Rapamycin Prevents Bronchiolitis Obliterans Rapamycin Prevents Bronchiolitis Obliterans Through Increasing Regulatory B Cells Through Increasing Regulatory B Cells

Infiltration in A Murine Tracheal Infiltration in A Murine Tracheal Transplantation ModelTransplantation Model

Yunge Zhao, Jacob R. Gillen, Akshaya K. Meher, Jordan A. Burns, David A. Yunge Zhao, Jacob R. Gillen, Akshaya K. Meher, Jordan A. Burns, David A. Harris, Irving L. Kron, and Christine L. Lau*Harris, Irving L. Kron, and Christine L. Lau*

Department of Surgery, University of Virginia Health System, Charlottesville, Virginia. Department of Surgery, University of Virginia Health System, Charlottesville, Virginia.

* Corresponding Author* Corresponding Author

Presenter DisclosurePresenter Disclosure

Yunge ZhaoYunge Zhao

The following relationships exist related The following relationships exist related to this presentation:to this presentation:

This study is supported by This study is supported by The The Advancing Research in Transplantation Advancing Research in Transplantation Science (ARTS) 2011 Grant Program Science (ARTS) 2011 Grant Program from Pfizerfrom Pfizer

IntroductionRapamycin

Epithelial Epithelial Progenitor CellsProgenitor CellsAnn Thorac Surg. 2013, Ann Thorac Surg. 2013, 96(2):464-7296(2):464-72

Recruitment of Recruitment of FibrocytesFibrocytes Ann Ann Thorac Surg. 2013 Thorac Surg. 2013 95(5):1768-7595(5):1768-75..

Bronchiolitis Obliterans Bronchiolitis Obliterans

Cellular Infiltration

?

Regulatory B Cells/BregsRegulatory B Cells/Bregs

B220+ B220+

Bregs secrete IL-10 and TGF-beta1. Bregs secrete IL-10 and TGF-beta1.

IgM+ but IgG- B cells. IgM+ but IgG- B cells.

Min Yang et al. Cell Mol Immunol 10: 122-132, 2013.

Mouse Heterotopic Tracheal Mouse Heterotopic Tracheal Transplantation (HTT) Model Transplantation (HTT) Model

Donor: Balb/c (BC), MHC class I Donor: Balb/c (BC), MHC class I

Recipient: C57BL/6 (B6), MHC class IIRecipient: C57BL/6 (B6), MHC class II

Allografts:

H-2d H-2b

Experimental Design

2. Luminex Assays of Cytokines and Growth Factors: 3. Immunohistochemistry and Densitometric Analysis:

1. Mouse HTT Model:

Isograft controls Experimental Allograft+DMSO

Groups Allograft+Rapamycin 5mg/kg/day (n=6) Allograft+Rapamycin 10mg/kg/day * DMSO and Rapamycin was diluted in saline and IP

Effects of Rapamycin on Luminal Obliteration in a mouse HTT Model

Increasing of Cellular InfiltrationPost Rapamycin Treatment

Identifying the Infiltrated Cells

Rapamycin Treatment Significantly Increased B Cells Infiltration

IgM+ & IgG-

B220+, IL-10+ & TGF-

IL-10 & TGF1

Treatment with RapamycinSignificantly Increased IL-10 and IL-4 Production in Allografts

Treatment with Rapamycin Markedly Increased Foxp3+ Treg Cells in the Allografts

Summary

Rapamycin

Bronchiolitis Obliterans Bronchiolitis Obliterans

BregsB220+IL-10+TGFβ1+IgM+IgG-

Tregs Foxp3+

IL-10/TGF

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