Mechanistic studies on human minor histocompatibility antigens in graft-versus-host disease

Kim, Y.H. (2013)

Doctoral Thesis

In this thesis, we have explored the mechanism of minor H antigen-related GVHD. Hereto, we developed and validated new methods to detect and to phenotype minor H antigen-specific T cells on cryo-preserved human tissues. Using these methods, we investigated the influence of the ubiquitously expressed minor H antigen HY in skin GVHD. This first report on the in situ detection of skin-infiltrating HY-specific T cells in GVHD affected tissue of pediatric patient__s points to an active role of these T cells in the pathophysiology of acute GVHD after gender mismatched HSCT. Using our skin explant methodologies, we also aimed at gathering insights into the postulated involvement of hematopoietic-system restricted HA-1 in GVHD. This study was challenged by the contradictory results of clinical studies on the influence of HA-1 with GVHD. We showed that recognition of skin samples reconstituted with mature DCs, facilitated infiltration and local activation of HA-1-specific T cells. Although the infiltrated and activated HA-1-specific T cells did not cause skin tissue destruction in our model, our results provide a first step in understanding the reported association of HA-1 mismatching with clinical GVHD. Finally, we performed a large multi-center population-based study comprising 849 HSCT pairs, investigating the effect of broadly expressed and hematopoietic restricted minor H antigen-mismatching on GVHD and on relapse incidence after HLA-matched and HLA-identical HSCT. We showed that mismatching for broadly expressed autosomally encoded minor H antigens is associated with increased GVHD in HLA-identical, but not in HLA-matched unrelated HSCT. Disparities between donor and recipient for hematopoietic system-specific autosomally encoded minor H antigens do neither influence the development of GVHD nor had an effect on relapse incidence. Importantly however were the significantly lower relapse rates and disease free survival observed in those patients who suffered from GVHD.

• Minor Histocompatibility antigens
• In situ visualization
• HSCT
• GVHD
• BMT
• Antigen-specific T cells

• All authors: Kim, Y.H.
• Supervisor: Goulmy, E.A.J.M.
• Co-supervisor: Spierings, E.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2013-01-30
• ISBN (print): 9789064646294