Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response
Cornelis A.M. van Bergen, … , Marieke Griffioen, J.H. Frederik Falkenburg
Cornelis A.M. van Bergen, … , Marieke Griffioen, J.H. Frederik Falkenburg
Published January 9, 2017
Citation Information: J Clin Invest. 2017;127(2):517-529. https://doi.org/10.1172/JCI86175.
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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 4

Tissue specificity of alloreactive T cell clones.

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Tissue specificity of alloreactive T cell clones. (A–C) T cell clones re...
(A–C) T cell clones representing the specificities targeted in patients with selective GVL reactivity (18 T cell clones, left) and patients with GVHD (46 T cell clones, right) were incubated at 833 and 2,500 T cells per well with 0.1-, 0.3-, 1-, 3-, and 9-fold excess of stimulator cells. On the x axis, T cell specificities are plotted for each patient, including the number of isolated T cell clones with identical specificity (see also “Response diversity “ in Supplemental Table 4). The following cells were used for stimulation: EBV-LCLs (A), FBs cultured under steady-state conditions (B), and FBs cultured for 4 days with 200 IU/ml IFN-γ (C). Bars represent the dose-response range between the lowest and highest ratio of stimulator cells as measured by the production of IFN-γ in femtograms per single T cell per 20 hours. (D–F) Mixed-models statistical analysis was applied to compare dose-response ranges between T cell clones from patients with selective GVL reactivity (dashed line) and those with GVHD (solid line) after stimulation with EBV-LCLs (D), steady-state FBs (E), and IFN-γ–treated FBs (F). The x axes of E and F are in log scale, since inclusion of the log(ratio) instead of the ratio led to a better model fit for FB outcomes. P values refer to differences in outcome between both patient groups at stimulator/T cell ratios of 9:1 for EBV-LCLs (D) and 1:1 for FBs (E and F).