MHC and transplant rejection Flashcards
what must be balanced in transplantation?
sensitivity and clinical benefit
is cellular rejection reversible?
yes usually reversible
what is allorecognition?
the ability of an organism to identify its own tissue and differentiate from another organisms
where is the MHC complex?
it is a gene complex on chromosome 6
what MHC proteins are in humans?
HLA’
how was the location of antibodies and immunological memory discovered?
location in serum as when tissue from serum added to mice was rejected
memory - skin grafts
how can you transfer immunological memory between mice?
transferring the lymphocytes
what is rejection determined by?
lymphocytes - antigens are rejected by them - basis of transplantation
what do antibodies do?
they destroy foreign white blood cells
what does MHC comprise?
alpha helices and beta pleated sheets - HLA have peptides running through the middle
what types of MHC antigens are there and what are the subtypes of these?
class I which has A B and C and class II which has DR DQ and DP
where are class I found?
on all nucleated cells - therefore not on RBC as they lose their nucleus
what does polymorphic mean and what does it apply to?
Class I is polymorphic HLA antigens and it means that they vary between different people of different backgrouns
what is the structure of the HLA antigen of class I?
three alpha helices with a groove between first two on top of beta pleated sheet - then completed by a heterodimer
what is a heterodimer?
it is a protein made of two different polypeptide chains
what is the structure of class II?
heterodimer with one chain as beta and one as alpha - they are expressed selectively on APCs most dendritic and also in Kupffer cells in the liver and Langerhans in the skin
how are HLA antigens arranged on chromosome 6?
they all sit on the same area
where are T cell receptors found?
sit on top of the HLA molecule
how are the HLA antigens adapted for evolution?
they have different peptides in the grooves allowing them to recognise different peptides to stay alive - highly polymorphic due to increased number of alleles
what is meant by humans are genetically outbred?
there are different HLA antigens in different people
what is the chance of offspring having same antigen as parents?
`1 in 4
why is it difficult to find a bone marrow transplant?
if the parent or sibling is not the same HLA antigen then it is hard due to diversity
what is a role of HLA molecules?
protection against infection
how do class I molecules work?
they work on intracellular foreign proteins - the foreign peptides are processed in the ER put on class I molecules and put on surface
how do class II molecules work?
foreign molecules are endocytosed - they are extracellular molecules
what is an example of HLA polymorphisms that are beneficial and some that are detrimental?
beneficial - the HLA-B53 interaction in sickle cell means that you have a protection against malaria - it is an unknown mechanism but is thought to be due to genetic diversity and maintaining a population through immune response and also HLA-DR13 for HIV-1.
detrimental - some may also have a higher risk of having a disease such as Goodpasture’s - if you have DR2 are 15x more likely to develop it
autoimmune conditions are also associated with HLA polymorphisms
how are cytosolic pathogens dealt with?
degraded in the cytosol and bind to MHC class I, then they are presented to effector CD8 T cells and this results in cell death
how are intervesicular pathogens dealt with?
the are degraded in endocytic vesicles with a low pH and bind to MHC class II - these are then presented to effector CD4 T cells and there is activation to kill intervesicular bacteria and parasites
how are extracellular pathogens and toxins?
they are degraded in endocytic vesicles with a low pH and bind to MHC class II, they are presented to effector CD4 T cells and then there is the activation of B cells to secrete Ig to eliminate extracellular bacteria/toxins
where are lymphocytes educated?
in the thymus - see their own APCs with own HLA molecules
what is positive selection?
selecting for T cells that recognise an HLA molecules
what is negative selection?
selecting against T cells taht recognise own HLA molecules too much
how do foreign antigens get recognised from donors in the recipient?
the foreign cells from the donor migrate to the inguinal lymph node and are recognised by lymphocytes in the recipient as foreign giving a vigorous immune response
what is the different between autologous and allogenic transplant?
autologous is the persons own stem cells whereas allogenic is from a donor who has the same HLA antigens as the recipient
what happens at the immunological synapse in order to get a full immunological repsonse?
co-stimulation - CD4 are activated and produce B for ABscells and release cytokokines for activation of macrophages and CD8 T cells will destroy any cells with a class I molecule on them
what type of reaction will CD4 produce?
delayed hypersensitivity reaction
what is the probability that siblings will share at least one haplotype?
get one haplotype from father and one from mother and therefore 1 in 2 chance of sharing one
what is tissue typing?
it is matching HLA types to avoid rejection - give drugs to make sure do not react as strongly
what do you sequence for matching?
the short arm of chromosome 6 - better long term outcome and less rejection if better matched
what does a 0 antigen mismatch mean?
they are most similar - best survival and least rejection
what are the two types of HLA typing?
serological and molecular
what is serological?
cell based
what is moelcular?
extraction of DNA, amplification and detection of sequence polymorphisms for hybridisation to probes and sequencing
what is the importance of HLA typing/?
less rejection episodes, better survival change of grafts, less sensitisation and establish relationship - paternity testing
what is the renal transplant pathway?
medically fit for listing, HLA typing, details on waiting list and regular screening scan for serum ABs, organ offer, real or virtual cross match, further test and monitoring
what is sensitisation?
it is when an organism becomes abnormally sensitive to antibodies
what happens during dialysis every 3 months?
screening to make sure that the individual is not sensitised - pregnancy, previous transplant or transfusion when white cells contaminate blood
what is the importance of screening for sensitisation?
it can occur generally to many HLA types or specifically against the donor . It avoids aborted transplantation and prevents hyperacute rejection
what is CDC?
complement dependent cytotoxicity test - detects complement fixing IgG/ IgM HLA and non HLAs
what are the complements of CDC?
over 30 years of experience and it is inexpensive
what are the disadvantages of CDC?
limited sensitivity, subjectivity, non complement ABs, viable reagent supply and quality control, non HLA AB interference
what is the process of CDC?
recipient serum is added to a petri dish and the donor T (class I) and B (class I and II) are added - complement is added and can see if have ABs as will bind
what is luminex antibody detection?
there are beads with recombinant HLA molecules on them - if the patient has ABs to these HLA molecules there will be fluorescence
out of cellular, flow cytometry and solid phase methods, what is the most expensive, sensitive and has the most non complement fixing antibodies?
cellular - least for all
flow - middle
solid - most for all
for cellular, flow cytometry and solid phase methods which is the most transplantable?
cellular then flow then solid phase
out of cellular, flow cytometry and solid phase which has the most non HLA ABs?
flow cytometry most, then cellular, non in solid phase
what is the earliest form of rejection?
acute antibody mediated rejection
what are the next two forms of rejection?
acute cellular rejection and chronic antibody mediated rejection
what is the process of rejection?
anti HLA antibodies will bind to epithelium and activate - this will then bind the antigen and activate the complement, the Fc portion of the AB binds immune cells
why is a pre-transplant crossmatch needed?
if there are pre-existing antibodies when the transplant occurs then when the blood flows in the antibodies will bind, activate the complement system resulting in clotting and death - hyperacute rejection
what are the 3 types of pre-formed antibodies?
blood group
anti-HLA molecules
antibodies against animals of lower species - these are directed against carbohydrates of all lower mammals in the evolutionary hierarchy
what types of rejection can there be?
xenography rejection - anti-gala1-3gal
HLA-incompatible transplantation - anti-HLA
ABO incompatible transplantation - ABO antibodies
what is the main cell in acute cellular rejection?
T cell dependent - need T cell immunosupression
what is acute cellular rejection directed against?
it is the effect of HLA mismatch - directed against foreign HLA antigens
what can trigger an acute cellular rejection?
interstitial infiltrate like ATIN
BK (SV40 and PCR)
how will acute cellular rejection present?
dark lymphocytes and invasion of lymphocytes 7-10 days after transplant
is acute cellular rejection reversible?
yes - immunosupressants and give large dose of methylprednisolone if exacerbations
what is a biomarker of poor transplant outcome?
post transplant anti HLA antibodies
why is post transplant anti HLA antibodies so detrimental?
it is expensive and there is no known treatment except the intensification of immunosupressants
