title: Collateral damage of nonhematopoietic tissue by hematopoiesis-specific T cells results in graft-versus-host disease during an ongoing profound graft-versus-leukemia reaction.
abstract: After allogeneic stem cell transplantation (allo-SCT), donor T cells may recognize minor histocompatibility antigens (MiHA) specifically expressed on cells of the recipient. It has been hypothesized that T cells recognizing hematopoiesis-restricted MiHA mediate specific graft-versus-leukemia (GVL) activity without inducing graft-versus-host disease (GVHD), whereas T cells recognizing ubiquitously expressed MiHA induce both GVL and GVHD reactivity. It also has been hypothesized that alloreactive CD4 T cells are capable of mediating specific GVL reactivity due to the hematopoiesis-restricted expression of HLA class II. However, clinical observations suggest that an overt GVL response, associated with expansion of T cells specific for hematopoiesis-restricted antigens, is often associated with GVHD reactivity. Therefore, we developed in vitro models to investigate whether alloreactive T cells recognizing hematopoiesis-restricted antigens induce collateral damage to surrounding nonhematopoietic tissues. We found that collateral damage to MiHA-negative fibroblasts was induced by misdirection of cytotoxic granules released from MiHA-specific T cells activated by MiHA-positive hematopoietic cells, resulting in granzyme-B-mediated activation of apoptosis in the surrounding fibroblasts. We demonstrated that direct contact between the activated T cell and the fibroblast is a prerequisite for this collateral damage to occur. Our data suggest that hematopoiesis-restricted T cells actively participate in an overt GVL response and may contribute to GVHD via induction of collateral damage to nonhematopoietic targets.
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Boris
authors.initials: B
authors.lastname: van der Zouwen
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Alwine B
authors.initials: AB
authors.lastname: Kruisselbrink
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Frederik Falkenburg
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: i.jedema@lumc.nl.
authors.forename: Inge
authors.initials: I
authors.lastname: Jedema
mesh_terms: D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology; D006410:Hematopoiesis / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D018613:Microscopy, Confocal; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D015778:Minor Histocompatibility Antigens
keywords: Allogeneic stem cell transplantation; Collateral damage; Graft-versus-host disease; Minor histocompatibility antigen; T cell