hla and transplantation

two types of hsct

autologous (patient is his own donor) and allogeneic (volunteer donor, can be related or unrelated)

autologous stem cell transplant

collection, high dose chemotherapy (conditioning: dose escalation, reduces risk of relapse), stem cell infusion, 2 weeks before blood cells normal

allogeneic stem cell transplant

high dose chemotherapy (slightly longer time - both to reduce risk of relapse but also immune suppression and allow space), stem cell infusion, takes longer till blood cells normal - 2-4 weeks.

sources of HSCs

bone marrow (general anaesthesia), peripheral blood (automated apheresis, pre-stimulation with G-CSF), umbilical cord blood (collected at birth, cryopreserved cells)

pros/cons of peripherla blood vs bone marrow donations

no hospital admission, no general anaesthetic, no significant blood loss, no transfusion risk, early return to work, 2-3x more progenitor cells as marrow, quicker engraftment.

PBSCs have 10x more CD3+ cells than bone marrow: worse graft-vs-host disease, better anti-tumour effect

main causes of treatment failure in HSC transplantation

toxicity (infection, haemorhage, organ failure, graft-vs-host disease, secondary malignancy), disease recurrance

HLA fucntion, location on chrmosome

presentation of antigens to T-cells, immune system regulation. chr6

HLA class 1

genes: A, B, C

non-covalently linked with beta-2 microglobulin chain.

heavy chain 3 amino acid domains: alpha 1&2 most polymorphisms (binding groove here). alpha 3 less variable.

HLA-2

2 chains. heavy (alpha) and light (beta). 2 domains per chain.

beta domain: n-terminal region antigen binding. c-terminal region: TCR binding

beta 1 contains most polymorphisms in 3 or 4 HVRs.

protein degradation

ubiquitination targets proteins for degradation in proteosome.

importance of hla on transplantation

need to be matched polymoprhisms. the number of polymorphisms in all populations are increasing. odds of finding a match vary by ethnic group.

effect of HLA-mismatch differs depending on what HLA is mismatched.

where is it safe to mismatch

HLA-2 DP or DQ. relative risk ratio not significantly altered with mismatch

where is it not safe to mismatch

HLA-1: A, B, or C, and HLA-2 DR all have significantly worse risk ratio.

Severe aplastic anaemia

bone marrow stops working and is empty. if no bone marrow transplant, death by bleeding or infection

why do relapses of CML occur in bone marrow transplants between identical twins

T-cells from donor are transplanted as well. can detect and destroy any residual cancer - will recognise slight differences in HLA as foreign to kill. so non-identical transplant is ideal in malignant conditions. (inducing mild graft-vs-host disease)

graft-vs-host disease

T-cells transplanted from donor recognise recipient’s HLA mismatch as foreign and attack the recipient’s tissues. can be fatal if severe.

balance between t-cell replete vs T-cell deplete trnasplants

want to get sweet spot between graft-vs leukaemia but minimal graft-vs-host disease to maximise remission but reduce toxicity

utilised in more recent times to reduce chemo doses before transplantation to reduce toxicity. infusion of only donor t-cells given to maximise this too.

reduced intensity conditioned HSCT

less toxic than traditional (myeloablative) conditioned HSCT (less mucositis and shorter duration of neutropenia/thrombocytopenia)

useful for patients less suited to traditional method (age/co-morbidities)

depends on graft-vs-tumour effect (takes 3 months tho so not suitable for patients with fast growing disease)

solid organ transplant rejection

direct and indirect recognition

direct recognition

donor apcs migrate to lymph node and induce anti-MHC immune response. happens via CD8 so is faster

indirect regonjsiton

recipient APCs process peptides derived from graft and anti-graft immune repsosne occurs. occurs by CD4 so slower

CAR T-cell therapy

genetically engineered T0cells altered to express an articifical receptir: CAR - is not MHC-restricted.

how to improve transplants in future

separate GvL from GvHD.

learn from cord blood (less immunogenic but still causes relapse)

build on reduced intensity conditioned HSCT, timely HSCT intervention, targeted immune therapy.