1. Manipulation of the Immune Response
Chapter 16
Manipulation of the Immune Response

2. Treatment of unwanted immune responses
ㆍConventional immunosuppressive drugs in clinical use
Figure 16.1
ㆍCorticosteroids are powerful anti-inflammatory drugs
that alter the transcription of many genes
⇒ suppress the harmful effects of immune responses
of autoimmune, allergic origin, graft rejection
· Anti-inflammatory effects of corticosteroid therapy
Figure 16.2

5. Cytotoxic drugs cause immunosuppression by killing
dividing cells and have serious side-effects
- azathioprine
- cyclophosphamide ⇒ interfere with DNA synthesis
- mycophenolate
- Azathioprine also interferes with CD28 co-stimulation
⇒ apoptotic signal through the blockade of the
small GTPase Rac1
⇒ killing dividing cells

6. Cyclosporin A, tacrolimus (FK506) and rapamycin
(sirolimus) are powerful immunosuppressive agents
that interfere with T cell signaling
- cyclosporin A and tacrolimus inhibit lymphocyte
and some granulocyte responses
Figure 16.3

8. - Cyclosporin A and tacrolimus inhibit T cell
activation by interfering with the serine/threonine
specific phosphatase calcineurine Figure 16.4
- Rapamycin bind to the FKBP family of immunophilins
→ no effect on calcineurin activity
→ inhibits a serine/threonine kinase known as
mTOR which is involved in the phosphatidylinositol
3-kinase/Akt (protein kinase B)
signaling pathway Figure 16.5
→ causes arrest of cells in the G1 phase of the cell
cycle and the cells die by apoptosis
→ blocking T cell proliferation
- Rapamycin increases the number of regulatory T cells
- Rapamycin enhances the formation of memory cells

11. - Fingolimod (FTY 270), a sphigosine 1-phosphate analog
→ blocks lymphocyte migration
→ used for treatment of multiple sclerosis

12. Antibodies against cell surface molecules can be used to eliminate lymphocyte subsets or to inhibit lymphocyte function
- anti-lymphocyte globulin (horse)
→ treat acute graft rejection
→ serum sickness
- monoclonal antibodies
- depleting Abs
- nondepleting Abs
Antibodies can be engineered to reduce their
immunogenicity in humans
Figure 16.6

14. Monoclonal antibodies can be used to inhibit allograft rejection
ㆍCampath-1H (CD52 Mab,alemtuzumab)
: solid organ and bone marrow transplantation
ㆍanti CD3 Mab (OKT3), anti-IL-2Ra Mabs
: kidney transplantation
ㆍCTLA4 Ig
ㆍCD40L Mab
ㆍanti-CD4 Mab
→ certain nondepleting anti-CD4 antibodies
⇒ induction of tolerance Via CD25 TReg induction
Figure 16.7
animal models

18. Depletion of autoreactive lymphocyte can treat autoimmune disease
- By ligating CD20, rituximab (Rituxan,MabThera) transduces
a signal that induces lymphocyte apoptosis and depletes
B cells for several months
→ clinical uses for treatment of hemolytic anemia, SLE,
RA, type II mixed cryoglobulinemia
- Alemtuzumab for treatment of multiple sclerosis (?)
- CD4 Mabs for treatment of RA → failed

19. Biological agents that block TNFa or IL-1 can alleviate autoimmune disease
- Anti TNF Mab (infliximab) Figure 16.8
: RA, Crohn’s disease, Inflammatory bowel disease
- TNFR-Fc (etanercept)
- IL-1Ra (anakinra) : blockade of the IL-1b receptor
- IL-6R Mab

21. IFNb : effective in treating multiple sclerosis
inhibits the activity of the NALP3(NLRP3) and
NLRP1 inflammasomes
reduces expression of the IL-1 pro-protein
ㆍBiological agent can block cell migration to sites of inflammation and reduce immune responses
- a4 integrin Mab(natalizumab)
blocking of VLA-4(a4b1)↔VCAM-1 interaction
and a4:b7 ↔ MAdCAM-1 interaction
multiple sclerosis, Crohn’s disease
Figure 16.9
ㆍDepletion or inhibition of autoreactive lymphocytes
can treat autoimmune diseases
ㆍdepleting anti CD4 Mab, anti CD52 Mab
→ depletion of T lymphocyte
→ failure in the depleting of primed TH1 cells
→ long standing lymphopenia
→ disappointing results
ㆍAnti-CD20 Mab : depletion of B cells

25. Blockade of co-stimulatory pathways that activate
lymphocytes can be used to treat autoimmune disease
ㆍCTLA4Ig (abatacept) : B7-CD28 blockade
⇒ RA,Psoriasis
ㆍLFA-3-IgG1 (Alefacet) : CD2-CD58(LFA-3)
→ reduction in CD4 and CD8 memory cells
in Psoriasis

26. A number of commonly used drugs have
immunomodulatory properties
- Statins : blocker of HMC-CoA reductase
→ reducing cholesterol levels
→ reducing MHC classII expression
→ switch TH1 response to TH2 response in
animal models
- Vitamin D3
decreases IL-12 production by dendritic cells
leads to a decrease in IL-2 and IFN-g by
CD4 T cells

27. ㆍControlled administration of antigen can be used to
manipulate the nature of an antigen-specific response
- Repeated treatment with higher doses of allergens
→ IgG1 and IgA response
- Oral administration of Ag : Myelin basic protein,
collagen type II
→ induction of immune tolerance
- The peptide drug glatiramer acetate(Copaxone) : an
approved drug for multiple sclerosis
→ mimics the amino-acid composition of MBP
→ induce TH2 response
- altered peptide ligand (APLs)
: act as partial agonist or antagonist
ㆍNew therapeutic agents for human autoimmunity
Figure 16.10

31. Using the immune response to attack tumors
The development of transplantable tumors in mice
led to the discovery that mice could mount a protective
immune response against tumors
- Tumor rejection antigens
(tumor specific transplantation antigens) are specific
to individual tumors Figure 16.11

33. Tumors are edited by the immune system as they evolve and can escape rejection in many ways
- Immune surveillance : the ability of the immune
system to detect tumor cells and destroy them
Figure 16.12
- The concept of immune surveillance has been
modified and is now considered in three phases
ㆍelimination phase
ㆍequilibrium phase : cancer immunoediting
ㆍescape phase

35. - Tumors can either avoid stimulating an immune response or evade it when it occurs Figure Loss of MHC class I expression in a prostatic carcinoma Figure Tumor that lose expression of all MHC class I molecules as a mechanism of escape from immune surveillance are more susceptible to NK cell killing Figure 16.15

41. Many tumors evade an immune response by making immunosuppressive cytokines such as TGFb, IL-10
induction of
regulatory T cell
Many tumors seem to contain myeloid-derived suppressor cells, a heterogeneous population composed of both monocytic and polymorphonuclear cells that can inhibit T cell activation within the tumor
Some tumors express cell-surface proteins that directly inhibit immune response e.g. PD-L1
tumor can produce enzymes that act to suppress local immune response e.g. IDO
tumor cells can produce materials such as collagen that create a physical barrier to interaction with cells of the immune system

42. Tumor-specific antigens can be recognized by T cells and form the basis of immunotherapies
ㆍ Tumor rejection antigens Figure 16.16
• Tumor rejection antigens may arise by point mutations or gene rearrangement which occur during oncogenesis
Figure 16.17
- The second category comprises proteins encoded by genes that are normally expressed only in male germ cells;Cancer-testis antigen e.g. NY-ESO-I
- The third category of tumor rejection antigens comprises differentiation antigens encoded by genes that are expressed only in particular types of tissues

47. The fourth category consists of antigens that are
strongly overexpressed in tumor cells compared with
their normal counter parts e.g. HER-2/neu
The fifth category : abnormal posttranslational
modification e.g. MUC-1
The sixth category : Retention of introns in the mRNA
The seventh category : oncoviral antigens

48. Adaptive T cell therapy involves the ex vivo
expansion of tumor-specific T cells to large
numbers and the infusion of those T cells into
patients
Another approach to transfer tumor specific
T cell receptor genes using retroviral vectors into
patients T cell before reinfusion

49. Monoclonal antibodies against tumor antigens, alone or linked to toxin, can control tumor growth
- Monoclonal antibodies that recognize tumor specific
antigens have been used to help eliminate tumors
Figure 16.18
- Examples of tumor antigens that have been targeted
by monoclonal antibodies in therapeutic trials
Figure 16.19
- Antibody-directed enzyme/pro-drug therapy (ADEPT)
- Monoclonal antibodies coupled to g-emitting
radioisotopes have also been used successfully to
image tumors

52. Enhancing the immune response to tumors by
vaccination holds promise for cancer prevention and
therapy
- A recombinant vaccine against human papilloma
virus(HPV) was 100% effective in preventing cervical
cancer caused by two key strains of HPV-16 and
HPV-18, which are associated with 70% cervical cancers
Figure 16.20
- Several candidate tumor vaccines
ㆍtumor lyzate, proteins or peptides
+ adjuvant (BCG, CpG DNA)
ㆍCTL peptide, other tumor Ags + DC
ㆍrecombinant viruses encoding tumor Ags
ㆍHeat-shock proteins for tumor Ag delivery

54. Checkpoint blockade can augment immune responses to existing tumors
- Other approaches to tumor vaccination attempt to strengthen the natural immune response against a tumor
· making the tumor more immunogenic
e.g. B7,GM-CSF
· relieving the normal inhibitory mechanisms
Figure 16.21
- anti-CTLA-4 antibody : blocking B7-CTLA4 interaction
⇒ enhance CD4 and CD8 T cell response
· ipilimumab, an anti-CTLA4 antibody has been used
clinically for melanoma patients

56. Fighting infectious diseases with vaccination
- Attenuated and killed vaccine
• attenuated organisms
→ reduced pathogenicity
→ stimulated protective immunity
• killed vaccine
→ safe, weak immunity
- Diseases for which effective vaccines are still needed
Figure 16.22
- Most effective vaccines generate antibodies that prevent the damage caused by toxins or that neutralize the pathogen and stop infection

58. There are several criteria for an effective vaccine
Figure 16.23

60. The route of vaccination is an important determinant
of success
- The ideal vaccination induces host defense at the
point of entry of the infectious agent ⇒ importance of
mucosal immunity
- Injections are painful, expensive, requiring needles,
syringes and a trained injectors
- There are efforts to develop vaccines that can be
administered to the mucosa orally or by nasal
inhalation
Bordetella pertusis vaccination illustrate the importance of perceived safety of a vaccine
- whole cell vaccine → acellular vaccine
(pertussis toxoid, filamentous hemagglutinin,
pertactin and fimbrial antigens)

61. Live-attenuated viral vaccines are usually more
potent than ‘killed’ vaccines and can be made safer
by using recombinant DNA technology
- viruses are traditionally attenuated by selecting
for growth in nonhuman cells Figure 16.24
- Attenuation can be achieved more rapidly and
reliably with recombinant DNA techniques
Figure 16.25

64. Live-attenuated bacterial vaccines can be developed
by selecting nonpathogenic or disabled bacteria or by creating genetically attenuated parasites
- Modified BCG · overexpression of an immunodominant
ag of M.tuberculosis
· expression of the pore-forming protein
listeriolysin
⇒ allow cross-presentation
- genetically attenuated parasite
Figure 16.26

66. Conjugate vaccines have been developed as a result
of understanding how T and B cells collaborate in an
immune response
- Conjugation of bacterial polysaccharide chemically
to protein carriers
⇒ T independent Ag (polysaccharide capsules of
bacteria) → T dependent Ag
eg. Haemophilus influenza type b
Neisseria meningitidis serogroup C
Streptococcus pneumoniae
Figure 16.27

68. Peptide-based vaccines can elicit protective immunity, but they require adjuvant and must be targeted to the appropriate cells and cell compartment to be effective
ㆍReverse immunogenetics can be used to identify
protective T cell epitopes against infectious
diseases

69. - most acellular vaccines require the addition of
Adjuvants are important for enhancing the immunogenecity of vaccines but few are approved for use in human
- most acellular vaccines require the addition of
adjuvants, which are defined as substances that
enhance the immunogenicity of antigens
- most adjuvants, if not all, act on antigen-presenting
cells, especially on dendritic cells
eg. aluminum salt, Freund’s complete adjuvant,
muramyl peptide, bacterial DNA,
LPS, monophosphoryl lipid A (LPS derivative),
unmethylated CpG DNA, GM-CSF, IL-12
imiquimod
NLRP3 stimulation

70. Protective immunity can be induced by DNA-based vaccination
- When DNA encoding a viral immunogen is injected
intramuscularly in mice, if leads to the development of
antibody responses and cytotoxic T cells that allow the
mice to reject a later challenge with whole virus
- DNA-based vaccine is to include genes that will express
cytokines and co-stimulatory molecules

71. The effectiveness of a vaccine can be enhanced by
targeting it to sites of antigen presentation
• mannose coating → mannose receptors on APC
• immune complex → Fc and complement receptor
on APC
• DEC205 antibody conjugation → directed to DC for
crosspresentation

72. An important question is whether vaccination can be
used therapeutically to control existing chronic
infections
- There are many chronic diseases in which infection
persists because of a failure of the immune system
to eliminate disease
- DC derived from the patients’ own bone marrow
were loaded with chemically inactivated HIV
⇒ induction of a robust T cell response to HIV
Figure 16.28