HLA und Stammzelltransplantation

31. Informationsgespräch der Blutspendezentrale für Wien,

Niederösterreich und Burgenland

Issues

• Humanes Leukozyten Antigen-System– Struktur & Zellbiologie– Polymorphismus &

Peptide– Alloreaktion (TCR,

KIR)– Typisierung

• Stammzelltransplantation– Spender-Auswahl– Unintelligent Mismatch– Intelligent Mismatch– HLA ist viel, und doch

nicht alles

Proteasome

Cytosol ER

TA

P

Cell membrane

ER MIIC

Cell membrane

DMDO

Systematik-Allele (n)

• Klasse I– Klassisch

• HLA-A 617

• HLA-B 960

• HLA-C 335

– nicht-klassisch

• HLA-E 9

• HLA-F 21

• HLA-G 28

– post-modern

• MICA 61

• MICB 30

• Klasse II

– Klassisch

• DRB1 542

• DQB1 87

• DPB1 127

– nicht-klassisch

• DMA 4

• DMB 7

• TAP1 7

• TAP2 4

HLA-Gene - Chromosom 6p21

B C ADP DQ DR

127 x 87 x 542 x 960x335 x 617

= 1,18 x 1015

Klasse II K l a s s e I

Anzahl der Allele:

TCRα, ß

HLA h.c.ß2 MGPeptide

allo

allo

alloallo

KIR-HLA vs. TCR-HLA

KIR2DL2

KIR2DL2

KIR2DL2

KIR2DL2

KIR2DL2

KIR2DL2

The Size Problem

Immunoglobulin

HLA

Donor Selection

Type Patient

Type Donor

Crossmatch

Interpretation

Blood Groups (easy)

Type Patient

Type Donor

Crossmatch

Interpretation

A

A

...

�

A

0

...

�

A

B

⌧

⌧

HLA (complicated)

Type Patient

Type Donor

How should we go on?

Interpretation

HLA-A2, B8, DRB1*0301

HLA-A*0201, B*0801, Cw*0701, DRB1*0301, DRB3*0101, DQB1*0201

?

�⌧

HLA (complicated, because)

Loci?

Resolution?

Match?

Technique?

Low resolution ... 2 digits A*02High resolution ... 4 digits A*0201

A, B, C, DRB1, DRB3/4/5, DQB1, DP

A mismatch is a mismatch is a ...

How many positions identified?

Cumulative incidence estimates of grades III-IV acute GVHD according to recipient disparityPetersdorf et al., Blood 1998

Mismatch

Time

Petersdorf et al. (Blood 2004; 104: 2976)

cGVHD

Greinix et al. (Bone Marrow Transplantation 2005; 35: 57)

Survival

Greinix et al. (Bone Marrow Transplantation 2005; 35: 57)

Intelligent Mismatch

Kärre, Science 295, 2002, 2029 - 2031

Relapse and KIR-Ligand Differences

Beelen et al. (Blood 2005; 105: 2594)

NOD2/CARD15

• an intracellular sensor to muramyl dipeptide

• mediating consecutive nuclear factor B (NF-B) activation4

• expression restricted to intestinal epithelial cells (IECs) and cells of monocyte-macrophage lineage

Holler et al., Blood 104:889 (2004)

NOD2/CARD15