HLA and transplantation

autologous transplant

dose escalation → eradicate residual disease and reduce the risk of relapse

bringing the tumour burden down in hope that the immune system will take over (current testing cant detect lower than 10^10 tumour cells - remission - so treatment has to carry on)

standard allogenic transplant

get stem cells from the donor and put it into recipient

dose escalation - eradicate residual disease and reduce risk of relapse

immune suppression - reduce rejection risk

source of stem cells for HSCT

bone marrow

peripheral blood

umbilical cord blood

PBSC VS BM VS UCB

PBSC contains 2-3x as many progenitor (CD34+) cells as BM

use of PBSC results in engraftment 5-7 days earlier than with BM

PBSC contain ~10 times as many CD3+ as bone marrow - potential for greater anti-tumour effect, results in more severe graft-v-host disease

UCB contains 10 times fewer nucleated cells as BM - double cord blood units frequently required for adult patients, longer time to engraftment

what is engraftment?

successful transplantation of stem cells where they begin to grow and divide and produce new blood cells in the recipient after stem cell transplant

HSC transplantation failure

toxicity - graft-v-host disease, infection, organ failure, haemorrhage, secondary malignancy

disease recurrence

human leukocyte system (HLA) or MHC

presentation on peptides on APC to T cells

regulation of the immune system

HLA class I structure

alpha chain covalently linked with beta-2-microglobulin

peptide binding groove is formed by alpha 1 and 2 domains (responsible for most polymorphisms)

binds short peptides (8-10aa)

HLA class II structure

alpha 1 and 2 (heavy) and beta 1 and 2 (light) chains

beta 1 accounts for most of the polymorphisms

binds longer peptides (13-25+ aa)

beta domain is arranged into 2 functional regions:

• N terminal - antigen binding

• C terminal - TCR binding

function of HLA

class I present endogenous peptides to CD8+ T cells

class II present exogenous peptides to CD4+ T cells

how is a protein degraded during normal cellular function?

protein is ubiquitinated → translocates to proteosome where it is degraded → ubiquitin and proteosome recycled → protein is broken down to fragments (peptides)

role of HLA in transplantation

HLA molecules present peptide antigens to T cells

if the recipient’s immune system recognises the donor HLA as foreign, it may initiate:

• acute rejection - T cell-mediated cytotoxic response

• chronic rejection - long term inflammation, fibrosis, graft failure

• hyperacute rejection - presence of pre-existing anti-HLA Abs

Class I: HLA-A, B, C - expressed on all nucleated cells, CD8+ mediated rejection

Class II: HLA-DR, DQ, DP - expressed on APCs, CD4+ mediated rejection

what is graft-v-host disease?

donor’s immune cells attack to recipient’s body following allogenic HSCT due to genetic differences and the donor-derived T cells recognise the recpient’s cells as foreign (HLA)

solid organ transplantation

immune system of the recipient stays the same

direct pathway: donor APC fragments migrate to lymph nodes and stimulate MHC-I for CD8+ T cell response

indirect pathway: recipient APCs process and present peptides derived from the graft and stimulate MHC-II for CD4+ T cell response