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Donor apoptotic cell-based therapy for effective inhibition of donor-specific memory T and B cells to promote long-term allograft survival in allosensitized recipients.

Publication ,  Journal Article
Dangi, A; Yu, S; Lee, FT; Burnette, M; Knechtle, S; Kwun, J; Luo, X
Published in: Am J Transplant
October 2020

Allosensitization constitutes a major barrier in transplantation. Preexisting donor-reactive memory T and B cells and preformed donor-specific antibodies (DSAs) have all been implicated in accelerated allograft rejection in sensitized recipients. Here, we employ a sensitized murine model of islet transplantation to test strategies that promote long-term immunosuppression-free allograft survival. We demonstrate that donor-specific memory T and B cells can be effectively inhibited by peritransplant infusions of donor apoptotic cells in combination with anti-CD40L and rapamycin, and this treatment leads to significant prolongation of islet allograft survival in allosensitized recipients. We further demonstrate that late graft rejection in recipients treated with this regimen is associated with a breakthrough of B cells and their aggressive graft infiltration. Consequently, additional posttransplant B cell depletion effectively prevents late rejection and promotes permanent acceptance of islet allografts. In contrast, persistent low levels of DSAs do not seem to impair graft outcome in these recipients. We propose that B cells contribute to late rejection as antigen-presenting cells for intragraft memory T cell expansion but not to alloantibody production and that a therapeutic strategy combining donor apoptotic cells, anti-CD40L, and rapamycin effectively inhibits proinflammatory B cells and promotes long-term islet allograft survival in such recipients.

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Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

October 2020

Volume

20

Issue

10

Start / End Page

2728 / 2739

Location

United States

Related Subject Headings

  • Surgery
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Graft Survival
  • Graft Rejection
  • B-Lymphocytes
  • Apoptosis
  • Animals
  • Allografts
 

Citation

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Dangi, A., Yu, S., Lee, F. T., Burnette, M., Knechtle, S., Kwun, J., & Luo, X. (2020). Donor apoptotic cell-based therapy for effective inhibition of donor-specific memory T and B cells to promote long-term allograft survival in allosensitized recipients. Am J Transplant, 20(10), 2728–2739. https://doi.org/10.1111/ajt.15878
Dangi, Anil, Shuangjin Yu, Frances T. Lee, Melanie Burnette, Stuart Knechtle, Jean Kwun, and Xunrong Luo. “Donor apoptotic cell-based therapy for effective inhibition of donor-specific memory T and B cells to promote long-term allograft survival in allosensitized recipients.Am J Transplant 20, no. 10 (October 2020): 2728–39. https://doi.org/10.1111/ajt.15878.
Dangi, Anil, et al. “Donor apoptotic cell-based therapy for effective inhibition of donor-specific memory T and B cells to promote long-term allograft survival in allosensitized recipients.Am J Transplant, vol. 20, no. 10, Oct. 2020, pp. 2728–39. Pubmed, doi:10.1111/ajt.15878.
Journal cover image

Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

October 2020

Volume

20

Issue

10

Start / End Page

2728 / 2739

Location

United States

Related Subject Headings

  • Surgery
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Graft Survival
  • Graft Rejection
  • B-Lymphocytes
  • Apoptosis
  • Animals
  • Allografts