Published online 2 June 2009
Haematologica, Vol 94, Issue 7, 956-966 doi:10.3324/haematol.2008.003103
Copyright © 2009 by Ferrata Storti Foundation
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Stem Cell Transplantation

Imbalance of effector and regulatory CD4 T cells is associated with graft-versus-host disease after hematopoietic stem cell transplantation using a reduced intensity conditioning regimen and alemtuzumab

Katie Matthews1,2, ZiYi Lim2, Behdad Afzali3, Laurence Pearce2, Atiyeh Abdallah2, Shahram Kordasti2, Antonio Pagliuca2, Giovanna Lombardi3, J. Alejandro Madrigal1, Ghulam J. Mufti2, Linda D. Barber2

1 The Anthony Nolan Research Institute, Royal Free Hospital, London;
2 Department of Haematological Medicine, King’s College London Denmark Hill Campus, London and
3 Department of Nephrology and Transplantation, King’s College London Guys and St. Thomas’ Hospital, London, UK

Correspondence: Linda D. Barber, Department of Haematological Medicine, King's College London, Denmark Hill Campus, 123 Coldharbour Lane, London SE5 9NU, UK. E-mail:linda.barber{at}kcl.ac.uk

Background: A variety of immune pathways can lead to graft-versus-host disease. A better understanding of the type of immune response causing graft-versus-host disease in defined clinical hematopoietic stem cell transplant settings is required to inform development of methods for monitoring patients and providing them tailored care.

Design and Methods: Twenty-five patients were recruited presenting with myeloid malignancies and treated with a reduced intensity conditioning transplant regimen with graft-versus-host disease prophylaxis comprising in vivo lymphocyte depletion with alemtuzumab and cyclosporin. A prospective study was performed of lymphocyte subset reconstitution in peripheral blood in relation to the incidence of graft-versus-host disease.

Results: Acute graft-versus-host disease was associated with significantly higher numbers of natural killer cells and donor-derived effector CD4 T cells (CD45RO+ CD27–) early (day 30) after transplantation (p=0.04 and p=0.02, respectively). This association was evident before the emergence of clinical pathology in six out of seven patients. Although numbers of regulatory CD4 T cells (CD25high Foxp3+) were similar at day 30 in all patients, a significant deficit in those who developed acute graft-versus-host disease was apparent relative to effector CD4 T cells (median of 41 effectors per regulatory cell compared to 12 to 1 for patients without graft-versus-host disease) (p=0.03). By day 180, a functional regulatory CD4 T-cell population had expanded significantly in patients who developed chronic graft-versus-host disease, reversing the imbalance (median of 3 effectors per regulatory cell compared to 9.6 to 1 for patients without graft-versus-host disease) (p=0.018) suggesting no overt absence of immune regulation in the late onset form of the disease.

Conclusions: Imbalance of effector and regulatory CD4 T cells is a signature of graft-versus-host disease in this transplantation protocol.

Key words: graft-versus-host disease, CD4 T cell, alemtuzumab.