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 February 1, 2017
Citation Information: J Clin Invest. 2017;127(2):517-529. doi:10.1172/JCI86175.
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Categories: Research Article Hematology Transplantation

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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Clinical course of selected patients. Interventions and follow-up for ea...

Figure 1

Clinical course of selected patients.

Interventions and follow-up for each patient are depicted on the horizontal dotted lines. Regular monitoring after alloSCT was conducted to detect donor chimerism (squares) or BCR-ABL (circles) by PCR and the presence of blasts in bone marrow aspirates as determined by morphology. White symbols indicate full donor chimerism or absence of disease. Disease recurrence was detected by the presence of blasts by bone marrow morphology (black squares), detectable BCR-ABL transcripts (black circles), or mixed chimerism (gray squares). DLI was administered (black triangles; doses were given in 106 CD3 T cells/kg), and patients experienced selective GVL reactivity (n = 6, A) or were diagnosed with GVHD (n = 5, white diamonds, B), requiring systemic immunosuppressive treatment (black diamonds). Arrows indicate collected samples. Vertical dotted line indicates 1 year after DLI. Patient 4716 died 74 days after DLI. For detailed patient characteristics, see Supplemental Table 1.