Browsing by Author "Husain, Irma"

Filter results by typing the first few letters
Now showing 1 - 2 of 2
  • 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
    Single cell transcriptomics of mouse kidney transplants reveals a myeloid cell pathway for transplant rejection.
    (JCI insight, 2020-10) Dangi, Anil; Natesh, Naveen R; Husain, Irma; Ji, Zhicheng; Barisoni, Laura; Kwun, Jean; Shen, Xiling; Thorp, Edward B; Luo, Xunrong
    Myeloid cells are increasingly recognized as major players in transplant rejection. Here, we used a murine kidney transplantation model and single cell transcriptomics to dissect the contribution of myeloid cell subsets and their potential signaling pathways to kidney transplant rejection. Using a variety of bioinformatic techniques, including machine learning, we demonstrate that kidney allograft-infiltrating myeloid cells followed a trajectory of differentiation from monocytes to proinflammatory macrophages, and they exhibited distinct interactions with kidney allograft parenchymal cells. While this process correlated with a unique pattern of myeloid cell transcripts, a top gene identified was Axl, a member of the receptor tyrosine kinase family Tyro3/Axl/Mertk (TAM). Using kidney transplant recipients with Axl gene deficiency, we further demonstrate that Axl augmented intragraft differentiation of proinflammatory macrophages, likely via its effect on the transcription factor Cebpb. This, in turn, promoted intragraft recruitment, differentiation, and proliferation of donor-specific T cells, and it enhanced early allograft inflammation evidenced by histology. We conclude that myeloid cell Axl expression identified by single cell transcriptomics of kidney allografts in our study plays a major role in promoting intragraft myeloid cell and T cell differentiation, and it presents a potentially novel therapeutic target for controlling kidney allograft rejection and improving kidney allograft survival.