Clinical immunology exam revision

Why does immuno-regulation occur

To conserve energy

To repair tissue

To prevent damage to non-diseased tissue

The 3 of immuno-regulation

Cell intrinisc mechanisms

Immuno-regulatory molecules and cytokines

Immuno-regulatory cells

Cell intrinisic immuno-regulation

Molecular regulators within cells can:

• Turn down signaling pathways after they’ve been triggered such as PRRs

• Can turn of chronic/strong signals (exhaustion)

• Can limit how many times a cell can divide

• Can limit the cells lifespan

Immuno-regulatory cytokine - Interleukin 10, production and function

Production:

• Made by many monocytes and lymphocytes

• Made later in the immune response

Function:

• Suppresses T-cell activation

• Promotes class switching and memory cells/LLPC’s

Immuno-regulatory cytokine - Transforming growth factor beta, production and function

Produciton:

• Made by macrophages later in the immune response

Function:

• Suppresses T and B cell acitvation

• Promotes generation of induced T regulatory cells

• Promotes stem cell activation and tissue repair

Immuno-regulatory cells - CD4 T regulatroy cell, function and types

Function:

• Produces IL-10, TGF-b and CTLA-3

  • Suppress all macrophages, DCs, T and B cells

• Consumes IL-2 (important for immune response)

Types:

• Natural = Differentiates in the thymus from cells that are slightly reactive for self-antigen

• Induced = Differentiates in the periphery from CD4 T cells activated in the presence of TGF-B or less antigens

Chemokine transportation

To lymphnode = CCR7 → CCL19 & 21

To inflamed tissue (T-cell) = CXCR4 → CXCL9 & 10

To inflamed tissue (monocyte) = CCR2 → CCL2

To inflamed tissue (neutrophil) = CXCR1 & 2 → IL-8

Symbiotic microbiota types

Mutualistic = both host an microbe benefit

Commensalisitcs = no benefit or harm to either organism

Transmissibility

The ability of a microbe to transmit infection from one host to another

Infectivity

The ability of a microbe to establish an infection

Pathogenicity

The ability of a microbe to cause disease upon infection

Virulence

The measure of damage done by a microbe

Viral infection → features

Intraceulluar

Rapid evolution

Zoonosis

Can be enveloped

Single-stranded or double stranded DNA or RNA

Viral infection → immune evasion

Viral proteins supress IFNs

Can downregulate MHCI

Can mutate their antigens

Viral infection → testing

Antigen testing

Molecular testing for viral genome e.g PCR

Serolgical testing for antibodies

Bacterial infection → features

Prokaryotic intra or extracellular pathogen

Contain many PAMPs

• LPS

• unmethylated CpG motifs in DNA

• Flagellin

• Carbohydrate capsule

Can undergoes zoonosis

Can undergoes dormancy/latency

Bacterial infection → immune evasion

Protease expression to degrade antimicrobial chemicals

Bacteria can swap their capsule and other antigens in different life phases

Bacterial infection → testing

Culture/grow bacteria

Microscope analysis for bacteria presence (post staining)

Serological testing for antibodies

Antigen testing

Molecular testing for genome e.g pcr

Parasitic infection → features

Intra or extraceullular eukaryotes

• Protozoa = single celled

• Helminth = worm

• Ectoparasite = live on skin e.g tick

Parasitic infection → immune evasion

Multi-stage lifecycle leads to cycling antigens

Can secrete immuno-suppressive proteins and enzymes

Parasitic infection → testing

Serological testing for antibodies

Molecular test for parasitic genome (PCR)

Microscopic test for parasite presence

Fungal infection → features

Eukaryotic, extracellular infection

• Yeast = single-celled organism

• Mycelial = multi-celled organisms

Fungal infection → testing

Culturing/growing fungus

Microscopic test for fungal invasion

Serologic testing for antibodies

Immunological memory → requirements and function

Requirements:

• Innate immune response

• Antigen uptake and presentation

• Adaptive immune response

Function:

• Increases frequency of memory B or T cells

• Decreases the amount of signal needed to activate memory cells

Passive immunisation → what, when to give, protection duration and good for

Transfer of antibodies from an immune to non-immune organism

• Ideally given before infection

• Immediate protection with limited duration

• Good for toxins and outbreaks where vaccines are not developed

Active immunisation → what, when to give, protection duration, 4 main outcomes

Induction of a specific, protective immune response

• Must be given well in advance as it take weeks to develop immunity

• Long duration i.e. years

Outcomes include:

• Eradication

• Sterilizing immunity

• Reduce disease symptoms

• Reduce infection transmission (Herd immunity)

Herd immunity

When immunity protects the individual and benefits the broader community

Herd immunity threshold (HIT) → description and dependancies

HIT is the frequency of people in a population that need to be immune to prevent widespread transimssion

Dependant on:

• Infectiousness of the pathogen (R0)

• Frequency of:

  • Infected individuals (resevoir)

  • Vaccinated individuals who dont develop protective immunity (vaccine efficacy)

  • Individuals who arent vaccinated (vaccine coverage)

  • Infected/vaccinatde individuals who develop protective immunnity

2 main components of a vaccine

Adjuvant = A compound that augment and/or enhance the immune response

Antigen = A component of the pathogen that is immunogenic

Criteria for selecting suitable antigens

1: Abundantly expressed and accessible to protective immune mechanisms e.g antigen expressed on cell if T-cells needed or antigen expressed on pathogen if B-cells are need

2: Does not vary during a pathogens life cycle

Adjuvant mechanism of actions

Augment the immune response by:

• Trigger innate PRRs via PAMPs

  • Each PRR triggers a differnt set of cytokines that acts differently on the adaptive immune system

• Promote antiegn presentation by DCs

  • Increase cytokine production

  • Directly promote uptake of antigen by DCs

Clinical testing phases

Types of vaccines

Hypersensitivity and examples

An exaggerated immune response directed against an antigen that is harmless e.g allergy, autoimmunity and transplantation

Types of antigens that trigger hypersensitivity

Allergen = antigen from environment

Auto-antigen = self antigen

Allo-antigen = non-self antigen from transplanted tissues

Type 1 hypersensitivity → Phases and associated granular contents

Phase 1 (sensitisation) = B-cells present allergen to CD4 T cells which produce cytokines IL-4,5 and 13 which promote B-cell activation and class switching to produce IgE which load onto mast cells and basophills

Phase 2 (activation) = Allergen crosslinks IgE on the surface of mast cells/basophils which triggers degranulation

Granular contents include:

• Histamines

• Leukotrienes and prostaglandins

• Cytokines/chemokines

Type 2 hypersensivitiy → phases

Phase 1 (sensitisation) = B-cells take up the antigen and either activate with a t cell (IgG) or without (IgM) into plasma cells which secrete the antibodies into circulation

Phase 2 (activation) = Complement proteins, phagocytes or NK cells encounter the antibody bound to the antigen and become activated

Type 2 hypersensitivity → description, immune cells/antibodies and causes

Antibody-mediated cytotoxic hypersensivitiy that builds when IgG or IgM in circulation bind to antigens on the surface of fixed tissues and trigger complement activation, phagocytosis or NK cell activation against the tissue

IgG or IgM + complement, phagocytotic, or NK cells

Caused by a failure of tolerance (self-antigens triggerring autoantibodies) or exposure to transplanted tissues (antibodies directed against allo-antibodies)

Type 1 hypersensitivity → description, immune cells/antibodies and causes

Immediate hypersensitivity that builds when IgE antibodies bind to a multivalent allergen and trigger a response in granulocytes

• Involves IgE + Mast cells, basophills and eosinophils

Caused by an imbalance between Th1 and Th2 (more Th2 = more humoral) due to:

• Air pollution

• Genetics

• High income

• Low microbiota

Type 1 hypersensitivity symptoms → phases and examples

Early = within minutes, mediated by mast cell and basophill degranulation

Late = within hours, mediated by eosinophills and neutrophils

Symptoms:

• Itchiness

• Swelling

• Mucus production

• Breathing problems

• Anaphylaxis (systematic)

Type 2 hypersensivity testing (indirect and direct)

Indirect = testing for preperation of blood transfer

• Mix patient plasma with donors blood and anti-human globulin (coombs reagent) to check for agglutination

Direct = testing to diagnose after blood transfer

• Mix patient blood with coombs reagent to check for agglutination

Type 1 hypersensitivity treatment (local, systematic and desensitiisation) and examples

Local = block immune mechanisms

• Anti-histamines block H1 receptors and block histamines

• Leukotriene antagonists to block leukotrienes

• Inhibitory steroids generally

Systematic = epinephrine prevents airway constriction

Desensitisation = repeated low dose exposure to allergen may reduce T1 hypersensivity

T1 hypersensivitiy testing

Apply a pael of allergens to skin, wait 15-20 mins, positive = wheal (raised tissue) and flare (redness), negative = nothing

Type 3 hypersensitivity → description, antibody/cells involved, physical causes

High concentrations of IgG or IgM antibodes form immune complexes that bind to blood vessel walls/deposit in tissues to cause tissue damage, complement activation and neutrophilr recruitment

• Antigen/antibody complexes in tissue/circulation + complement and neutrophills

Causes:

• Self-antigen (tolerance failure)

• Insect bite

• Transplanted tissues

• Repeated administration of foreign protein e.g vaccinating whilst already having antibodies

Type 3 hypersensitivity → phases

Phase 1 (sensitisation) = B-cells take up antigen and either activate by themselves (IgM) or with CD4 T cells (IgG) into plasma cells which produce high levels of antibodies

Phase 2 (activation) = Antigen binds to antibodies in circulation/tissue and form immune complexes that deposit in blood vessels/tissues and trigger strong local immune responses

Type 3 hypersensitivity → symptoms and testing

Arthus reaction

• Damage to BV can cause leakiness, swelling and bruising around site

Testing:

• staining tissue sections to look for immune complexes

• Testing plasma for:

  • Complement levels (decreasesd if high disease activity)

  • Anti-rheumatoid factor (RA)

  • Anti-nuclear antibodies (lupus)

Type 4 hypersensitivity → description

Delayed hypersensitivy as a result of sensitised cd4 t cells and macrophages and infections or allergens

Type 4 hypersensitivity → phases

Phase 1 (sensitisation) = DCs present antigens to CD4 T cells which become activated and prolifereate into TH1 cells

Phase 2 (activation) = DCs activate memory Th1 CD4 cells which migrate to site of inflamation and produce Interferon gamam to recruit and activate macrophages

Phase 2.5 (prolonged effector phase) = Occurs if macrophages cannot clear the antigen, triggering chronic inflammation, fibrosis and granuloma

Type 4 hypersensitivity → testing

Inject an antigen intradermally and wait 48-72 hours for a wheal (raised skin) and flare (redness) reaction

Central vs peripheral tolerance

Central = negative selection in the thymus and bone marrow

Peripheral tolerance = regulatory cells such as

• Natural Treg cells (self-Ag)

• Induced Treg cells (low Ag)

• Anergy (Ag with no co-stim)

Hashimoto’s disease → hypersensitivity types, symptoms and testing

Autoantibodies (type 2) and T-cell sensitisation (type 4) to thyroid antigens

Symptoms include goiter (swollen thyroid/neck) and T4/3 deficiency

Testing incldues looking for anti-thyroid peroxidase,thyrogloublin antibodies or low T4 yet high TSH

Type 1 diabetes → hypersensitivity types, symptoms and testing

Autoantibodies (type 2) and T cell hypersensitisation (type 4) to insulin producing beta cells in pancreas

Symptoms include hyperglycaemia, nerve and kidney damage

Testing includes looking for anti-glutamic acid decarboxylase antibodies, high blood glucose and glycated hemoglobin

Rheumatoid Arthiritis → hypersensitivity types, symptoms and testing

Systematic Lupus Erythematosus → hypersensitivity types, symptoms and testing

Types of tissue grafting

Autograft = from self

Isograft = from identical twin

Allograft = from a member of the same species who is not genetically identical

Xenograft = from other species

Commonly transplanted tissues

Blood transfer which includes:

• RBC’s platelets and plasma

• Must deplete donor WBC to prevent graft vs host disease

  • Can be done through size exclusion filters during aphresis (how we get blood out of individiuals) or gamma irradiation

Organ transplants which includes:

• Heart, liver, lung and kidney

Bone marrow transplants, haematopoetic stem cells or umbilical cord blood

• To replenish WBCs

Skin

• Like a bandage

Autoimmunity → Major histocompatibility antigens/human leukocyte antigen class 1 v 2

The most common antigen known to trigger autoimmunity after organ transplants.

Class II has 2 chains:

• heavy chain can be encoded for by 3 possible genes (HLA-A,B or C)

• beta-2-microglobulin

Class II has 2 chain:

• alpha chain can be encoded for by HLA-DP, DQ or DR genes

• Beta chain can be encoded by 3 different genes of the same name (generally pair with alpha chain)

Depending on parents and homo/heteozygousity humans can express typically 6 MHC I complexes and 6-8 MHCII complexes on 1 cell

Minor histocompatibility antigens (MiHA)

Normal proteins that are polymorphic, the differences between humans can be a less frequent cause of graft rejection

• Mostly coded on y chromasome

Outcomes of MHC/MiHA mismatch

Transplant services aim to match donor recipient with most polumorphisms however less matching can still result in high degrees of survival due to high dose immunosuppressants stem cells excluded

Xenograft matching

Cannot match MHC or MiHA

Certain proteins are expressed in different species but not humans

Rhesus D antigen, pregnancy and preventative measures

Ion channal proteins on the surface of RBCs, the most important one being the D antigen:

• RH D negative = can recieve Rh D transfusion once, after which IgG generation against Rh D antigen occurs

• Pattern occurs in pregnancy with Rh D- mother and Rh D+ father, causing haemolysis in the sercond Rh D+ fetus

  • Anti-D IgM prevents this by mopping up fetal RBC’s before they can enter the bloodstream but fails to cross the placenta

A and B RBC/platelet antigens → description, and allelic variants

Carbohydrate modifications on the surface of RBC’s, there are 2 dominant allelic variants (A, B) and 1 submissive null variant (O)

• Blood type A can recieve A and O blood

• Blood type B can recieve B and O blood

• Blood type AB can recieve A, B. AB and O blood

• Blood type O can recieve O blood

Plasma transfusion

The inverse of blood transfusion

Determining blood/plasma type

Mix patient blood/plasma with reference blood/plasma and coombs reagent and look for agglutination

Hyperacute rejection → timespan, symptoms, causes, treatment

Timespan = minutes to 48 hours

Symptoms = thrombosis (blood clot), followed by ischrmia (loss of blood flow) and necrosis (death of tissue)

Causes = pre-exisiting antibodies in the recipient graft - T2 hypersensitivity

Treatment = remove tissue

Hyperacute rejection management

Prior to transplant:

• Screen for pre-existing antibodies

  • e.g transplant history or complement dependent cytotoxicity crossmatch assay

After transplant

• Monitor tissue and patient

Hyperacute rejection process

Acute rejection → timespan, symptoms, causes, treatment

Timespain = days to weeks after transplant

Symptoms include:

• T cells mediated interstitial lymphocytic infiltration and focal necrosis of tissues

• B cell mediated vasculitis, thrombosis, ischemia and necrosis of vasculature

Causes = driven by new T cells or antibodiies against recipient MHC or MiHA (T2 and 4 sensitivity)

Treatment = active management via depletion of T cells

Process of acute rejection → indirect vs direct

Both involve DCs taking up graft Ag in graft tissue and presenting it to T cells in the lymph node.

• Direct = donor DC present their non-self MHC + tissue

  • More potent in allograft

  • Weak in xenograft due to MHC being biologically incompatible in edition to other mismatches (e.g incorret costimulatory molecules)

• Indirect = recipient DC presents tissue (only dependent on antigen)

  • Weak in allograft

  • Potent in xenograft due to being able to present all of the antigens

Process of acute rejection → b-cell

Acute rejection management

Prior to transplant

• Screen for matching MHC loci

  • e.g serological or molecular matching

After transplant = immunosuppression

Post-trasnplantation immunosuppression - broad therapy

Conventionally there are 3 different targets of immune therapy (triple therapy)

• Inhibition of T-cell activation

  • Tacrolimus blocks activation and IL-2

• Block proliferation

  • Azathoprine as a purine analogue disrupts cell division

• Block inflammation

  • Corticosteroids inhibit transcription of inflammatory genes

Post-transplantation immunosuppression - targetted therapy

Involves the useage of antibodies and fusion proteins

• Antibodies can deplete lymphocytes from graft e.g

  • Anti-thymocyte globulin depletes T cells

    • Rabbit-derived polyclonal serum specific for human leukocytes

• Inhibit T cell activtion e.g

  • Anti-CD3 mAb

  • Anti-IL-2 mAb

Chronic graft rejection → timespan, symptoms, causes, treatment

Timespan = months to years after transplant

Symptoms = fibrosis in intersitial tissues, arteriosclerosis (thickened intima due to proliferation of endothelia & SM), ischemia and atrophy

Cause = T cells generated by the recipient against the graft and graft damage that releses more antigen (acute rejection episodes)

Management of chronic rejection

Before transplant:

• Screen for matching MHC and MiHA loci

• Siblings tend to perform better than unrelated

After transplant:

• Immunosuppression can only delay/reduce chronic rejection

• New graft

Graft versus host disease → desription, frequency amongst specific transplantations and treatments

T cells from graft targetting recipient tissue, often the skin, gut and liver

Frequent among bone marrow or stem cell transplantation

Infrequent among transplanted organs

Can be treated with T-cell depletion and immunosuppression

Graft versus host disease → acute vs chronic features

Acute = <100 days:

• Skin rash, liver dysfunction and jaundice, nausea and diarrhea

Chronic = >100 days:

• Skin, liver and intestinal symptoms as well as other systems e.g vitiligo and alopecia

Management of GvHD

Before:

• Deplete bone marrow or stem cells of T cells

• MHC match (related individuals help)

• Use umbilical cord blood

After:

• Prophylactic (preventative) immunosuppression

• Additional immunosuppression if it occurs

Cancer/Neoplasm → general description and 3 growth types

When a cell begins to lose control of its cell cycle and grow abnormally, forming a neoplastic growth

3 types of neoplastic growths are:

• Benign = unable to invade surrounding tissue or grow indefinetly (can become malignant by accumulating multiple genetic alterations - malignant transformation)

• Malignant = start to invade surrounding tissue (cancer)

• Metastatic = start to leave primary tumour site and migrate to other distant tissues (mestastision)

Malignant neoplasm types → how and different types

Grouped based on the original cell type

• Carcinoma = epithelial origins

• Sarcoma = connective tissue origins

• hematological cancers:

  • Leukaemia = less differentiated hematopoeitc origin cells inside the bone marrow

  • Lymphoma = more differentiated hematopoietic origin cells outside the bone marrow e.g lymph node

  • Myeloma = plasma cells in bone marrow

Cause of neoplasm and factors that can increase the likelhood

Caused by genetic alterations in the DNA related to the cells division, survical or death

Factors that increase the likelhood of DNA damage is

• Chronic inflammation

• Carcinogenic chemicals

• Ionising radiation

• Oncogenic viruses

Genes that cause cancer

Oncogenes = inappropriately expressed genes that promote cell division and survival

• E.g Mutated Her2 can upregulate EGF production resulting in excesscell division

• Proto-oncogenes = genes that promote normal division and survival, they become oncogenes when dysregulated due to mutation

  • E.g Her2 typically form the receptor for epidermal growth factor (EGF) which when HER binds to signals cells to divide

Mutated tumour-suppress = inhibited due to mutations, permitting abnormal growth

• Tumour-suppressor genes usually prevent inappropriate cell division or survival by promoting cell death or DNA repair

  • E.g p53 senses ocogenes and DNA damage

DNA mutation → chromosomal translocations and example

Genetic material from one chromasome is swapped with another, there tends to be hotspots where this occurs e.g

• End of Chr 8 with Chr 14’s

  • Shifts the proto-oncogene myc close to an enhancer on Chr 14, converting it to an oncogene

  • Expressed at high levels in B-cells, leading to Burkitt’s lymphoma

DNA mutations → acquired vs germ-line mutations

Acquired = after birth e.g p53 mutation and infection with oncogenic viruses

Germline = inhertied e.g BRCA1/2 mutations can be inherited and predispose to the development of breast and ovarian cancers

Malignant transformation steps

1. initiation = genetic alteration that changes cell division or survival (benign)

2. Promotion = accumulation of cells (benign)

3. Progression = additional genetic alterations that enable unlimited proliferation and development of malignancy (malignant)

4. Metastatis = malignant cells lose adhesion and move away from original state (metastasis)

Tumour antigens → 4 types

Overexpressed antigens = normal genes that are overexpressed in tumours (tumour-associated) e.g EGF receptors

Oncofetal antigens = normally expressed only at certain stages of development (tumour-associated)

Neoantigens = mutated versions of normal genes due to carcinogens or radiation (tumour-specific)

Oncoviral antigens = expressed in cells after infection with an oncogenic virus (tumour-specific) e.g HPV protein E6 which inhibits p53

Tumour immunity → cells

NK cells can cells that are stressed, have downregulated MHCI or via antibody dependent cellular cytotoxicity

Macrophages can phagocytose cancer cells or generate cytokines

CD8 T cells can kill malignant cells expressing tumour specific antigens with CD4 T cell assistance - can be tumour infiltrating lymphocytes

B cells can make anti-tumour antibodies (can be problematic by masking from CD8 T cells)

Tumour immunity → cytokines

IL-12 promotes strong CD4 Th1 (cytotoxicity) and CD8 T cell responses

Type I IFN and IFN gamma can enhance tumour immunity

TNF can promote cancer apoptosis

Tumour microenvironment → desription, 4 parts and the impact of chronic inflammation

An environment comprised of the tumour cells and other cells recruited by the tumour using cytokines:

• Tissue remodelling from fibroblasts that have been converted to cancer-associated fibroblasts (CAFs) by TGF beta

• Incresed invasion via epithelial cancer cells that have been converted to mesenchymal cancer cells by IL’s and TNF A

• Angiogenisis (abnormal vessel growth) via VEGF

• Immune evasion via the recruitment of supressive myeloid derived suppressor cells from macrophages and T reg cells

Chronic inflammation supports the microenvironment by increasing cellular stress signals (causing the release of the growth factors and cytokines above), increasing mutation rate (genotoxic stress) and it is a proangiogenic

Cold tumour → cells excluded and included, and diagnostic implication

CD8 T cells and NK cells excluded

CD4 Treg cells present

Poor prognosis and response to immune-based therapies

Hot tumour → cells excluded and included, and diagnostic implication

CD8 T cells and NK cells present

CD4 Treg cells excluded

Improved prognosis and response to immune based therapies

Immune editing → description/downside and steps

The process by which cancer cells are eliminated, can lead to a natural selection of only the best cancer cells

Steps include:

1. Initiation → cancer forms

2. Elimination → cytotoxic mechanism elmiminate abnormal cells

3. Equilibrium → a balanced state between cancer regeneration/survival and elimination

4. Escape → the best (aggressive, less immunogenic) cancer cells survive and create their microenvironment

How cancerous cells evade the immune system

Tumour micro-environment - contains suppressive cells and high antigen load exausts T-cells

Antibody masking - hidden immunogenic epitops on tumour-specific antigens can limit CD8 T cells (antibodies can unintentionally do this)

MHCI down regulation - reduces presentation of tumour-associated antigens which reduces activation of CD8 T cells

Poorly immunogenic tumour antigens are poorly immunogenic/self

Polyclonal vs monoclonal antibodies → location, creator and target

Antibodies in serum are polyclonal

• created by B cells

• target multiple distinct epitopes

Therapeutic and labelling antibodies are monoclonal

• created by cloned b cells

• targets a single epitope

Monoclonal antibodies usecases

Labelling e.g tagging her2 breast cancer for identification

Blocking e.g blocking receptor on cancer cell

depleting e.g depleting TNF concentrations in auto-immunity

Activating e.g activating CD3 on T cells

Targetting e.g targeting Her2 cancer cells with conjugated drugs

Monoclonal antibodies production

1. immunise animals with target antigen

2. Isolate plasma cells

3. fuse with specialised tumour cells to form hybridomas (immortal plasma cells)

4. Clone out a single hybridoma with antibody for target antigen

5. Humanise antibodies to reduce immunogenicityt

T-cell inhibitory molecules that are upregulated by tumours presence

CTLA-4

• Competes with cd28 (costimulation)

• Switches T cell activation off

PD-1

• Delivers the exhaustion signal to T cell

Immune checkpoint blockade

Monoclonal antibodies bind to PD-1 and CTLA-4 receptors and prevents the molecules from binding to said receptors which would exhaust/inactivate T-cells. also drives said molecules to interact with cd28 instead enabling costimulation

Car T cell therapy → prepeartaion and attack

Living drug for lymphoma that uses modified patient immune cells that express synthetic tumour speciic receptors (Chimeric antigen receptor)

Preperation (3 weeks)

Isolate and activate T cells, transduce them with DNA that encodes tumour-specific synthetic receptor, expand, isolate and reinfuse

Attack (weeks to months)

Migrate around the body, encounter tumour cells with CAR and activate

CAR description and advantage and what makes a good one

Uses short chain variable fragments attatched to a hinge domain and CD3 domain (sends activation signal) and CD28 domain (costimulation domain)

• Can bind to membrane bound unprocessed proteins, doesnt need mhc, antigen processing or presentatino

A good CAR must be:

• Highly expressed

• accessible on cancer cell surface

• Unlikely to be mutated