Browsing by Author "Yu, Shuangjin"

Now showing 1 - 5 of 5
  • Thumbnail Image
    ItemOpen Access
    Acute murine cytomegalovirus disrupts established transplantation tolerance and causes recipient allo-sensitization.
    (American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2020-07-13) Yu, Shuangjin; Dangi, Anil; Burnette, Melanie; Abecassis, Michael M; Thorp, Edward B; Luo, Xunrong
    We have previously shown that acute cytomegalovirus (CMV) infection disrupts the induction of transplantation tolerance. However, what impact acute CMV infection would have on the maintenance of established tolerance and on subsequent recipient allo-sensitization is a clinically important unanswered question. Here we used an allogeneic murine islet transplantation tolerance model to examine the impact of acute CMV infection on: (a) disruption of established transplantation tolerance during tolerance maintenance; and (b) the possibility of recipient allo-sensitization by CMV-mediated disruption of stable tolerance. We demonstrated that acute CMV infection abrogated transplantation tolerance during the maintenance stage in 50%-60% recipients. We further demonstrated that acute CMV infection-mediated tolerance disruption led to recipient allo-sensitization by reverting the tolerant state of allo-specific T cells and promoting their differentiation to allo-specific memory cells. Consequently, a second same-donor islet allograft was rejected in an accelerated fashion by these recipients. Our study therefore supports close monitoring for allo-sensitization in previously tolerant transplant recipients in whom tolerance maintenance is disrupted by an episode of acute CMV infection.
  • Thumbnail Image
    ItemOpen Access
    Blocking CCL8-CCR8-Mediated Early Allograft Inflammation Improves Kidney Transplant Function.
    (Journal of the American Society of Nephrology : JASN, 2022-08-16) Dangi, Anil; Husain, Irma; Jordan, Collin Z; Yu, Shuangjin; Natesh, Naveen; Shen, Xiling; Kwun, Jean; Luo, Xunrong; Luo, Xunrong

    Background

    In kidney transplantation, early allograft inflammation impairs long-term allograft function. However, precise mediators of early kidney allograft inflammation are unclear, making it challenging to design therapeutic interventions.

    Methods

    We used an allogeneic murine kidney transplant model in which CD45.2 BALB/c kidneys were transplanted to CD45.1 C57BL/6 recipients.

    Results

    Donor kidney resident macrophages within the allograft expanded rapidly in the first 3 days. During this period, they were also induced to express a high level of Ccl8, which, in turn, promoted recipient monocyte graft infiltration, their differentiation to resident macrophages, and subsequent expression of Ccl8. Enhanced graft infiltration of recipient CCR8+ T cells followed, including CD4, CD8, and γδ T cells. Consequently, blocking CCL8-CCR8 or depleting donor kidney resident macrophages significantly inhibits early allograft immune cell infiltration and promotes superior short-term allograft function.

    Conclusions

    Targeting the CCL8-CCR8 axis is a promising measure to reduce early kidney allograft inflammation.
  • Thumbnail Image
    ItemOpen Access
    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.
    (American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2020-10) Dangi, Anil; Yu, Shuangjin; Lee, Frances T; Burnette, Melanie; Knechtle, Stuart; Kwun, Jean; Luo, Xunrong
    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.
  • Thumbnail Image
    ItemOpen Access
    Emerging approaches and technologies in transplantation: the potential game changers.
    (Cellular & molecular immunology, 2019-02-13) Dangi, Anil; Yu, Shuangjin; Luo, Xunrong
    Newly emerging technologies are rapidly changing conventional approaches to organ transplantation. In the modern era, the key challenges to transplantation include (1) how to best individualize and possibly eliminate the need for life-long immunosuppression and (2) how to expand the donor pool suitable for human transplantation. This article aims to provide readers with an updated review of three new technologies that address these challenges. First, single-cell RNA sequencing technology is rapidly evolving and has recently been employed in settings related to transplantation. The new sequencing data indicate an unprecedented cellular heterogeneity within organ transplants, as well as exciting new molecular signatures involved in alloimmune responses. Second, sophisticated nanotechnology platforms provide a means of therapeutically delivering immune modulating reagents to promote transplant tolerance. Tolerogenic nanoparticles with regulatory molecules and donor antigens are capable of targeting host immune responses with tremendous precision, which, in some cases, results in donor-specific tolerance. Third, CRISPR/Cas9 gene editing technology has the potential to precisely remove immunogenic molecules while inserting desirable regulatory molecules. This technology is particularly useful in generating genetically modified pigs for xenotransplantation to solve the issue of the shortage of human organs. Collectively, these new technologies are positioning the transplant community for major breakthroughs that will significantly advance transplant medicine.
  • Thumbnail Image
    ItemOpen Access
    Murine cytomegalovirus dissemination but not reactivation in donor-positive/recipient-negative allogeneic kidney transplantation can be effectively prevented by transplant immune tolerance.
    (Kidney international, 2020-07) Dangi, Anil; Yu, Shuangjin; Lee, Frances T; Burnette, Melanie; Wang, Jiao-Jing; Kanwar, Yashpal S; Zhang, Zheng J; Abecassis, Michael; Thorp, Edward B; Luo, Xunrong
    Cytomegalovirus (CMV) reactivation from latently infected donor organs post-transplantation and its dissemination cause significant comorbidities in transplant recipients. Transplant-induced inflammation combined with chronic immunosuppression has been thought to provoke CMV reactivation and dissemination, although sequential events in this process have not been studied. Here, we investigated this process in a high-risk donor CMV-positive to recipient CMV-negative allogeneic murine kidney transplantation model. Recipients were either treated with indefinite immunosuppression or tolerized in a donor-specific manner. Untreated recipients served as controls. Kidney allografts from both immunosuppressed and tolerized recipients showed minimal alloimmunity-mediated graft inflammation and normal function for up to day 60 post-transplantation. However, despite the absence of such inflammation in the immunosuppressed and tolerized groups, CMV reactivation in the donor positive kidney allograft was readily observed. Interestingly, subsequent CMV replication and dissemination to distant organs only occurred in immunosuppressed recipients in which CMV-specific CD8 T cells were functionally impaired; whereas in tolerized recipients, host anti-viral immunity was well-preserved and CMV dissemination was effectively prevented. Thus, our studies uncoupled CMV reactivation from its dissemination, and underscore the potential role of robust transplantation tolerance in preventing CMV diseases following allogeneic kidney transplantation.