title: Donor-Reactive Regulatory T Cell Frequency Increases During Acute Cellular Rejection of Lung Allografts.
abstract: Acute cellular rejection is a major cause of morbidity after lung transplantation. Because regulatory T (Treg) cells limit rejection of solid organs, we hypothesized that donor-reactive Treg increase after transplantation with development of partial tolerance and decrease relative to conventional CD4 (Tconv) and CD8 T cells during acute cellular rejection.
  
  
  
  To test these hypotheses, we prospectively collected 177 peripheral blood mononuclear cell specimens from 39 lung transplant recipients at the time of transplantation and during bronchoscopic assessments for acute cellular rejection. We quantified the proportion of Treg, CD4 Tconv, and CD8 T cells proliferating in response to donor-derived, stimulated B cells. We used generalized estimating equation-adjusted regression to compare donor-reactive T cell frequencies with acute cellular rejection pathology.
  
  
  
  An average of 16.5 ± 9.0% of pretransplantation peripheral blood mononuclear cell Treg cell were donor-reactive, compared with 3.8% ± 2.9% of CD4 Tconv and 3.4 ± 2.6% of CD8 T cells. These values were largely unchanged after transplantation. Donor-reactive CD4 Tconv and CD8 T cell frequencies both increased 1.5-fold (95% confidence interval [95% CI], 1.3-1.6; P < 0.001 and 95% CI, 1.2-1.6; P = 0.007, respectively) during grade A2 rejection compared with no rejection. Surprisingly, donor-reactive Treg frequencies increased by 1.7-fold (95% CI, 1.4-1.8; P < 0.001).
  
  
  
  Contrary to prediction, overall proportions of donor-reactive Treg cells are similar before and after transplantation and increase during grade A2 rejection. This suggests how A2 rejection can be self-limiting. The observed increases over high baseline proportions in donor-reactive Treg were insufficient to prevent acute lung allograft rejection.
authors.affiliation: 1 Medical Service, Veterans Affairs Medical Center, San Francisco, CA. 2 Department of Medicine, University of California, San Francisco, San Francisco, CA. 3 Department of Surgery, University of California, San Francisco, San Francisco, CA. 4 Department of Radiology, University of California, San Francisco, San Francisco, CA. 5 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA.
authors.forename: John R
authors.initials: JR
authors.lastname: Greenland
authors.forename: Charissa M
authors.initials: CM
authors.lastname: Wong
authors.forename: Rahul
authors.initials: R
authors.lastname: Ahuja
authors.forename: Angelia S
authors.initials: AS
authors.lastname: Wang
authors.forename: Chiyo
authors.initials: C
authors.lastname: Uchida
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Golden
authors.forename: Steven R
authors.initials: SR
authors.lastname: Hays
authors.forename: Lorriana E
authors.initials: LE
authors.lastname: Leard
authors.forename: Raja
authors.initials: R
authors.lastname: Rajalingam
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Singer
authors.forename: Jasleen
authors.initials: J
authors.lastname: Kukreja
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
authors.forename: George H
authors.initials: GH
authors.lastname: Caughey
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Tang
mesh_terms: D000208:Acute Disease; D000368:Aged; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014019:Tissue Donors; D014184:Transplantation, Homologous