Browsing by Author "Jordan, Collin Z"

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    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.
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    ItemOpen Access
    Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions.
    (Blood advances, 2024-02) Bracken, Sonali J; Suthers, Amy N; DiCioccio, Rachel A; Su, Hsuan; Anand, Sarah; Poe, Jonathan C; Jia, Wei; Visentin, Jonathan; Basher, Fahmin; Jordan, Collin Z; McManigle, William C; Li, Zhiguo; Hakim, Frances T; Pavletic, Steven Z; Bhuiya, Nazmim S; Ho, Vincent T; Horwitz, Mitchell E; Chao, Nelson J; Sarantopoulos, Stefanie

    Abstract

    Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing alloreactivity and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs after transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B-cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-like receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from patients with cGVHD also demonstrated increased interleukin-6 production after TLR7 stimulation with R848. Low-dose B-cell receptor (BCR) stimulation augmented B-cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor interferon regulatory factor 5. Because RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD immunoglobulin G (IgG) were nucleic acid-binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD.