The Rough Guide to Transplant Immunology

Brendan Clark

Transplant Immunology, St James's University Hospital, Leeds.

Paediatric Nephrology Trainees Meeting

'If I were to stick my organ in you, you'd probably reject it'

Blood Groups

•Immunofluorescent staining has revealed blood group substance in the cell membranes of all vascular endothelial cells, and certain epithelial cells. Szulman, A. E. Chemistry, distribution, and function of

blood group substances.Ann. Rev. Med. 17:307-322, 1966

• Normal individuals have naturally occurring anti-A or anti-B isoagglutinins

• Poor outcome of transplants performed between blood group incompatible individuals.

Transfusion Rules

Donor

A B AB O

A Y N N Y

B N Y N Y

Recipient

AB Y Y Y Y

O N N N Y

First and Second Set Rejection

Medawar

Rabbit skin graft model

Recipient Donor Graft loss strain strain

X Y 10-14 days 1st set rejection

X' Y 5-7 days 2nd set rejection

X' Z 10-14 days 1st set rejection

Major Histocompatibility Antigens

HLA Class I (HLA-A, B, Cw)

HLA Class II (HLA-DR, DQ, DP)

6p21.3

Heterodimeric molecules

Heavy and light chain non-covalently associated

Membrane bound glycoproteins

HLA CI A,B,C molecules composed of MHC encoded 45kd heavy chain non-covalently associated with non-polymorphic B2 microglobulin

HLA CII DR, DQ, DP molecules composed of MHC encoded 31-34 kd associated a chain non-covalently associated with 26-29 kd B chain

HLA CI bound peptides usually 8-9 aa in length. CII generally longer and more variable in length 14-21 aa.

Polymorphic residues encoded by different alleles are found in this peptide binding groove

Principal CI genes are those encoding heavy chains of the six CI isoforms HLA-A,B,C, E,F,G. The gene encoding B2 microglobulin is located on Chr. 15

There are five isotypes of the CII protein – HLA-DM, DO, DP,DQ,DR. Genes for both the CII a and B chains are located in the CII region

HLA Polymorphism (DNA vs Serology)

HLA Class I

HLA-A 414 (18)HLA-B 788 (35)HLA-Cw 210 (8)

HLA Class II

HLA-DRB1 506 (14)HLA-DQB1 100 (6)HLA-DPB1 143

Major Histocompatibility Antigens

Class I antigens found on all nucleated cells

Class II antigens primarily expressed on B lymphocytes but expression can be induced on T lymphocytes and other cells

Inheritance

Mendelian inheritance

En-bloc from each parental chromosome (HLA- A,B,Cw, DR, DQ,DP). Each individual inherits two antigens at a given locus.

Codominant expression. All of the inherited antigens are displayed on the cell surface (HLA phenotype).

Haplotype segregation (HLA genotype)

ab x cd ac ad bc bd

Terasaki (Transplantation 1969: 7: 246-250)

Transplants between HLA-identical siblings have best outcome.

HLA-DR ~ HLA-B > HLA-A

Terminology of Mismatching

HLA A B DR

0 0 0 Matched

1 0 0

0 1 0 Favourable mismatch

1 1 0

1 1 1 Non-favourable mismatch

Direct and Indirect Antigen Presentation

Renal Rejection

Hyperacute Pre-existing DSA

‘Hidden Hyperacute’ Low level pre-existing DSA

Accelerated acute Memory – humoral/cellular

Acute de-novo – humoral/cellular

Chronic smouldering humoral/cellular & non-immune

-Cellular Infiltrate - Arterial fibrosis

- Intimal thickening

Acute Cellular Rejection Chronic Allograft Nephropathy

Sensitisation

Any event which elicits an HLA directed immune response

Origins of Patient Sensitisation

Pregnancy

Blood transfusion

Transplantation

Kissmeyer-Nielson ( Lancet 1966: 2: 662-665)

Hyperacute rejection of kidney allografts associated with pre-existing humoral antibodies against donor cells.

Antibody-Mediated Rejection

Antibody reacts with the endothelial lining of theblood vessel wall

Complement fixation leadsto neutrophil recruitmentand endothelial destruction

Damaged endotheliumcauses platelet accumulationand thrombus formation

Hyperacute Rejection

- fibrin accumulation

- thrombosis

- vessel occlusion

- necrosis

Effect of Sensitisation on Waiting Time to Transplantation

Sensitisation Size of Median Status group waiting

time

unsensitised 2027 353

sensitised 510 553

highly sensitised 42 716

Statistics prepared by UK Transplant from the National Database maintained on behalf of transplant services in the UK and ROI

Reasons for > Waiting Times in Sensitised Patients

• Eligibility > opportunity for transplant

• Unacceptable antigens > opportunity for transplant

• Positive crossmatch > opportunity for transplant

UKT Allocation Rules

Allocation in priority order 000 HSP or DR hom paeds > 000 non-HSP paeds > 000 HSP or DR hom adults > 000 non-HSP adults and 100,010,110 paeds > all others

Paediatric patients in first two groups sorted on wait time

In other groups points score used to sort rank order [points score = waiting time points + HLA match and age points combined + age difference points+ location points + HLA-B homozygous points + HLA-DR homozygous points + local priority points