title: 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.
abstract: 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.
  
  
  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 (CD25(high) 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.
authors.affiliation: Anthony Nolan Research Institute, Royal Free Hospital, London, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Matthews
authors.forename: ZiYi
authors.initials: Z
authors.lastname: Lim
authors.forename: Behdad
authors.initials: B
authors.lastname: Afzali
authors.forename: Laurence
authors.initials: L
authors.lastname: Pearce
authors.forename: Atiyeh
authors.initials: A
authors.lastname: Abdallah
authors.forename: Shahram
authors.initials: S
authors.lastname: Kordasti
authors.forename: Antonio
authors.initials: A
authors.lastname: Pagliuca
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
authors.forename: J Alejandro
authors.initials: JA
authors.lastname: Madrigal
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
authors.forename: Linda D
authors.initials: LD
authors.lastname: Barber
mesh_terms: D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D005260:Female; D006086:Graft vs Host Disease / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D000074323:Alemtuzumab