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Cell Therapy & Immunotherapy
The allogeneic HLA-DP-restricted T-cell repertoire provoked by allogeneic dendritic cells contains T cells that show restricted recognition of hematopoietic cells including primary malignant cells
Aicha Laghmouchi, Conny Hoogstraten, Peter van Balen, J.H. Frederik Falkenburg and Inge Jedema
Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands
ABSTRACT
Stem cell grafts from 10/10 HLA-matched unrelated donors are often mismatched for HLA-DP. In some patients, donor T-cell responses targeting the mismatched HLA-DP allele(s) have been found to induce a specific graft-versus-leukemia effect without coinciding graft- versus-host disease, whereas in other cases significant graft-versus-host disease occurred. Cell-lineage-specific recognition patterns within the allogeneic HLA-DP-specific donor T-cell repertoire could explain the dif- ferential clinical effects mediated by donor T cells after HLA-DP-mis- matched allogeneic stem cell transplantation. To unravel the composi- tion of the HLA-DP T-cell repertoire, donor T-cell responses were pro- voked by in vitro stimulation with allogeneic HLA-DP-mismatched monocyte-derived dendritic cells. A strategy including depletion of reac- tivity against autologous dendritic cells allowed efficient identification and enrichment of allo-reactive T cells upon stimulation with HLA-DP- mismatched dendritic cells. In this study we elucidated that the allogene- ic HLA-DP-restricted T-cell repertoire contained T cells with differential cell-lineage-specific recognition profiles. As expected, some of the allo- geneic HLA-DP-restricted T cells showed broad recognition of a variety of hematopoietic and non-hematopoietic cell types expressing the tar- geted mismatched HLA-DP allele. However, a significant proportion of the allogeneic HLA-DP-restricted T cells showed restricted recognition of hematopoietic cells, including primary malignant cells, or even restricted recognition of only myeloid cells, including dendritic cells and primary acute myeloid leukemia samples, but not of other hematopoiet- ic and non-hematopoietic cell types. These data demonstrate that the allogeneic HLA-DP-specific T-cell repertoire contains T cells that show restricted recognition of hematopoietic cells, which may contribute to the specific graft-versus-leukemia effect without coinciding graft-versus- host disease.
Introduction
T-cell-depleted allogeneic stem-cell transplantation (alloSCT) can be applied in the treatment of patients suffering from hematologic malignancies.1-4 The aim of this approach is to replace the hematopoietic system of the patient (including the malignant cells) with a healthy hematopoietic system reconstituted from a stem cell graft of an HLA-matched donor.5-9 The depletion of T cells from the graft reduces the occurrence of acute graft-versus-host disease (GvHD) mediated by alloreactive donor T cells targeting normal, non-hematopoietic cells of the patient.3,10-12 However, donor T cells are essential in the beneficial graft-versus- leukemia (GvL) effect and T-cell immunity is also required for anti-viral protec-
Ferrata Storti Foundation
Haematologica 2019 Volume 104(1):197-206
Correspondence:
a.laghmouchi@lumc.nl
Received: March 22, 2018. Accepted: August 17, 2018. Pre-published: September 20, 2018.
doi:10.3324/haematol.2018.193680
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/1/197
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