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MHC and transplant rejection Flashcards

1
Q

what must be balanced in transplantation?

A

sensitivity and clinical benefit

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2
Q

is cellular rejection reversible?

A

yes usually reversible

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3
Q

what is allorecognition?

A

the ability of an organism to identify its own tissue and differentiate from another organisms

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4
Q

where is the MHC complex?

A

it is a gene complex on chromosome 6

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5
Q

what MHC proteins are in humans?

A

HLA’

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6
Q

how was the location of antibodies and immunological memory discovered?

A

location in serum as when tissue from serum added to mice was rejected
memory - skin grafts

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7
Q

how can you transfer immunological memory between mice?

A

transferring the lymphocytes

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8
Q

what is rejection determined by?

A

lymphocytes - antigens are rejected by them - basis of transplantation

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9
Q

what do antibodies do?

A

they destroy foreign white blood cells

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10
Q

what does MHC comprise?

A

alpha helices and beta pleated sheets - HLA have peptides running through the middle

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11
Q

what types of MHC antigens are there and what are the subtypes of these?

A

class I which has A B and C and class II which has DR DQ and DP

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12
Q

where are class I found?

A

on all nucleated cells - therefore not on RBC as they lose their nucleus

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13
Q

what does polymorphic mean and what does it apply to?

A

Class I is polymorphic HLA antigens and it means that they vary between different people of different backgrouns

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14
Q

what is the structure of the HLA antigen of class I?

A

three alpha helices with a groove between first two on top of beta pleated sheet - then completed by a heterodimer

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15
Q

what is a heterodimer?

A

it is a protein made of two different polypeptide chains

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16
Q

what is the structure of class II?

A

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

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17
Q

how are HLA antigens arranged on chromosome 6?

A

they all sit on the same area

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18
Q

where are T cell receptors found?

A

sit on top of the HLA molecule

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19
Q

how are the HLA antigens adapted for evolution?

A

they have different peptides in the grooves allowing them to recognise different peptides to stay alive - highly polymorphic due to increased number of alleles

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20
Q

what is meant by humans are genetically outbred?

A

there are different HLA antigens in different people

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21
Q

what is the chance of offspring having same antigen as parents?

A

`1 in 4

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22
Q

why is it difficult to find a bone marrow transplant?

A

if the parent or sibling is not the same HLA antigen then it is hard due to diversity

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23
Q

what is a role of HLA molecules?

A

protection against infection

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24
Q

how do class I molecules work?

A

they work on intracellular foreign proteins - the foreign peptides are processed in the ER put on class I molecules and put on surface

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25
Q

how do class II molecules work?

A

foreign molecules are endocytosed - they are extracellular molecules

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26
Q

what is an example of HLA polymorphisms that are beneficial and some that are detrimental?

A

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

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27
Q

how are cytosolic pathogens dealt with?

A

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

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28
Q

how are intervesicular pathogens dealt with?

A

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

29
Q

how are extracellular pathogens and toxins?

A

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

30
Q

where are lymphocytes educated?

A

in the thymus - see their own APCs with own HLA molecules

31
Q

what is positive selection?

A

selecting for T cells that recognise an HLA molecules

32
Q

what is negative selection?

A

selecting against T cells taht recognise own HLA molecules too much

33
Q

how do foreign antigens get recognised from donors in the recipient?

A

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

34
Q

what is the different between autologous and allogenic transplant?

A

autologous is the persons own stem cells whereas allogenic is from a donor who has the same HLA antigens as the recipient

35
Q

what happens at the immunological synapse in order to get a full immunological repsonse?

A

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

36
Q

what type of reaction will CD4 produce?

A

delayed hypersensitivity reaction

37
Q

what is the probability that siblings will share at least one haplotype?

A

get one haplotype from father and one from mother and therefore 1 in 2 chance of sharing one

38
Q

what is tissue typing?

A

it is matching HLA types to avoid rejection - give drugs to make sure do not react as strongly

39
Q

what do you sequence for matching?

A

the short arm of chromosome 6 - better long term outcome and less rejection if better matched

40
Q

what does a 0 antigen mismatch mean?

A

they are most similar - best survival and least rejection

41
Q

what are the two types of HLA typing?

A

serological and molecular

42
Q

what is serological?

A

cell based

43
Q

what is moelcular?

A

extraction of DNA, amplification and detection of sequence polymorphisms for hybridisation to probes and sequencing

44
Q

what is the importance of HLA typing/?

A

less rejection episodes, better survival change of grafts, less sensitisation and establish relationship - paternity testing

45
Q

what is the renal transplant pathway?

A

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

46
Q

what is sensitisation?

A

it is when an organism becomes abnormally sensitive to antibodies

47
Q

what happens during dialysis every 3 months?

A

screening to make sure that the individual is not sensitised - pregnancy, previous transplant or transfusion when white cells contaminate blood

48
Q

what is the importance of screening for sensitisation?

A

it can occur generally to many HLA types or specifically against the donor . It avoids aborted transplantation and prevents hyperacute rejection

49
Q

what is CDC?

A

complement dependent cytotoxicity test - detects complement fixing IgG/ IgM HLA and non HLAs

50
Q

what are the complements of CDC?

A

over 30 years of experience and it is inexpensive

51
Q

what are the disadvantages of CDC?

A

limited sensitivity, subjectivity, non complement ABs, viable reagent supply and quality control, non HLA AB interference

52
Q

what is the process of CDC?

A

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

53
Q

what is luminex antibody detection?

A

there are beads with recombinant HLA molecules on them - if the patient has ABs to these HLA molecules there will be fluorescence

54
Q

out of cellular, flow cytometry and solid phase methods, what is the most expensive, sensitive and has the most non complement fixing antibodies?

A

cellular - least for all
flow - middle
solid - most for all

55
Q

for cellular, flow cytometry and solid phase methods which is the most transplantable?

A

cellular then flow then solid phase

56
Q

out of cellular, flow cytometry and solid phase which has the most non HLA ABs?

A

flow cytometry most, then cellular, non in solid phase

57
Q

what is the earliest form of rejection?

A

acute antibody mediated rejection

58
Q

what are the next two forms of rejection?

A

acute cellular rejection and chronic antibody mediated rejection

59
Q

what is the process of rejection?

A

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

60
Q

why is a pre-transplant crossmatch needed?

A

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

61
Q

what are the 3 types of pre-formed antibodies?

A

blood group
anti-HLA molecules
antibodies against animals of lower species - these are directed against carbohydrates of all lower mammals in the evolutionary hierarchy

62
Q

what types of rejection can there be?

A

xenography rejection - anti-gala1-3gal
HLA-incompatible transplantation - anti-HLA
ABO incompatible transplantation - ABO antibodies

63
Q

what is the main cell in acute cellular rejection?

A

T cell dependent - need T cell immunosupression

64
Q

what is acute cellular rejection directed against?

A

it is the effect of HLA mismatch - directed against foreign HLA antigens

65
Q

what can trigger an acute cellular rejection?

A

interstitial infiltrate like ATIN

BK (SV40 and PCR)

66
Q

how will acute cellular rejection present?

A

dark lymphocytes and invasion of lymphocytes 7-10 days after transplant

67
Q

is acute cellular rejection reversible?

A

yes - immunosupressants and give large dose of methylprednisolone if exacerbations

68
Q

what is a biomarker of poor transplant outcome?

A

post transplant anti HLA antibodies

69
Q

why is post transplant anti HLA antibodies so detrimental?

A

it is expensive and there is no known treatment except the intensification of immunosupressants

CP (38 decks)

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