Immune modulating therapies Flashcards
How can we boost the immune system?
Vaccination
Replacement of missing components
Cytokine therapy
Blocking immune checkpoints
What do we vaccinate against in kids?
Diphtheria
Tetanus
Pertussis
Polio
Haem Infl B
Pneum C
Men B
Men C
Rotavirus
MMR
Flu
HPV
Men ACWY
BCG
Which vx are travel vx?
Hepatitis B
BCG
Chicken pox
Hepatitis A
Typhoid
Yellow fever
Rabies
Cholera
What do we vx the old against?
Pneum PPV
Flu
Shingles
What is immune memory in the context of measles?
Infection was ‘remembered’ and individuals were ‘protected’ 65 years later
Feature of the adaptive immune response
History:
In 1781 an epidemic of measles occurred on the Faroe Islands
No further outbreaks of measles until 1846 when a major outbreak affected more than ¾ of the population
None of those who had measles in 1781 got the disease again
Describe the adaptive immune response
Adaptive Immune Response
B cells and T cells
Wide repertoire of antigen receptors
Receptor repertoire is not entirely genetically encoded
Genes for segments of receptors are rearranged and nucleic acids deleted/added at the sites of rearrangement almost randomly
Potential to create in order of 1011 to 1012 receptors
Autoreactive cells are likely to be generated
Mechanisms must exist to delete or tolerise these autoreactive cells
Exquisite specificity
able to discriminate between very small differences in molecular structure
What are APCs?
APCs are cells that can present peptides to T lymphocytes to initiate an acquired immune response
These cells include:
Dendritic cell
Macrophage
B lymphocyte
Macrophages include Langerhans cells, mesangial cells,
Kupffer cells, osteoclasts, microglia etc
What is Clonal expansion following exposure to antigen?
T cells with appropriate specificity will proliferate and differentiate into effector cells (cytokine secreting, cytotoxic)
B cells with appropriate specificity will proliferate and
differentiate to T cell independent (IgM) (memory and) plasma cells
undergo germinal centre reaction and differentiate to T cell dependent IgG/A/E(M) memory and plasma cells
What is Immunological memory?
Following infection, residual pool of specific cells with enhanced capacity to respond if re-infection occurs
How do we respond to EBV?
High frequency of CD8+
T cells specific for single
epitopes from EBV in
humans with primary EBV
infection and acute
Infectious mononucleosis
Fall in frequency of
EBV specific CD8+
T cells following
resolution of primary
infection
CD4+ T cells from patients with primary and persistent EBV infection respond to a lysate preparation of EBV proteins by
expressing IFN-gamma
The frequency
of CD4+ T cells
specific for EBV
falls following
primary infection
What is the CD8 T cell response?
What is the CD4 T cell response?
What are the CD4 subsets and what do they do?
What is T cell memory?
Longevity
Memory T cells are maintained for a long time without antigen by continual low-level proliferation in response to cytokines
Different pattern of expression of cell surface proteins involved in chemotaxis cell adhesion
These allow memory cells to access non-lymphoid tissues, the sites of microbial entry.
Rapid, robust response to subsequent antigen exposure
There are more memory cells
These cells are more easily activated than naïve cells
What is the B cell response?
Activated B cells enter the follicles, proliferate, and displace resting cells. They form germinal centers and differentiate into both plasma cells that form antibody and long-lived memory B cells. Those B cells synthesizing antibodies provide defense against microorganisms, including bacteria and viruses.
It is specific to the antigen they have been exposed to.
What are the features of B cell memory?
Longevity
Long lived memory B cells and plasma cells
Rapid, robust response to subsequent antigen exposure
There are more memory cells
These cells are more easily activated than naïve cells
Pre-formed antibody
Circulating high affinity IgG antibodies
What do we want from a vaccine?
- Generate protective, long-lasting immune response
- No adverse reactions
- Single shot
- Easy storage
In influenza how does the Vx protect?
For influenza although CD8 T cells control the virus load it is antibody which provides a protective response
Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and the target for infectivity-neutralizing antibodies.
What is the Haemagglutination inhibition assay?
Sialic acid receptors on RBC bind to haemagluttinin of influenza virus to ‘haemagluttinate’
Reaction inhibited by antibodies to haemagluttin
Plate with RBC + virus, Add serum from patients 1 - 8 (Dilution of serum)
Clear correlation between resistance to infection and levels of IgG antibody to haemagglutinin (HA)
How does the BCG confer protection?
BCG – bacilli Calmette-Guerin
Attenuated, strain of bovine tuberculosis
Protects against primary infection (19-27%)
Protects against progression to active TB (71%)
T cell response is important in protection
What is the Mantoux test?
- Inject 0.1 ml of 5 tuberculin units of liquid tuberculin intradermally.
- The tuberculin used in the Mantoux skin test is also known as purified protein derivative, or PPD.
- The patient’s arm is examined 48 to 72 hours after the tuberculin is injected.
- The reaction is an area of induration (swelling that can be felt) around the site of the injection.
How does response maintenace work in influenza and TB?
Influenza
Antibody protection begins within 7 days after immunization. Protection can last for approximately 6 months or longer in the general population.
TB
Protection in the UK after BCG lasts about 10-15 years.
What are the types of vaccines?
Live vaccines
Inactivated/Component/Conjugate vaccines
+ Adjuvants to increase immunogenicity
DNA vaccines
Dendritic cell vaccines
What are live attenuated vaccine examples?
MMR
BCG
Yellow fever
Typhoid (oral)
Polio (Sabin oral)
Vaccinia
Use a live but modified organism to induce an immune response but limit pathogenesis (avoid in immunocompromised)
What are the advantages of live vaccines?
Establishes infection – ideally mild symptoms
Raises broad immune response to multiple antigens – more likely to protect against different strains
Activates all phases of immune system. T cells, B cells – with local IgA, humoral IgG
Often confer lifelong immunity after one dose
What are the disadvantages of live vaccines?
Storage problems
Possible reversion to virulence (recombination, mutation).
Vaccine associated paralytic poliomyelitis (VAPP, ca. 1: 750,000 recipients)
Spread to contacts
Spread to contacts of vaccinee who have not consented to be vaccinated
Spread to immunosuppressed/immunodeficient patients
Which vaccines are inactivated/ component?
Inactivated Vaccines
Influenza, Cholera, Bubonic plague, Polio (Salk), Hepatitis A, Pertussis, Rabies.
Toxoids (inactivated toxins)
Diphtheria, Tetanus.
Component/subunit vaccines
Hepatitis B (HbS antigen), HPV (capsid), Influenza (haemagglutinin, neuraminidase).
What are the advantages of Inactivated vaccines/ component vaccines?
No mutation or reversion
Can be used with immunodeficient patients
Can lead to elimination of wild type virus from the community
Storage easier
Lower cost
What are the disadvantages of Inactivated vaccines/ component vaccines?
Often do not follow normal route of infection
Some components have poor immunogenicity
May need multiple injections
May require conjugate protein carrier or adjuvants to enhance immunogenicity
What is a conjugate vaccines?
Polysaccharide plus protein carrier
Polysaccharide alone induces a T cell independent B cell response – transient
Addition of protein carrier promotes T cell immunity which enhances the B cell/antibody response
Give examples of conjugate vaccines?
Haemophilus Influenzae B
Meningococcus
Pneumococcus
What is an adjuvant?
Adjuvant increases the immune response without altering its specificity
Mimic action of PAMPs (pathogen associated molecular patterns) on TLR (toll-like receptors) and other PRR (pattern recognition receptors)
Give examples of adjuvants
Aluminium salts (humans)
Lipids – monophosphoryl lipid A (humans)
Oils -Freund’s adjuvant (animals)
ISCOMS
CpG DNA
What is Alum?
Primary adjuvant utilized in humans – safe and effective
Mechanism not fully elucidated
Alum may allow antigens to be slowly released, prolonging the immune stimulation
Alums induce a mild inflammatory reaction that will then promote development of adaptive immune response
Alum activates Gr1+ IL4+ eosinophils to help prime naïve B cells leading to antibody response
Used in many vaccines including hepatitis A, hepatitis B, Hib
What is ISCOMs?
- Immune stimulating complexes
- Cage-like structure composed of Quillaja saponins, cholesterol, phospholipids, and protein
- Mixed with antigen to provide multimeric presentation with built-in adjuvant
- Enhance cell mediated immune response
- Experimental ISCOMS – induce protective immunity to viruses, parasites, bacteria in several species
What is CpG?
·”CpG” stands for cytosine and guanine separated by a phosphate which links the two nucleotides together in DNA
Stimulatory DNA; TCC ATG ACG TTC
·Adjuvant activity is linked to DNA motifs that are rich in CpG dinucleotides which should be unmethylated
·
·CpG motifs bind via pattern recognition receptors (TLR-9).
What are DNA vaccines?
Plasmid containing gene of choice
(Easy to produce in quantity, very stable easy to store)
Insertion into muscle cell
(several copies)
No replication of the plasmid. Gene encodes protein presented at cell surface
What are pros and cons for DNA vaccines?
Advantages
Mimics a virally infected cell
Stimulates T cell responses
Disadvantages
Possible plasmid integration into host DNA
Possible response to DNA could lead to autoimmune diseases such as SLE
What are dendritic cell vaccines?
Acquired defects in DC maturation and function associated with some malignancy suggests a rationale for using ex vivo–generated DC pulsed with tumour antigens as vaccines
Need to find antigens that clearly mark the cancer cells as different from host cells
How can we replace missing components in the immune system?
Haematopoietic stem cell transplantation
Indications
• Life-threatening primary immunodeficiencies
–Severe combined immunodeficiency
–Leukocyte adhesion defect
•Haematological malignancy etc
Offers potential for complete and permanent cure
What is antibody replacecment?
Human normal immunoglobulin
Prepared from pools of >1000 donors
Contains preformed IgG antibody to a wide range of unspecified organisms
Blood product:
- Donors screened for Hep B, Hep C and HIV
- Further treated to kill any live virus
Administration
•IV or SC
What is indications for antibody replacement therapy?
Primary antibody deficiency
X linked agammaglobulinaemia
X linked hyper IgM syndrome
Common variable immune deficiency
Secondary antibody deficiency
Haematological malignancies
- Chronic lymphocytic leukaemia
- Multiple myeloma
After bone marrow transplantation
What are some specific immunoglobulins in use?
Human immunoglobulin used for post-exposure prophylaxis (passive immunisation)
Derived from plasma donors with high titres of
IgG antibodies to specific pathogens
- Hepatitis B immunoglobulin - Bites, needles, sex
- Tetanus immunoglobulin - IVIG for suspected in UK
- Rabies immunoglobulin - potential exposure
- Varicella Zoster immunoglobulin - <20wks women or aciclovir CI
How do we replace T cells?
Autologous T cells expanded in vitro and then re-infused
Donor (HLA matched) T cells expanded in vitro and then infused
‘Banks’ of HLA matched, virus specific T cells being developed
Who should we replace T cells for?
Immunosuppression results in failure to control infection with persistent viruses – CMV, EBV
Patients develop CMV pneumonitis, retinitis…..
Patients develop EBV related B cell lymphoproliferative disease
What is the aim of recombinant cytokines?
Modify immune response
What is the clinical use of IFN alpha, alpha 2, gamma and IL2?
How does Blocking immune checkpoints - Ipilimumab
Antibody specific for CTLA4?
Action
- Antibody binds to CTLA4
- Blocks immune checkpoint
- Allows T cell activation
Indications
- Advanced melanoma
How does Blocking immune checkpoints –
Pembrolizumab and Nivolumab
Antibodies specific for PD-1 work?
-
Action
- Antibody binds to PD-1
- Blocks immune checkpoint
- Allows T cell activation
Indications and dosing
- Advanced melanoma
Match them up:
- BCG vaccination
- Bone marrow transplantation
- IFN gamma
- EBV-specific CD8 T cells
- Human normal immunoglobulin
- Pembrolizumab (anti-PD1)
- Varicella zoster immunoglobulin
A. Post-transplant lymphoproliferative disorder
B. Reduce risk of TB infection
C. X linked hyper IgM syndrome
D. X linked SCID
E. Chronic granulomatous disease
F. Immunosuppressed VZ seronegative individual after chicken pox exposure
G. Metastatic melanoma
You’re on your own for this one man.
What are mRNA vaccines?
f
What are adenovirus vaccines?
v
What are dendritic cell vaccines?
x
How do we use Virus specific T cell therapy in EBV?
This may be indicated for adneoviruse/ EBV lymphoproliferative disorders
What is TIL?
T cells infused back after IV expansion
What is TCR and CAR T therapy?
What is CAR T?
Good for ALL and NHL
Less successful in solid tumours
T cell with chimeric receptors to CD 19 using pts own T cells which are genetically engineered in vitro.
What is anti CTLA4 antibody?
Ab binds to CTLA4, blocks immun checkpoint and allows T cell activation
Used for advanced melanoma
But may cause auto immunity
What is PD-1 Ab?
Binds to PD 1, blocks checkpoint and allows T cell activation
Used in advanced melanoma and metastatic renal cell cancer
May cause autoimmunity
The purpose of vaccination is to stimulate and enhance immunological memory. Which cells mediate immunological memory?
Neutrophils
B and T lymphocytes
Platelets
Eosinophils
Macrophages
B and T lymphocytes
Which of the following vaccines should not be given to an immunosuppressed individual?
BCG- bacilli Calmette-Guerin
Diphtheria toxoid
Quadrivalent inactived influenza vaccine
Polio (Salk - injected)
Pfizer Covid mRNA vaccine
BCG- bacilli Calmette-Guerin
A 23 year old has metastatic melanoma. which of the following may reduce disease progressoin?
BCG vaccination
Bone marrow transplantation
CAR-T cells with specificity for CD19
Nivolumab, an antibody specific for programmed death 1 (PD1)
Normal human immunoglobulin
Nivolumab, an antibody specific for programmed death 1 (PD1)
