title: Homing characteristics of donor T cells after experimental allogeneic bone marrow transplantation and posttransplantation therapy for multiple myeloma.
abstract: Relapse and graft-versus-host disease remain major problems associated with allogeneic bone marrow (BM) transplantation (allo-BMT) and posttransplantation therapy in patients with multiple myeloma (MM) and other hematologic malignancies. A possible strategy for selectively enhancing the graft-versus-myeloma response and possibly reducing graft-versus-host disease is to increase the migration of alloreactive T cells toward the MM-containing BM. In the present study, we characterized the BM-homing behavior of donor-derived effector T cells in a novel allo-BMT model for the treatment of MM. We observed that posttransplantation immunotherapy consisting of donor lymphocyte infusion (DLI) and vaccination with minor histocompatibility antigen-loaded dendritic cells (DCs) was associated with prolonged survival compared with allo-BMT with no further treatment. Moreover, CD8(+) effector T cells expressing inflammatory homing receptors, including high levels of CD44, LFA-1, and inflammatory chemokine receptors, were recruited to MM-bearing BM. This was paralleled by strongly increased expression of IFN-γ and IFN-γ-inducible chemokines, including CXCL9, CXCL10, and CXCL16, especially in mice treated with DLI plus minor histocompatibility antigen-loaded DC vaccination. Remarkably, expression of the homeostatic chemokine CXCL12 was reduced. Furthermore, IFN-γ and TNF-α induced BM endothelial cells to express high levels of the inflammatory chemokines and reduced or unaltered levels of CXCL12. Finally, presentation of CXCL9 by multiple BM endothelial cell-expressed heparan sulfate proteoglycans triggered transendothelial migration of effector T cells. Taken together, our data demonstrate that both post-transplantation DLI plus miHA-loaded DC vaccination and MM growth result in an increased expression of inflammatory homing receptors on donor T cells, decreased levels of the homeostatic BM-homing chemokine CXCL12, and strong induction of inflammatory chemokines in the BM. Thus, along with increasing the population of alloreactive T cells, post-transplantation immunotherapy also might contribute to a more effective graft-versus-tumor response by switching homeostatic T cell migration to inflammation-driven migration.
authors.affiliation: Department of Laboratory Medicine, Laboratory of Hematology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. r.vandervoort@labgk.umcn.nl
authors.forename: Robbert
authors.initials: R
authors.lastname: van der Voort
authors.forename: Thomas J H
authors.initials: TJ
authors.lastname: Volman
authors.forename: Viviènne
authors.initials: V
authors.lastname: Verweij
authors.forename: Peter C M
authors.initials: PC
authors.lastname: Linssen
authors.forename: Frans
authors.initials: F
authors.lastname: Maas
authors.forename: Konnie M
authors.initials: KM
authors.lastname: Hebeda
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000276:immunology; D054357:Chemokine CXCL10 / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology; D054370:Chemokine CXCL9 / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology* / Q000637:transplantation; D020350:Graft vs Tumor Effect / Q000276:immunology; D007167:Immunotherapy; D007371:Interferon-gamma / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology; D017710:Lymphocyte Transfusion; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000737:chemistry / Q000276:immunology; D009101:Multiple Myeloma / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology
chemical_list: D054357:Chemokine CXCL10; D054377:Chemokine CXCL12; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C515256:Cxcl12 protein, mouse; C498926:Cxcl16 protein, mouse; C485969:Cxcl9 protein, mouse; D015778:Minor Histocompatibility Antigens; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma