Immunity is the ability of the body to defend itself against disease-causing organisms. The immune system refers to a collection of cells, chemicals and processes that function to protect the body from foreign antigens, such as microbes (organisms, such as bacteria, fungi, and parasites), viruses, cancer cells, and toxins. The structural and chemical barriers which protect us from infection, the immune system can be classified into two “lines of defense”: innate immunity and adaptive immunity

1. IMMUNOSTIMULANTS AND
IMMUNOSUPPRESANTS
1
Deepanjali Sharma
M.Pharm (Pharmacology)

2. Immunity
• Immunity is the ability of the body to defend itself against disease-causing
organisms.
• The immune system refers to a collection of cells, chemicals and processes
that function to protect the body from foreign antigens, such as microbes
(organisms, such as bacteria, fungi, and parasites), viruses, cancer cells, and
toxins.
• The structural and chemical barriers which protect us from infection, the
immune system can be classified into two “lines of defense”: innate
immunity and adaptive immunity
3

3. 4

4. Immunity
Innate
immune
response
Anatomic
responses
Physiologic
responses
Cellular
responses
Adaptive
immune
responses
Humoral
immunity
Cell-
Mediated
immunity
5

5. 6

6. Innate immunity
• Also known as Native immunity
• The first line of defense to an intruding pathogen.
• It is an antigen-independent (nonspecific) defense mechanism that is used
by the host immediately or within hours of encountering an antigen.
• It has no immunologic memory and, therefore, it is unable to recognize or
“memorize” the same pathogen should the body be exposed to it in the future
7

7. 8

8. • An important function is the rapid recruitment of immune cells to sites of infection and
inflammation through the production of cytokines
• Cytokine production during innate immunity mobilizes many defense mechanisms throughout
the body while also activating local cellular responses to infection or injury.
• Innate immunity can be viewed as comprising three types of defensive barriers:
 Anatomic (skin and mucous membrane),
 Physiologic (temperature, low pH and chemical mediators),
 Cellular responses.
9

9. 10

10. 11

11. Pathogen Recognition
• Through the recognition and binding of some common molecules on the surface of
pathogens, apoptotic host cells, and damaged cells, pattern recognition receptors (PRRs)
induce immuno-protective effects, such as antiinfection and antitumor effects, and participate
in the initiation and effect process of specific immune response
• PRRs serve to identify pathogen-associated molecular patterns (PAMPs) and danger-
associated molecular patterns (DAMPs)
• Some unique and conserved components of pathogenic microorganisms can induce the
second signal required to activate T cells, so as to control the adaptive immunity from being
activated under normal conditions
• Innate immunity recognizes pathogenic microorganisms and assists in the activation and
expression of second signals that activate the adaptive immunity
• Through the recognition and binding of ligands, PRRs can produce nonspecific anti-infection,
antitumor, and other immuno-protective effects.
12

12. 1

13. • Most PRRs in the innate immune system of vertebrates can be
classified into the following five types based on protein domain
homology:
 Toll-like receptors (TLRs),
 Nucleotide oligomerization domain (NOD)-like receptors (NLRs),
 Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs),
 C-type lectin receptors (CLRs)
14

14. Toll-Like Receptors(TLRs)
• Class of proteins that play a key role in the innate immune system and received their name from
their similarity to the protein encoded by the toll gene in Drosophila
• TLRs are a family of receptors with conserved architecture consisting of leucine-rich repeat-
(LRR-) containing ectodomains and intracellular Toll-interleukin-1 receptor (TIR) signaling
domains.
• The TLRs include TLR1–TLR10 and TLR11–TLR13, the latter three are not found in humans.
• TLRs are able to recognize a variety of PAMPs including lipoproteins and di- and triacyl
lipopeptides (TLR2/1 and TLR2/6), peptidoglycan, lipoteichoic acid, fungal zymosan (TLR2),
double-stranded RNA (TLR3), flagellin (TLR5), unmethylated CpG DNA (TLR9), and a variety of
synthetic molecules such as imidazoquinolines and guanosine analogues (TLR8)
• These molecules are recognized by individual TLRs in combination with coreceptors, or by TLR
heterodimers
• TLR2 is involved in the recognition and development of immunological responses against Gram-
positive bacteria
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15. 16

16. 17
Leucine-rich repeat- (LRR-)
Toll-interleukin-1 receptor (TIR)

17. Pathogen derived molecular pattern
Bound to
TLRs
Myeloid Differentiation factor 88 (MyD88)
Activation of kinases (E.g. IRAK, TRAF6)
Activation of NF-kB
Transcription
18

18. • All TLRs contain an extracellular leucine-rich repeat (LRR) domain that is responsible
for ligand binding.
• The LRR domain is connected to a transmembrane domain and an intracellular
Toll/IL-1 receptor (TIR) domain that is responsible for signal transduction. When bound to
a ligand, TLRs form homodimers or heterodimers and initiate signaling path-ways
• TLR signaling is initiated when the cytoplasmic TIR domain interacts with adaptor
molecules such as Myeloid Differentiation factor 88(MyD88)
• MyD88 is the adaptor molecule that is used by all TLRs except TLR3.
• The binding of MyD88 to TLRs leads to the activation of IL-1 receptor-associated kinases by
MyD88 which causes downstream activation of a complex containing TNF receptor-associated
factor (TRAF)6 and transforming growth factor (TGF)-activated kinase 1-binding protein 2
• TAK-1 then serves as a branch point, leading to the activation of both NF-B and MAPK signaling
pathways
19

19. C-Type Lectin Receptors(CLRs)
• CLRs possess a transmembrane PRR with a carbohydrate-binding domain.
CLRs recognize carbohydrates on pathogens and are mainly expressed by
monocytes, macrophages, and DCs
• Pathogen recognition by CLRs leads to pathogen internalization and
degradation and subsequent antigen presentation.
• CLRs recognize mannose, fucose, and glucan carbohydrate structures
present in bacterial, viral, and fungal components
• Mincle, a C-type lectin, detects infection by fungi; and it is sensed on both
monocytes and neutrophils as well as on macrophages differentiated in vitro
20

20. 21
CARD9 Caspase Recruitment Domain 9 NFK-B Nuclear factor kappa B

21. Nucleotide-binding Oligomerization Domain
(NOD) receptors
• NOD receptors are intracellular sensors of PAMPs that enter the cell via
phagocytosis or pores and of danger-associated molecular patterns (DAMPs) that
are associated with cell stress
• They are found in lymphocytes, macrophages, and DCs and also in
nonimmune cells, for example, in epithelia
• NLRs (NOD Like Receptors) constitute a large family of intracellular PRRs,
several of which—such as NOD1, NOD2, and NALP3
• NOD1 and NOD2 recognize peptidoglycan components common to both
Gram-positive and Gram-negative bacteria. Both proteins drive activation of
MAPK and NF-𝜅B pathways, leading to proinflammatory cytokine production
• NOD1 and NOD2 recognize intracellular bacterial cell products, but NALP3
responds to multiple stimuli to form a multiprotein complex termed the NALP3
inflammasome

22. Adaptive Immunity
• It is antigen-dependent and antigen-specific
• Critical when innate immunity is ineffective in eliminating
infectious agents
• Involves a lag time between exposure to the antigen and
maximal response
• Has the capacity for memory which enables the host to mount a
more rapid and efficient immune response upon subsequent
exposure to the antigen
• The primary functions of the adaptive immune response are: the
recognition of specific “nonself” antigens, distinguishing them
from “self” antigens
• The adaptive immune system includes of two main types of
lymphocytes: T and B cells.
23

23. • The cells of the adaptive immune system include:
 Antigen-specific T cells, which are activated to proliferate through the action of APCs
 B cells which differentiate into plasma cells to produce antibodies
• T cells develop in the thymus, and B cells, in mammals, develop in the bone marrow in adults
or the liver in fetuses.
• The activated T cells react directly against a foreign antigen that is presented to them on the
surface of a host cell
• T cell also produces signal molecules (e.g. cytokines) that activate macrophages to destroy the
invading microbes that they have phagocytosed.
• In antibody responses, B cells secrete antibodies, which are proteins called immunoglobulins
which circulate in the bloodstream and permeate the other body fluids, where they bind
specifically to the foreign antigen that stimulated their production.
24

24. T-cells
• T cell precursors, known as prothymocytes, migrate from the
bone marrow to the thymus
• Prothymocytes entering at the cortical region, now properly
called thymocytes, lack TCRs, CD3, CD4, and CDS surface
molecules
• The thymocytes, undergo a series of maturation steps that
can be identified based on the expression of different cell
surface markers
• T-Cells bind to the antigen on the surface of antigen-presenting
cells (APCs). 25

25. Types of T-cells
• T helper cells (TH cells)
• T helper cells (TH cells) assist other lymphocytes, including maturation of B
cells into plasma cells and memory B cells, and activation of cytotoxic T
cells and macrophages
• These cells are also known as CD4+ T cells as they express
the CD4 glycoprotein on their surfaces
• Cytotoxic CD8+ T cells
• Cytotoxic T cells (TC cells, CTLs, T-killer cells, killer T cells) destroy virus-
infected cells and tumor cells and are also implicated in transplant rejection.
• These cells are defined by the expression of the CD8 protein on their cell
surface.
26

26. • Regulatory CD4+ T cells
• Regulatory T cells are crucial for the maintenance of immunological tolerance.
• Their major role is to shut down T cell–mediated immunity toward the end of an
immune reaction and to suppress autoreactive T cells that escaped the process of
negative selection in the thymus
• Natural killer T (NKT) cells
• Natural killer T cells bridge the adaptive immune system with the innate immune
system.
• NKT cells recognize glycolipid antigens presented.
• Once activated, these cells can perform functions ascribed to both helper and
cytotoxic T cells: cytokine production and release of cytolytic/cell killing molecules
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27. 28
Memory T Cells
• Some types of T lymphocytes are present even after removing
a pathogen.
• These long-living lymphocytes are memory T cells and are
highly capable of responding to antigens upon reintroduction.

28. B cells
• B cells, also known as B lymphocytes, are a type of white blood cell of
the lymphocyte subtype
• B cells produce antibody molecules which may be either secreted or
inserted into the plasma membrane where they serve as a part of B-
cell receptors
• B cells develop from hematopoietic stem cells (HSCs) that originate
from bone marrow
29

29. Types of B-cell
• Transitional B Cells
• A transitional B cell is the link between immature and mature B cells.
• They cannot perform any actions to help fend off harmful pathogens, they do
travel between the bone marrow and secondary lymphoid tissues.
• Naïve B Cells
• After the B lymphocyte matures, whether in the bone marrow or secondary
lymphoid organs, it will remain a naïve blood cell until it is activated.
• Activation occurs when a mature B cell is exposed to the antigen-presenting cells
specific to its B cell receptor.
• Upon activation, a naïve B cell can become a plasma B cell or a memory B cell.
30

30. • Memory B Cells
• Necessary for building long-term immunities within the body
• These cells remain in the bloodstream after an infection subsides. If the
host is re-exposed to that same antigen in the future, memory B cells can
quickly activate with the help of T cells.
• Plasma B Cells
• Plasma B cells, also called effector B cells, are large cells with a very
large endoplasmic reticulum (ER).
• The ER is responsible for helping to synthesize and transport proteins.
This composition allows plasma cells to produce large quantities of
antigen-specific antibodies.
31

31. B-cell Receptors and T-Cell Receptors
• The BCRs and TCRs are structurally related molecules
• The BCR, also called immunoglobulin, is composed of two identical heavy
chains and two identical light chains.
• The TCR is composed of an α chain (TCRα) and a β chain (TCRβ), both
anchored in the T-cell membrane by a transmembrane region.
• The α and β chains consist of a variable region that contains the antigen-
binding site and a constant region.
• In contrast to immunoglobulins, TCRs remain membrane bound and are not
secreted
33

32. T-cell receptor (TCR)
• It is a protein complex found
on the surface of T cells,
that is responsible for
recognizing fragments
of antigen as peptides bound
to major histocompatibility
complex (MHC) molecules.
• TCR is a heterodimer
consisting of the alpha and
beta chain, a variable region,
a constant region, a
transmembrane region and a
short cytoplasmic region
34

33. Immunoglobulins
• Immunoglobulins are glycoprotein molecules produced by plasma cells.
• They act as a critical part of the immune response by specifically recognizing and
binding to particular antigens, such as bacteria or viruses, and aiding in their destruction
• The soluble forms of immunoglobulins are called antibodies.
• Antibody (or immunoglobulin) molecules are glycoproteins composed of one or more
units, each containing four polypeptide chains:
 two identical heavy chains (H)
 two identical light chains (L)
• The amino terminal ends of the polypeptide chains show considerable variation in amino
acid composition and are referred to as the variable (V) regions to distinguish them
from the relatively constant (C) regions.
• Each L chain consists of one variable domain, VL, and one constant domain, CL
35

34. 36

35. Classes of immunoglobulins
• The five primary classes of immunoglobulins are IgG, IgM, IgA, IgD and IgE.
• These are distinguished by the type of heavy chain found in the molecule.
• IgG molecules have heavy chains known as gamma-chains; IgMs have mu-chains; IgAs have alpha-
chains; IgEs have epsilon-chains; and IgDs have delta-chains.
• IgG class
• Molecular weight: 150,000
• H-chain type (MW): gamma (53,000)
• Serum concentration: 10 to 16 mg/mL
• Percent of total immunoglobulin: 75%
• Glycosylation (by weight): 3%
• Distribution: intra- and extravascular
• Function: secondary response
37

36. • IgM class
• Molecular weight: 900,000
• H-chain type (MW): mu (65,000)
• Serum concentration: 0.5 to 2 mg/mL
• Percent of total immunoglobulin: 10%
• Glycosylation (by weight): 12%
• Distribution: mostly intravascular
• Function: primary response
• IgA class
• Molecular weight: 320,000 (secretory)
• H-chain type (MW): alpha (55,000)
• Serum concentration: 1 to 4 mg/mL
• Percent of total immunoglobulin: 15%
• Glycosylation (by weight): 10%
• Distribution: intravascular and secretions
• Function: protect mucus membranes
38

37. • Properties of IgD:
• Molecular weight: 180,000
• H-chain type (MW): delta (70,000)
• Serum concentration: 0 to 0.4 mg/mL
• Percent of total immunoglobulin: 0.2%
• Glycosylation (by weight): 13%
• Distribution: lymphocyte surface
• Function: unknown
• Properties of IgE:
• Molecular weight: 200,000
• H-chain type (MW): epsilon (73,000)
• Serum concentration: 10 to 400 ng/mL
• Percent of total immunoglobulin: 0.002%
• Glycosylation (by weight): 12%
• Distribution: basophils and mast cells in saliva and nasal secretions
• Function: protect against parasites
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38. 40

39. Activation of T-cell and B-cell
• Dendritic cells provide an essential link between innate and adaptive immunity.
• DCs engulf pathogens at the site of infection and travel to the lymphoid organs.
• They then activate T cells by presenting them with fragments of the engulfed pathogen loaded on MHC molecules
Antigen Processing and Presentation
• There are two types of MHC molecules involved in antigen presentation: MHC class I and MHC class II.
• MHC class I molecules
• MHC class I molecules consist of a transmembrane glycoprotein α chain noncovalently associated with a β2m
molecule.
• They present peptides from endogenous antigens to CD8 TC cells
• MHC class II molecules
• MHC class II molecules consist of two noncovalently associated transmembrane glycoproteins, an α chain and
a β chain.
• They present peptides from exogenous antigens to CD4 TH cells. 41

40. 42
ENDOGENEOUS PATHWAY EXOGENEOUS PATHWAY

41. • Endogenous antigens, those derived from intracellular pathogens, are processed by
the cytosolic pathway for presentation by MHC class I molecules.
• Proteins in the cytosol are degraded into peptides by the proteosome. The resultant peptides
are then transported out of the cytosol and into the ER by a protein called the TAP, which is
embedded in the ER membrane.
• Once newly synthesized MHC class I molecules are translocated into the ER membrane, the
molecules associate and bind peptide, forming a peptide-MHC complex. These peptide-MHC
complexes make their way to the plasma membrane in membrane-enclosed vesicles of the Golgi
apparatus.
• Exogenous antigens, those derived from extracellular pathogens, are processed by the
endocytic pathway for presentation by MHC class II molecules.
• In this pathway, extracellular pathogens are internalized by host cells through endocytosis or
phagocytosis and are degraded by proteolytic enzymes within endocytic vesicles. Newly
synthesized MHC class II are translocated into the ER membrane
• Once in the endocytic vesicles, MHC class II molecules bind peptide and are carried to the cell
surface by outgoing vesicles
43

42. T-cell and B-cell activation
44
• Extracellular antigens are displayed
(presented) by MHC class II molecules
by APC and forms a weak bond that is
stabilized by the noncovalent
interaction of the T cell's CD4
molecule with the non peptide-binding
portion of MHC class I I .
• Once T-cell is activated, it further
activates the B-cell

43. Humoral immunity
• It is mediated by molecules in the blood and mucosal secretions called antibodies. The antibodies
are secreted by a subset of lymphocytes known as B cells.
The antibodies recognize microbial antigens,
Combine specifically with the antigens,
Neutralize the infectivity of microbes, and target microbes
Elimination by various effector mechanisms.
45

44. Cell-mediated immunity
• It is mediated by both activated TH cells and cytotoxic T lymphocytes/ cells (CTLs) .
Cytokines secreted by TH cells activate various phagocytic cells,
Enabling them to phagocytose and kill microorganisms.
This type of cell-mediated immune response is especially important against
a host of bacterial and protozoal pathogens.
• CTLs play an important role in killing virus-infected cells and tumor cells. They act by killing
altered self-cells.
46

45. 47
B Cells T Cells
Origin Bone marrow Thymus
Often called B lymphocytes T lymphocytes
Position Outside lymph node Inside lymph node
Surface antibodies Present Absent
Connect
They connect to the surface of
invading bacteria and virus
They connect only to the antigen on the
outside
Membrane receptor for antigen B Cell Receptor T Cell Receptor
Life Span Short Long
Secrete Antibodies Lymphokines

46. 48

47. Immunosuppressants
51

48. Immunosuppressants
• Immunosuppressive drugs are used to dampen the immune response in organ transplantation and
autoimmune disease.
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49. 53

50. 54

51. 55

52. Calcineurin (CaN)
• It is a calcium and calmodulin dependent serine/threonine protein
phosphatase (also known as protein phosphatase 3, and calcium-
dependent serine-threonine phosphatase)
• It activates the T cells of the immune system and can be blocked by
drugs
• Calcineurin activates Nuclear Factor of Activated T-cell cytoplasmic
(NFATc), a transcription factor, by dephosphorylating it.
• The activated NFATc is then translocated into the nucleus, where it
upregulates the expression of interleukin 2 (IL-2), which, in turn,
stimulates the growth and differentiation of the T cell response.
56

53. Cyclosporine
• Prophylaxis of organ rejection
in kidney, liver, and heart
allogeneic transplants; has
been used in combination with
azathioprine and
corticosteroids
• The mechanism by which
cyclosporin selectively
inhibiting calcineurin
• AE=Nephrotoxic, Neurotoxic
58

54. Components of the
immune response
affected by cyclosporin
Ag = antigen; BCDF = B cell differentiation
factor; GM-CSF = granulocyte-macrophage
colony-stimulating factor; IFN-γ = interferon-
gamma;
59

55. CORTICOSTEROIDS
• The corticosteroids were the first pharmacologic agents to be used as
immunosuppressives, both in transplantation and in various autoimmune
disorders
• Diminish the responsiveness of both B and T cells.
• The most common agents are prednisone, methylprednisolone and
prednisolone
• The use of these agents is associated with numerous adverse effects. For
example, they are diabetogenic and can cause hypercholesterolemia,
cataracts, osteoporosis, and hypertension with prolonged use
• The exact mechanism responsible for the immunosuppressive action of the
corticosteroids is unclear but it is suggested that they reduce the activation
of NF-κB, suppress formation of pro-inflammatory cytokines such as IL-1 and
IL-6, inhibit T cells from making IL-2 and proliferating, and inhibit the
activation of Cytotoxic T- lymphocytes
60

56. • On entering cells, they bind to the glucocorticoid receptor. The
complex passes into the nucleus and regulates the transcription of
DNA
• The inactive GR is complexed with other proteins, including
heat-shock protein (HSP) 90,70.
• Steroid binding results in receptor activation and translocation
to the nucleus
• There, it interacts with specific DNA sequences within the
regulatory regions of affected genes
• The short DNA sequences that are recognized by the activated
GR are called glucocorticoid responsive elements (GREs) and
provide specificity to the induction of gene transcription by
glucocorticoids.
61
S- Cortisol
GR- glucocorticoid Receptor
CBG- corticosteroid-binding globulin
HSP90- the 90-kd heat-shock protein;
HSP70, the 70-kd heat
shock protein;
IP- the 56-kd immunophilin;
GRE- glucocorticoid response elements

57. PROLIFERATION SIGNAL INHIBITORS (PSIs)
(mTOR inhibitors )
• A newer class of immunosuppressive agents called proliferation signal
inhibitors includes sirolimus (rapamycin) and its derivative everolimus.
• PSIs bind the circulating immunophilin FK506-binding protein 12, resulting
in an active complex that blocks the molecular target of rapamycin (mTOR).
• The mTOR is a key component of a complex intracellular signaling pathway
involved in cellular processes such as cell growth and proliferation,
angiogenesis, and metabolism
• mTOR regulates cellular metabolism, growth, and proliferation by forming
and signaling through two protein complexes, mTORC1 and mTORC2
63

58. • Activated mTORC1 acts on a broad range of downstream substrates
• One mechanism by which mTORC1 induces protein synthesis is through
inhibition of the eukaryotic initiation factor 4E binding protein 1 (4E-
BP1), which itself acts as a translation inhibitor .
• Another major downstream target of mTORC1 is the p70 ribosomal S6
kinase (S6K),when activated, S6K upregulates protein translation and
elongation, mRNA synthesis, and ribosome biogenesis
• Early studies demonstrated that mTORC2 was activated by insulin via the
PI3K pathway but signaling steps beyond PI3K are distinct from mTORC1
activation and have mostly remained unclear.
64

59. • Sirolimus is available only as an oral drug. Its half-life is
about 60 hours, while that of everolimus is about 43 hours.
• Toxicities of the PSIs can include profound
myelosuppression (especially thrombocytopenia),
hepatotoxicity, diarrhea, hypertriglyceridemia,
pneumonitis, and headache.
• The nephrotoxicity of mTOR inhibitors is less than
calcineurin inhibitors
65

60. ANTIMETABOLITES
• Azathioprine
 Azathioprine is a prodrug that is converted first to 6-mercaptopurine (6-MP)
 Azathioprine inhibits DNA and RNA synthesis by preventing interconversion
among the precursors of purine synthesis and suppressing purine synthesis.
 Because of their rapid proliferation in the immune response and their dependence
on the synthesis of purines required for cell division, lymphocytes are
predominantly affected by the cytotoxic effects of azathioprine
 Concomitant use with angiotensin-converting enzyme inhibitors or cotrimoxazole in
renal transplant patients can lead to an exaggerated leukopenic response.
66

61. • Mycophenolate mofetil
 Replaced azathioprine because of its safety and efficacy
 It has been successfully used in heart, kidney, and liver transplants.
 As an ester, it is rapidly hydrolyzed in the GI tract to mycophenolic
acid, which is a potent, reversible, noncompetitive inhibitor of
inosine monophosphate dehydrogenase (IMPDH), which blocks the
de novo formation of guanosine phosphate
 Thus, like 6-MP, it deprives the rapidly proliferating T and B cells
of a key component of nucleic acids
67

62. METHOTREXATE
 Methotrexate was employed in the treatment of
RA as early as 1951, but its popularity with
regard to RA did not come until the 1980s
 As an analogue of folic acid, methotrexate is
an inhibitor of purine and pyrimidine
synthesis and thereby suppresses cellular
proliferation
 Decreases in purine and pyrimidine
concentrations in the serum have been observed
following a single dose of methotrexate, along
with decreased proliferation of antigen
stimulated lymphocytes.
68

63. IL-2 receptor antagonist
• The CD-25 acts as a high affinity receptor for IL-2 through which
cell proliferation and differentiation are promoted.
• The CD-25 molecule is expressed on the surface of
immunologically activated, but not resting T-cells.
• Daclizumab
 It is a highly humanized chimeric monoclonal anti CD-25 antibody which binds to and acts as
IL-2 receptor antagonist.
 Combined with glucocorticoids, calcineurin antagonists and/or azathioprine
 Can cause anaphylactic reactions and promote opportunistic infection.
 Peripheral edema, fever, headache, dyspnoea are the side effects
69

64. 70

65. •Basiliximab
 Monoclonal antibody
 Binds to IL-2 receptor
 Similar affinity as IL-2 and effectively competes with IL-2
•Anti-thymocyte globulins
 Polyclonal antibodies
 Bind to surface of t-cell
 Cell death by cytotoxicity and apoptosis
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66. 72

67. 73

68. Immunostimulants
74

69. Immunostimulants
• Immunopotentiators
• Substances that stimulate the immune system by inducing activation or
increasing the activity of any of its components
• Edward Jenner developed the first vaccination to prevent smallpox.
• Evidence exists that the Chinese employed smallpox inoculation as
early as 1000 CE.
• The hallmarks of an immune response to pathogens are the recognition
and activation of the innate immune response that limits pathogen
spread when microbes breach the host’s natural protective barriers.
75

70. 76

71. Vaccines
• They contain killed or
attenuated bacteria or virus
that activate the immune
system
• Antibodies are built against
that particular bacteria or virus
and prevents infection later.
• Example:-Rabies vaccine,
hepatitis vaccine, polio vaccine,
combined vaccines etc.
77

72. Vaccines
• Killed (Inactivated) vaccines
 Microorganisms killed by heat or chemicals.
 The immunity is relatively shorter-lasting;
 Such as the Salk polio vaccine
• Live attenuated vaccines
 The immunity is relatively shorter-lasting;
 Live bacteria or viruses which have been rendered avirulent
 Such as the MMR (measles, mumps and rubella) vaccine
• Toxoids
 Modified bacterial exotoxins so that toxicity is lost but antigenicity is retained.
 Such as the tetanus vaccine
• Subunit vaccine
 Purified fragments of the pathogen
 Such as the pertussis (whooping cough) vaccine, use purified proteins from the pathogen’s surface
• Nucleic acid vaccines
 Use genetic material (DNA or RNA) from a disease-causing virus or bacterium
 Examples include HIV, Zika virus and COVID-19 vaccines
• Virus-like particles (VLP) vaccines,
 Use structures similar to viruses, but without the virus’ genetic material, that are recognised by the immune system
 Such as the human papillomavirus (HPV) vaccine
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73. 80

74. BCG Vaccine
• Bacillus Calmette–Guérin (BCG) vaccine
• Named after Albert Calmette and Camille Guérin
• Live attenuated form of Mycobacterium bovis
• Used to prevent tuberculosis and other mycobacterial infections
• Induces a granulomatous reaction at the site of administration
• Dose=0.05 ml (neonate) 0.1 ml (older infants and children) intracutaneous injection
• The BCG vaccine was first used medically in 1921
• Available as freeze-dried preparations of viable bacilli, and are administered by intradermal
injection
• This preparation is active against tumors
• Adverse effects include hypersensitivity, shock, chills, fever, malaise, and immune complex
disease.
81

75. • Proteins that leak or are secreted by the bacillus
within the phagosome enter an endosomic
pathway and are eventually presented by class II
major histocompatibility complex (MHC)
molecules to CD4+ T cells.
• At the same time, the T cell is exposed to
interleukin 12 (IL12) produced by the activated
macrophage, which induces the T cell to secrete
interferon g (IFN-g).
• This cytokine then activates the macrophage,
resulting in proton pumps on the phagosomal
membrane, which reduce the pH around the
bacillus, and the production of nitric oxide and
superoxide, all of which can damage or kill the
TB bacillus.
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76. 83
•Bacilli binds to macrophage receptors and other cells(monocytes,dendritic cells,and
neutrophils) in lungs
• Detected by the immune system
•Inflammatory molecules like TNF-α,IL-6,IL-10,IL-12, IFN-γ are secreted
•Activation of macrophages to kill the mycobacterium by altering the pH

77. COVAXIN®
• Covaxin (codenamed as BBV152) is an whole inactivated virus-based COVID-19
vaccine developed by Bharat Biotech in collaboration with the Indian Council of
Medical Research (ICMR) - National Institute of Virology(NIV)
• The WHO granted emergency use listing to COVAXIN on November 3, 2021
• COVAXIN mainly contains 6µg of whole-virion inactivated SARS-CoV-2 antigen
• The vaccine is used along with Alhydroxiquim-II to improve immune response and
longer-lasting immunity
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Vaccines in trial stage
Vaccine
Type
(technology)
Phase I Phase II Phase III
No. of
Participants
in Clinical
Trial
Planned
Capacity
BBV154
Adenovirus vector
(intranasal)
Completed In progress Pending 175 100 million
HGC019 mRNA Completed In progress Pending 120 60 million

79. BBV154
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80. 10 Vaccines Approved for Use in India
• Serum Institute of India COVOVAX (Novavax
formulation)
• Biological E Limited Corbevax
• Zydus Cadila ZyCoV-D
• Moderna Spikevax
• Gamaleya Sputnik Light
• Gamaleya Sputnik V
• Janssen (Johnson & Johnson) Ad26.COV2.S
• Oxford/AstraZeneca Vaxzevria
• Serum Institute of India Covishield
(Oxford/ AstraZeneca formulation)
• Bharat Biotech Covaxin
14 Vaccines in Clinical Trials in India
• Biological E Limited Corbevax
• Novavax Nuvaxovid
• Serum Institute of India COVOVAX (Novavax formulation)
• University Medical Center Groningen AKS-452
• Zydus Cadila ZyCoV-D
• Bharat Biotech BBV154
• Gamaleya Sputnik V
• Oxford/AstraZeneca Vaxzevria
• Serum Institute of India Covishield (Oxford/ AstraZeneca
formulation)
• Bharat Biotech Covaxin
• Biological E Limited BECOV2B
• Biological E Limited BECOV2C
• Biological E Limited BECOV2D
• Gennova Biopharmaceuticals Limited HGCO19
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81. Interferons
• Potent cytokines that possess antiviral, immunomodulatory, and antiproliferative activities
• Interferons are a family of structurally related, species-specific proteins that enhance the
immune system released by host cells in response to the presence of pathogens such as
viruses, bacteria, parasites, and tumor cells
• The interferons bind to specific cell surface receptors that initiate a series of intracellular
events:
 Induction of certain enzymes,
 Inhibition of cell proliferation, and
 Enhancement of immune activities, including increased phagocytosis by macrophages and augmentation of
specific cytotoxicity by T lymphocytes.
• IFNs are divided into two classes,
 Type-I IFNs (IFN-α, IFN-β produced by nearly all cells in response to viral infection )
 Type-II IFNs (IFN-γ has less antiviral activity but more potent immunoregulatory effects, particularly
macrophage activation, expression of class II MHC antigens, and mediation of local inflammatory )
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82. IFN-G
• Two genes, IFN-gR1 and IFN-gR2, encode the receptor components
• The human IFN-gR1 (IFNGR1 ) and IFN-gR2 (IFNGR2) genes are
located on the chromosome 6 and 21 respectively
• The mouse gene for IFN-gR2 is on chromosome 16. Study of the mouse
gene promoter has revealed that it contains binding sites for a number
of activated transcription factors, suggesting that unlike IFN-gR1,
IFN-gR2 expression can be regulated. Both proteins must be expressed
on the cell surface and associate in order for IFN-g signaling to occur,
but there is evidence that some T cells control their responsiveness to
IFN-g by modulating the cell-surface expression of IFN-gR2.
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83. • IFN-g binds to the extracellular domain of IFN-gR1 only.
• In the absence of IFN-gR1, IFN-gR2 cannot bind IFN-g
• The biological effects of IFN-γ are elicited through
activation of JAK/STAT pathway
• Upon IFN-g binding, the intracellular domains of
IFNγR2 oligomerize and transphosphorylate with
IFNγR1, activating the downstream signaling
components, JAK1 and JAK2
• The activated JAKs phosphorylate the intracellular
domain of the receptor (tyrosine 440 on human IFNγR1),
creating binding sites for STAT1
• and acts as a transcription factor interferon-rSTAT1 is
then phosphorylated regulatory factor 1 (IRF1),
• IRF1 functions as a transcription activator of interferon-
stimulated response elements (ISRE or IRE), leading to
the transcription of a large number of secondary
response genes
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84. • Upon the binding of IFN-g, the receptor complex is internalized, IFN-g then disassociates
from the receptor, goes to the lysosome, and is degraded.
• STAT-dependent signaling is the best-studied IFN-g signaling pathway, but there is
evidence that STAT1-independent signaling pathways can also be activated by IFN-g
through IFN-gR1 and IFN-gR2. In cell lines lacking STAT1, activation of the IFN-g
receptor by IFN still causes the induction of a set of genes.
• Mutation of either Leu 270 or Ile 271 inhibits the internalization of the receptor, leading
to the accumulation of IFN-g ligand–receptor complexes on the surface of the cell.
• Type II IFN enhances Th1 cell, cytotoxic T cell, and APC activities, which results in an
enhanced immune response against the malignant tumor cells, leading to tumor
cell apoptosis and necroptosis (cell death)
• Type II IFN suppresses the activity of regulatory T cells, which are responsible for silencing
immune responses against pathogens, preventing the deactivation of the immune cells
involved in the killing of the tumor cells
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85. • Injection of recombinant IFN doses of ≥1 to 2 million units (MU) usually is
associated with an acute influenza like syndrome beginning several hours
after injection
• Tolerance develops gradually in most patients
• The principal dose-limiting toxicities of systemic IFN are depression,
myelosuppression with granulocytopenia and thrombocytopenia;
neurotoxicity manifested by somnolence, confusion, behavioral disturbance,
and rarely, seizures; autoimmune disorders including thyroiditis and
hypothroidism
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86. • Researchers are studying the effects of type II IFN on cancer, both
as a solo form of treatment and as a form of treatment to be
administered alongside other drugs. But type II IFN has not been
approved by the Food and Drug Administration (FDA) to treat cancer,
except for malignant osteoporosis.
• This is most likely due to the fact that while type II IFN is involved
in antitumor immunity, some of its functions may enhance the
progression of a cancer. When type II IFN acts on tumor cells, it may
induce the expression of a transmembrane protein known as
programmed death-ligand 1 (PDL1), which allows the tumor cells to
evade an attack from immune cells. Type II IFN-mediated signaling
may also promote angiogenesis (formation of new blood vessels to
the tumor site) and tumor cell proliferation
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87. Interleukins
• Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are
expressed and secreted by white blood cells as well as some other body cells
• Cytokines are proteins made in response to pathogens and other antigens that regulate and
mediate inflammatory and immune response
• The function of the immune system primarily depends on interleukins.
• The majority of interleukins are synthesized by helper T-lymphocyte, as well as
through monocytes, macrophages, and endothelial cells.
• They promote the development and differentiation of T and B lymphocytes,
and hematopoietic cells.
• Interleukin 2 (IL-2) and its receptor (IL-2R) were the first cytokine and cytokine receptor to be
cloned, more than 20 years ago
• The first function attributed to IL-2 was a potent capacity to enhance in vitro T-cell proliferation
and differentiation
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89. Interleukin-2
• Human IL-2 has 133 amino acids
• Human recombinant IL-2 (aldesleukin, PROLEUKIN; des-alanyl-1, serine-125 human IL-2) is produced
by recombinant DNA technology in E. coli
• IL-2 is secreted primarily from activated T lymphocytes
• DCs of myeloid and lymphoid lineages can also produce IL-2, but only in the presence of IL-15 cytokine
• IL-2 has an immunoregulatory role; it promotes the growth and development of peripheral immune cells
in the initiation of the (defensive) immune response, and keeps them alive as effector cells
• IL-2 receptor (IL-2R) has three subunits:
 α (CD25),
 β (CD122),
 γc (CD132), c = “common”; a shared chain with other cytokine receptors
• Assembly of all three subunits of the receptor is important for the signal transduction into the B and T
cells
• immunity is profoundly activated with lymphocytosis, eosinophilia, thrombocytopenia, and release of
multiple cytokines (e.g., TNF, IL-1, IFN-α).
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90. IL-2 receptor • The IL-2R is composed of three subunits.
• The Box1 and Box2 domains (yellow) are conserved
among members of the cytokine receptor superfamily
and a variable spacer region (‘‘V’’) intervenes Box1
and Box2.
• The Box1-V box-Box2 regions encompass the sites of
association with Janus (JAK) kinases; JAK1
associates constitutively with IL-2R and JAK3
• Both IL-2R and c encode multiple cytoplasmic
tyrosine residues (‘‘Y’’).
• At least some of these tyrosines on both chains
become phosphorylated following receptor activation,
whereupon they serve to recruit signaling molecules
that subsequently direct downstream signaling events.
• Following phosphorylation of the activating receptor,
STATs are recruited to specific tyrosines within the
receptor and induced to form dimers
• STAT dimers migrate to the nucleus where they activate
transcription of target genes
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91. Thymic Factors
• Thymic factors are naturally occurring substances that promote T-
lymphocyte differentiation and differentiation of early stem cells into
prothymocytes.
• Each of the available preparations (e.g., thymic humoral factor, thymosin
fraction 5, and thymodulin) are mixtures of several polypeptides isolated
from a calf thymus extract.
• By promoting the formation of T lymphocytes, thymic factors are used to
enhance T-lymphocytic functions.
• Studies with thymodulin show promise in treating symptoms in asthmatics and
patients with allergic rhinitis. The primary consideration in the use of thymic
factors for immunodeficiency states is the presence of T-lymphocyte
precursors. Few major side effects have been reported, especially with purer
forms produced by genetic engineering. Crude thymic preparations have
produced allergic side effects in some patients.
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92. Levamisole
• Imidothiazole derivative with a wide variety of
applications in medical field
• It has long been used as an anti-helminthic
where its primary action is through the
opening of acetyl choline receptor channels.
• The role of levamisole has contradicting view
as an effective immunomodulator.
• It appears to restore depressed immune
function of B-cells,T-cells, monocytes and
macrophages
• It is widely used as an immunomodulatory
drug through its action on dentritic cells and
by enhancing the release of cytokines like
interleukins 12 and 10
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