Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response
Cornelis A.M. van Bergen, Simone A.P. van Luxemburg-Heijs, Liesbeth C. de Wreede, Matthijs Eefting, Peter A. von dem Borne, Peter van Balen, Mirjam H.M. Heemskerk, Arend Mulder, Fransiscus H.J. Claas, Marcelo A. Navarrete, Wilhelmina M. Honders, Caroline E. Rutten, Hendrik Veelken, Inge Jedema, Constantijn J.M. Halkes, Marieke Griffioen, J.H. Frederik Falkenburg
Cornelis A.M. van Bergen, Simone A.P. van Luxemburg-Heijs, Liesbeth C. de Wreede, Matthijs Eefting, Peter A. von dem Borne, Peter van Balen, Mirjam H.M. Heemskerk, Arend Mulder, Fransiscus H.J. Claas, Marcelo A. Navarrete, Wilhelmina M. Honders, Caroline E. Rutten, Hendrik Veelken, Inge Jedema, Constantijn J.M. Halkes, Marieke Griffioen, J.H. Frederik Falkenburg
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Research Article Hematology

Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response

Abstract

Patients with leukemia who receive a T cell–depleted allogeneic stem cell graft followed by postponed donor lymphocyte infusion (DLI) can experience graft-versus-leukemia (GVL) reactivity, with a lower risk of graft-versus-host disease (GVHD). Here, we have investigated the magnitude, diversity, and specificity of alloreactive CD8 T cells in patients who developed GVL reactivity after DLI in the absence or presence of GVHD. We observed a lower magnitude and diversity of CD8 T cells for minor histocompatibility antigens (MiHAs) in patients with selective GVL reactivity without GVHD. Furthermore, we demonstrated that MiHA-specific T cell clones from patients with selective GVL reactivity showed lower reactivity against nonhematopoietic cells, even when pretreated with inflammatory cytokines. Expression analysis of MiHA-encoding genes showed that similar types of antigens were recognized in both patient groups, but in patients who developed GVHD, T cell reactivity was skewed to target broadly expressed MiHAs. As an inflammatory environment can render nonhematopoietic cells susceptible to T cell recognition, prevention of such circumstances favors induction of selective GVL reactivity without development of GVHD.

Authors

Cornelis A.M. van Bergen, Simone A.P. van Luxemburg-Heijs, Liesbeth C. de Wreede, Matthijs Eefting, Peter A. von dem Borne, Peter van Balen, Mirjam H.M. Heemskerk, Arend Mulder, Fransiscus H.J. Claas, Marcelo A. Navarrete, Wilhelmina M. Honders, Caroline E. Rutten, Hendrik Veelken, Inge Jedema, Constantijn J.M. Halkes, Marieke Griffioen, J.H. Frederik Falkenburg

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Figure 5

Gene expression for MiHA and accessory molecules

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Gene expression for MiHA and accessory molecules Gene expression for Mi...
Gene expression for MiHA (A) and accessory molecules (B) were determined in 6 different third-party EBV-LCLs (white bars) and 4 different FBs (gray and black bars) using Illumina Human HT-12 v3 BeadChips. FBs were analyzed in steady state (gray bars) and after treatment with 200 IU/ml IFN-γ for 4 days (black bars). (A) Gene expression is depicted for each gene as the MFI ± SD (left panel). T cell recognition of patient EBV-LCLs and FBs (steady-state and IFN-γ–treated) was measured by IFN-γ ELISA after incubation at stimulator/T cell ratios of 9:1 (right panel). Specificities were stratified by the GVHD status of the patient from whom the T cell clones were isolated (top panel shows patients with selective GVL reactivity; bottom panel shows patients with GVHD). MiHA specificities with comparable recognition patterns were grouped as follows: type 1, no FB recognition; type 2, recognition of IFN-γ–treated FBs only; type 3, recognition of both steady-state and IFN-γ–treated FBs. (B) Expression of genes involved in antigen processing and presentation was analyzed, and MFI values ± SD are depicted for the immunoproteasome subunits PSMB8 and PSMB9, the peptide transporters TAP1 and TAP2, and the peptide-presenting HLA-A, HLA-B, and HLA-C molecules.