FOXP3+ Regulatory T-Cells Are Associated with Acute Rejection in Lung Transplants
Jakub Pecl, Marie Christine Aubry, Sarah M Jenkins, JP Scott, Stephen D Cassivi, Anja C Roden. Mayo Clinic, Rochester
Background: Acute rejection (AR) is the major risk factor for bronchiolitis obliterans syndrome, the clinical manifestation of chronic rejection in lung transplants. AR is thought to be a T-cell mediated process. The balance of Tregulatory (Treg) and Teffector (Teff) cells likely ultimately determines graft acceptance or rejection. The best characterized Treg are CD4+CD25+ T cells that express FoxP3 transcription factor. In heart, kidney and liver transplant, increased FoxP3+ cells and mRNA expression were shown during AR in post-transplant biopsies suggesting that FoxP3+ cells are associated with antidonor immune reactivity rather than with immunological quiescence. Targeting Tregs might become an important treatment tool to prevent chronic rejection. We herein characterize changes of FoxP3+ and total CD4+ cells in post-lung transplant transbronchial biopsies (TTBx).
Design: TTBx were selected from pts transplanted at our institution. Rejection was histologically classified according to the 2007 Revision of the 1996 working formulation for lung rejection. TTBx were stained with FoxP3, and CD4. FoxP3+ cells and CD4+ cells were counted in 10 Hpf by two authors (ACR, JP) independently. % FoxP3+ cells of total CD4+ cells was calculated as (100*FoxP3)/CD4. Distributions were compared between groups using linear regression with generalized estimating equations to adjust standard errors for repeated data within patients. Analyses were conducted in SAS version 9 (Cary, NC).
Results: 61 TTBx from 28 pts were included. In B0C0 cases, numbers of FoxP3+ cells and CD4+ cells in TTBx without (A0) and with (A1-A4) acute cellular rejection (ACR) are shown in Table 1.
|Grade of ACR||A0||A1||A2||A3||A4||p-value (for comparison A0 vs A1-A4)|
|N (# of biopsies)||32||14||1||2||1|
|FoxP3+cells¹||1.0; 0.0, 3.0||4.0; 1.0, 5.0||3.0||22.0, 106.0²||45.0||0.039|
|CD4+cells¹||28.0; 10.0, 77.0||53.8; 33.0, 101.0||17.0||347.0, 406.0²||352.0||0.044|
|%FoxP3+/total CD4+ cells¹||1.5; 0.0, 7.1||6.7; 2.1, 8.9||17.6||6.3, 26.1²||12.8||0.84|