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CD4+ T-cell alloreactivity towards mismatched HLA-class II alleles early after double umbilical cord blood transplantation (dUCBT)

Cor H.J. Lamers, Rebecca Wijers, Cornelis A.M. van Bergen, Judith A.E. Somers, Eric Braakman, Jan Willem Gratama, Reno Debets, J.H. Frederik Falkenburg and Jan J. Cornelissen

Key points

  • Graft vs graft alloreactivity after dUCBT involves recognition of mismatched HLA-class II alleles by allele-specific CD4+ effector T-cells.

  • Alloreactive donor CD4+ T-cells may recognize recipient leukemia, if mismatched for individual HLA-class II alleles.

Abstract

While double umbilical cord blood transplantation (dUCBT) in adult patients may be associated with less graft failure as compared to single UCBT, hematopoietic recovery generally originates from a single cord blood unit (CBU). CBU predominance is still incompletely understood. We recently showed that blood CD4+ T-cell numbers rapidly increase after dUCBT and early CD4+ T-cell chimerism predicts for graft predominance. Given the frequent HLA-class II allele mismatches between CBUs in dUCBT, we hypothesized that alloreactive HLA-class II-specific CD4+ T-cells from the 'winning' CBU may contribute to rejection of the 'loser' CBU. We evaluated whether CD4+ T-cells originating from the predominant (PD)-CBU would recognize HLA-class II allele mismatches, expressed by the non-engrafting (NE)-CBU. Alloreactive effector CD4+ T-cells towards one or more mismatched HLA-class II alleles of the NE-CBU were detected in 11 out of 11 patients towards 29 out of 33 (88%) tested mismatches with strongest reactivity towards DR and DQ alleles early after dUCBT. Mismatched HLA-class II allele-specific CD4+ T-cells recognized primary leukemic cells when the mismatched HLA-class II allele was shared between NE-CBU and patient. Our results suggest that cytotoxicity exerted by CD4+ T-cells from the PD-CBU drives the rapid rejection of the NE-CBU, which alloreactive effect might also contribute to graft-versus-leukemia.

  • Submitted June 6, 2016.
  • Accepted August 9, 2016.