Dynamics of human regulatory T cells in lung lavages of lung transplant recipients.
BACKGROUND
Despite advances in the field of lung transplantation, the median survival after lung transplant remains below 5 years. Early rejection is a risk factor for the development of chronic rejection. In animal models of transplant tolerance, regulatory T cells (Tregs) can prevent the establishment of rejection.


METHODS
This study was designed to explore the dynamics of Tregs focally and systemically in lung transplant recipients. Sequential surveillance bronchoscopy results were available in 51 patients with at least four sequential samples recovered from each patient at defined times posttransplant. In 36 individuals, a complete year of follow-up data for BAL was analyzed. In 33 of these individuals had a complete year of follow-up data for peripheral blood monocyte cell specimens were also analyzed. Lung lavage cells were recovered from each bronchoscopy and corresponding blood draw and subjected to polychromatic flow cytometry. The percentage of CD4 lymphocytes, which expressed the intracellular transcription factor FoxP3 was recorded at each point. At each time point, lung biopsy specimens were scored for rejection.


RESULTS
Lung Treg frequency was significantly more variable than blood Treg frequency. Treg frequency in the lung was increased in the aftermath of acute rejection. In contrast, lung Treg frequency declined sequentially in patients demonstrating continued quiescence. Mean BAL Treg level integrated over the first transplant year correlated inversely with the degree of acute cellular rejection. In contrast, blood Treg levels demonstrated no correlation with lung pathology.


CONCLUSIONS
Lung Tregs increase in the setting of acute cellular rejection, whereas declining levels of BAL Tregs correlates with immunologic quiescence.
Neujahr
David C
DC
McKelvey Center for Lung Transplantation and Pulmonary Vascular Diseases, Emory University School of Medicine, Atlanta, GA 30322, USA. david.neujahr@emoryhealthcare.org
Cardona
Adriana C
AC
Ulukpo
Onome
O
Rigby
Mark
M
Pelaez
Andres
A
Ramirez
Allan
A
Gal
Anthony A
AA
Force
Seth D
SD
Lawrence
E Clinton
EC
Kirk
Allan D
AD
Larsen
Christian P
CP
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008137:Longitudinal Studies; D008168:Lung / Q000276:immunology / Q000473:pathology; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors
Transplantation. 2004 Mar 15;77(5):762-6
15021844
J Thorac Cardiovasc Surg. 2005 May;129(5):1144-52
15867792
Am J Transplant. 2007 Apr;7(4):914-22
17286616
Ann Thorac Surg. 2000 May;69(5):1520-4
10881834
J Heart Lung Transplant. 2007 Aug;26(8):763-8
17692780
J Heart Lung Transplant. 2002 May;21(5):559-66
11983546
J Immunol. 2006 Jan 1;176(1):329-34
16365425
Am J Pathol. 2004 Oct;165(4):1223-32
15466388
Am J Respir Crit Care Med. 2004 Jul 15;170(2):181-7
15130908
Nat Rev Immunol. 2003 Mar;3(3):199-210
12658268
Am J Transplant. 2006 Sep;6(9):2080-8
16796722
J Immunol. 2004 May 15;172(10):5900-7
15128770
Nihon Rinsho. 2007 Mar;65(3):557-67
17354576
Science. 2003 Feb 14;299(5609):1033-6
12532024
Am J Transplant. 2004 Oct;4(10):1614-27
15367216
Nat Immunol. 2008 Feb;9(2):194-202
18157133
J Heart Lung Transplant. 2008 Feb;27(2):203-7
18267228
Exp Hematol. 2007 Mar;35(3):416-25
17309822
J Immunol. 2007 Mar 15;178(6):3983-95
17339499
N Engl J Med. 2005 Dec 1;353(22):2342-51
16319383
J Immunol. 2007 Aug 15;179(4):2041-5
17675459
Immunity. 2003 Oct;19(4):503-14
14563315
J Immunol. 2002 Feb 1;168(3):1080-6
11801641
J Immunol. 2006 Apr 15;176(8):4632-9
16585554