6 receptor antagonists (e.g. anakinra, tocilizumab, sarilumab,
siltuximab)
Janus kinase (JAK) inhibitors (e.g. baricitinib, ruxolitinib)
Anti-tumor necrosis factor-α (e.g. adalimumab, infliximab)
Granulocyte-macrophage colony-stimulating factors (e.g. gimsilumab,
lenzilumab, namilumab)
Human immunoglobulin
Corticosteroids (e.g. dexamethasone)
Interferons
Statins
Angiotensin pathway modulators, macrolides (e.g. azithromycin, clarithromycin)
Hydroxychloroquine and chloroquine, Colchicine
Prostaglandin D2 modulators (e.g. ramatroban)
Non-specific immune modulators
Specific immune modulators
 To treat the cytokine storm and inhibit cytokines – immunomodulators are used.
COVID-19 – The actual fate
Management and treatment of Covid is still a research with promising to negative
trials or recovery trials.
Not routinely
recommended

38.  Uncontrolled diabetes
mellitus
 Immunosuppression
by steroids
 Prolonged ICU stay
 Co-morbidities – post
transplant/malignancy
Covid-19 and Mucormycosis
What predisposes the Covid-19 patients to the deadly black fungal infection?

39.  Utilizes body’s own immune
system to fight disease
 Drugs act on immune system so
they don’t harm any other organ or
cellular tissue
 Less potential treatment but has
very less side effects
 It prolongs the life span
 Kills Cancer cells directly
 Damages surrounding tissues
 More potential treatment but has
more side effects
 Quicker results as compared to
immunotherapy
Therapeutic Advances
Immunotherapy vs Chemotherapy
Immunotherapy
Chemotherapy

40. Recent technologies
 For melanoma
 T cells are removed from a
patient, genetically modified
or treated with chemicals to
enhance their activity or
numbers, and then re-
introduced into the patient
with the goal of improving the
immune system’s anti-cancer
response.
 Designed to elicit an immune
response against tumor-
specific or tumor-associated
antigens, encouraging the
immune system to attack
cancer cells bearing these
antigens.
 For melanoma
 Combination of Hyper
Acute-Melanoma vaccine
(dorgenmeltucel-L) and
ipilimumab in patients
Adoptive T Cell Therapy Therapeutic cancer vaccines Checkpoint inhibitors