Kidney Week 2025 Annual Meeting-Novel Immune Modulators of Allograft Rejection

Video Transcription

Video Summary

The session “Novel Immune Modulators of Allograft Rejection” highlighted emerging mechanisms and therapeutic targets across adaptive and innate immunity in kidney transplantation, focusing on antibody-mediated rejection (ABMR), tolerance, and intragraft immune regulation.<br /><br />Peter Sage described how T follicular helper (TFH) cells drive germinal center B-cell responses and rejection, including “germinal center–like” B cells within the graft. Using a kidney transplant mouse model, he showed T follicular regulatory (TFR) cells restrain donor-specific antibodies and ABMR; deleting TFRs accelerated rejection and increased alloreactive B cells in lymph node and graft. CTLA4-Ig altered TFR differentiation and reduced clonal expansion. He mapped sequential TFR developmental states and showed instability can involve FOXP3 loss, influenced by TCF7/TCF1. Translationally, he identified high endothelial venule–like structures in rejecting grafts and used MECA-79–targeted nanoparticles delivering anti–IL-21 to lymph nodes and graft, reducing donor-specific antibody, C4d, intragraft GC-like B cells, and modestly prolonging survival.<br /><br />Xunrong Liu focused on monocytes/macrophages. Donor-resident macrophages proliferated early post-transplant and induced recipient myeloid recruitment via a CCL8–CCR8 axis; blocking CCL8 or depleting donor macrophages reduced infiltrates, improved function, and lowered the threshold for tolerance induction with ECDI-treated donor splenocytes given only post-transplant. Recipient monocytes required AXL to differentiate into inflammatory, antigen-presenting macrophages; AXL inhibition reduced macrophage differentiation, T-cell stimulation, and prolonged heart graft survival. She also presented evidence of donor-specific “memory” in monocytes from tolerized hosts.<br /><br />Anna Konvalinka linked glycoproteins/glycans to ABMR. Proteomics of microdissected human biopsies identified galectin-1 increased in ABMR glomeruli, localized largely to endothelial cells. In glomerular endothelial cells, galectin-1 knockdown and interferon-γ signaling altered adhesion/cytoskeletal pathways and reduced cavin-1 phosphorylation, promoting cavin/caveolin dissociation and potentially affecting caveolae, complement handling, and chronic glomerulopathy. Separately, microfluidic profiling of DSA Fc features plus machine learning distinguished DSA+ patients with vs without ABMR and differentiated early vs late AMR, implicating IgG subclasses, IgM, sialylation, C1q binding, and increased galactosylation in late AMR.<br /><br />Jonathan (MGH) presented a spontaneous kidney acceptance mouse model to study natural tolerance. Single-cell data showed intragraft CD8 T cells shift from cytotoxic to exhausted/regulatory-like states (“defensive tolerance”), involving IFN-γ–dependent induction of FGL2; disrupting IFN-γ receptor signaling prevented reprogramming and led to rejection. Intragraft B cells acquired regulatory features; loss of inhibitory FcγR2B in B cells triggered ABMR-like pathology. He proposed “stealth immunogenicity,” where dormant intragraft memory cells can rekindle rejection under inflammatory triggers, potentially via disruption of tolerogenic tertiary lymphoid organs.

Asset Subtitle

Moderator(s): Naoka Murakami, Hamid Rabb

Presentation(s):

Modulation of Rejection via T and B Cell Interaction with Intrarenal Stromal Cells - Peter Sage
Role of Monocytes/Macrophages in Transplant Tolerance - Xun-Rong Luo
Role of Glycoproteins in Antibody-Mediated Rejection in Kidney Transplantation - Ana Konvalinka
Limiting Rejection via Defensive Tolerance in Kidney Allografts - Alessandro Alessandrini

Meta Tag

Date 11/6/2025

Pathway 1 Kidney Transplantation

Session ID 504553

Keywords

kidney transplantation

allograft rejection

antibody-mediated rejection (ABMR)

donor-specific antibodies (DSA)

T follicular helper (TFH) cells

T follicular regulatory (TFR) cells

germinal center B cells

CTLA4-Ig

IL-21 blockade

high endothelial venule (HEV)-like structures

monocytes and macrophages

CCL8–CCR8 axis

AXL signaling

galectin-1

transplant tolerance