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Front. Immunol. | doi: 10.3389/fimmu.2018.00331

Tissue damage caused by myeloablative, but not non-myeloablative, conditioning before allogeneic stem cell transplantation results in dermal macrophage recruitment without active T-cell interaction.

  • 1Hematology, Leiden University Medical Center, Netherlands
  • 2Pathology, Leiden University Medical Center, Netherlands
  • 3Molecular Cell Biology, Leiden University Medical Center, Netherlands
  • 4Center for Gynaecologic Oncology, VU University Amsterdam, Netherlands

Introduction
Conditioning regimens preceding allogeneic stem cell transplantation (alloSCT) can cause tissue damage and acceleration of the development of graft-versus-host disease (GVHD). T-cell depleted alloSCT with postponed donor lymphocyte infusion (DLI) may reduce GVHD because tissue injury can be restored at the time of DLI. In this study, we investigated the presence of tissue injury and inflammation in skin during the period of hematologic recovery and immune reconstitution after alloSCT.

Methods
Skin biopsies were immunohistochemically stained for HLA class II, CD1a, CD11c, CD40, CD54, CD68, CD86, CD206, CD3 and CD8. HLA class II expressing cells were characterized as activated T-cells, antigen presenting cells (APC) or tissue repairing macrophages. In sex mismatched patient and donor couples, origin of cells was determined by multiplex analysis combining XY-FISH and fluorescent immunohistochemistry.

Results
No inflammatory environment due to pretransplant conditioning was detected at the time of alloSCT, irrespective of the conditioning regimen. An increase in HLA class II positive macrophages and CD3 T-cells was observed 12-24 weeks after myeloablative alloSCT, but these macrophages did not show signs of interaction with the co-localized T-cells. In contrast, during GVHD, an increase in HLA class II expressing cells coinciding with T-cell interaction was observed, resulting in an overt inflammatory reaction with presence of activated APC, activated donor T-cells and localized upregulation of HLA class II expression on epidermal cells. In the absence of GVHD, patient derived macrophages were gradually replaced by donor derived macrophages, although patient derived macrophages were detectable even 24 weeks after alloSCT.

Conclusion
Conditioning regimens cause tissue damage in the skin, but this does not result in a local increase of activated APC. In contrast to the inflamed situation in GVHD, when interaction takes place between activated APC and donor T-cells, the tissue damage caused by myeloablative alloSCT results in dermal recruitment of HLA class II positive tissue repairing macrophages co-existing with increased numbers of patient and donor derived T-cells, but without signs of specific interaction and initiation of an immune response. Thus, the local skin damage caused by the conditioning regimen appears to be insufficient as single factor to provoke GVHD induction.

Keywords: HLA class II, Tissue damage, allogeneic stem cell transplantation, Graft vs Host Disease, Macrophages, Skin

Received: 05 Dec 2017; Accepted: 06 Feb 2018.

Edited by:

Hermann Einsele, University of Würzburg, Germany

Reviewed by:

Ralf Dressel, Universitätsmedizin Göttingen, Germany
Amir A. Toor, Virginia Commonwealth University, United States  

Copyright: © 2018 Van Balen, Van der Zouwen, Kruisselbrink, Eefting, Szuhai, Jordanova, Falkenburg and Jedema. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD. Peter Van Balen, Leiden University Medical Center, Hematology, Leiden, Netherlands, p.van_balen@lumc.nl