Allergy and Transplantation Flashcards
What is an allergy?
Type 1 (immediate) hypersensitivity Excess immune response to allergens, harmless antigens
Allergies damaging clinical needs?
Key drugs e.g. penicillin make conditions harder to treat
Egg proteins in vaccines trigger egg allergies, adding to vaccine hesitancy
Type 1 hypersensitivity in asthma?
IgE in airways = lung epithelium inflammation, smooth muscle contraction and mucus production
- Sensitisation
Ag specific IgE produced: allergen stimulates Th2 = IL4 for B cell IgE production, which circulate and associate with mast cells in mucosal and connective tissues with Fc region - Re-exposure and activation
Allergen binds Fc IgE on mast cells, cross linking receptors
Mast cells release mediators of inflammation = symptoms
Role of mast cell localisation?
GI tract = increased fluid secretion and peristalsis = diarrhea, vomiting
Airways = decreased diameter, increased mucus = congestion, wheezing, swelling in nasal passages
Blood vessels = increased blood flow and permeability = greater fluid in tissues increasing lymph drainage to nodes = effector response
Anaphylaxis?
Systemic response triggered by excessive histamine - blood vessels severely dilate = unconsciousness, airways narrow, oedema occurs
Often in nut allergies
Other hyper sensitivities?
Type 2; IgG mediated against cell or cellular-matrix associated antigens
e.g. haemolytic anaemia
Type 3; IgG against soluble antigens in immune complexes
e.g. lupus
Type 4; delayed type responding to contact hypersensitivity i.e. allergic response from skin contact, cell mediated and only involves T cells
e.g. MS
Type II hyper sensitivities?
IgG/IgM
React with anitgens on cells/tissues
Cause blood transfusion reactions, haemolytic disease of the new born, haemolytic anaemia, drug induced hypersensitivity (autoimmune)
Blood transfusion - IgM binds RBCs for complement activation
Haemolytic disease of newborn - Rhesus antibodies interacting
Type III hypersensitivities?
Immune complexes causes this
Systemic disease e.g. infections like malaria
Local disease e.g. Farmer’s lung from mould in hay
e.g. serum sickness
Animal serum = antibodies
Re-injection = immune complexes
Type IV?
NO ANTIBODIES
Not always harmless antigens e.g. poison ivy response
Cell mediated and localised
Allergy testing?
Skin prick test giving wheal and flare reaction quickly, and late phase later on
ELISA - detects IgE in serum when it should not be suggests you are atopic i.e. predisposed to allergens
Patch tests for type 4 - left for 24-72 hours
Causes of allergy?
Again, twin studies show concordance suggesting genetic component, not 100% = environment too
Genetic causes of allergy?
MHC genes
Non-MHC genes e.g. for rest of immune response
Environmental causes of allergy?
Increased Th2 polarising substances e.g. pollutants
Urbanisation - more common in developed countries
Hygiene
Expososome increased
Hygiene Hypothesis?
Children from more rural environments less likely to develop allergy as exposed to more things early on helps immune system develop
Old Friends hypothesis?
Few worm infections in areas with common AD and allergy - suggests losing these from our microbiome contributes to disease
Role of parasitic worms?
Th2 and IgE evolved in tandem with worm infections, where IgE initial response was to protect us from these
Disproving the hygiene hypothesis?
Not universal - South/Latin America has higher asthma than Spain/Portugal
Worm infections still common in parts of USA
Asthma on the rise in poverty-living African Americans
Influenza A in childhood linked to increased asthma
Industrialised nations still dirty - pollution, food additives
Balanced immune systems?
Th2 cells inhibiting Th1 and vice versa
Skewing of this e.g. allergic Th2 responses more upregulated
Treating allergies
Avoid allergen
Anti-histamines
Steroids to reduce inflammation
Epi-pens
Types of allergen therapies?
Low dose - de-sensitisation, raising IgG rather than IgE
Antibody - blocks IL4 cytokines that promote Th2 activation of B cells
Oral tolerance - exposure to antigens that usually cause T cell tolerance with Tregs
Worm therapy - may induce Tregs, reduce Th2. Hookworms used clinically to treat asthma
What did Peter Medawar find about rejection?
First set rejection kinetics - rapid rejection of graft to allogeneic (different MHC) recipient
Second set rejection - even more accelerated, same donor to same recipient i.e. showing immunological memory
Transfer of 2nd set kinetics to naive mouse if T cells from a mouse who has received a transplant are transferred to naive, who then receives a graft from same donor as the first mouse
Immune suppressant drugs?
Another key breakthrough in transplantation science -e.g. Azathioprine and cyclosporin A
Current issues?
Managing organ rejection - drugs must be taken long term, but this also suppresses the immune system leading to infections etc
Organ supply - very limited
Ageing society
What affects frequency of transplantation?
Organ availability
Other treatments
Risk/reward
Clinical demand
Autograft?
One site to another on same individual
Isograft?
Between genetically identical individuals (syngeneic)
Allograft?
Requires immune suppression
One donor to different (allogeneic) recipient
Xenograft?
Requires immune suppression
Between species
Histocompatible?
Does not induce an immune response
Congenic mice?
Identical except for small region of retained genome; studies highlight that acceptance of graft is dependent on if genome region contains antigens for mediating the rejection response
Major transplantation antigens?
Major histocompatibility antigens - strongest immune response
Located in MHC, lead to T cell cross-reactivity, in HLA region in humans
MHCI and II in transplantation?
Both polygenic
B, C and A genes encode MHCI molecules on all nucleated cells for CD8 detection
DP, DQ and DR loci encode alpha and beta chains of MHCII for CD4 recognition
These loci are also polymorphic
Both alleles from parents are expressed co-dominantly, varying individuals and causing immune mismatch
HLA typing?
Determining the alleles of an individual at DR locus of MHCI and II
Minor histoincompatability antigens?
Explains why even MHC matching does not ensure graft survival, although more slowly
Allelic differences in non-MHC genes, to present peptides not tolerised against in the recipient e.g. allopeptides
These are often inherited together
Allorecognition mechanisms?
Passenger DCs from donor to recipient interact with DAMPs at site and interact with T cells at lymph nodes
Direct allorecognition?
Donor MHC and donor peptide recognised by recipient T cells, cross-reactivity occurs and a high-frequency polyclonal response occurs
Indirect allorecognition?
Recipient MHC and processed donor peptide recognised by recipient T cells, giving more conventional response through low frequency of cognate T cells
Balance of immune responses from allorecognition?
Initially direct response, then donor MHCs die out and shift to indirect
Types of graft rejection?
Hyperactive (in minutes)
Acute
Chronic
Hyperactive rejection?
Soon as organ is placed, using pre-formed antibodies from previous sensitising events like blood transfusions or previous transplants
Complement activation
Clotting cascade
Acute rejection?
- sensitisation phase, allorecognition of CD4+ Th cells = effector cells
- Effector phase, attacks graft 7-10 days after surgery (combat with immune suppression)
Massive T cell and macrophage infiltration
Chronic rejection?
Months to years, slow progressive loss of graft function
Don’t fully get, not easy to treat
What is graft vs host disease?
Where mature donor T cells attack cells and tissues of the host, often in bone marrow and haematopoietic stem cell treatments where donor immune system is transferred
Needs best match - identical twins
Avoiding graft rejections?
Organ retrieval (cadaveric, living related, brain dead etc) Pre-screening and matching
Preventing graft rejection?
Immune suppression
Suppresses alloresponses, but long term use not great
Screening/matching process?
HLA typing - avoids allorecognition
Blood typing
HLA-specific antibody screening (avoids previous sensitisation)
Cross-matching with recipient serum
Drugs involved in immunosuppression?
Early on:
Corticosteroids
Anti-mitotic agents e.g. cyclosporin A to target proliferating T cells
Later on:
IL2 targeting agents (blocks T cell formation)
Lymphocyte trafficking targets to block T cell exit
Biological agents for immunosuppression?
rATG - rabbit derived anti-thymoglobulin to deplete lymphocyres
Humanised monoclonal antibodies e.g. antiCD52 (also depletes), anti-IL2R and CTLA4-Ig to block costimulation for anergic T cells
Dosage of drugs?
Induction therapy - high dose at/before transplantation blocks sensitisation and inhibits allorecognition in inflammation period
Maintenance therapy - lower dose continually
Allows minimum use of drugs
Better option for immunosuppression?
Tolerance - avoids immune system suppression that causes illness in patients later on
Short term intervention at the time to ignore transplant antigens, keeps rest of the system active
