Christian Schütz

Granulocytic myeloid-derived suppressor cells (G-MDSCs) are immunoregulatory cells of the neutrophil lineage. Here, we show that immunoregulation by G-MDSCs is imprinted by the joint tissue microenvironment in patients with axial spondyloarthritis and in animal models of inflammatory arthritis. We demonstrate that the suppressive function of G-MDSCs is significantly enhanced in the joint tissue, but not in the circulation. Analysis of public single-cell RNA sequencing datasets was consistent with Cd200r1 ^high Hmgb2 ⁺ precursors differentiating into G-MDSCs following interaction with Cd200 ⁺ fibroblasts. In hTNFtg/ Il23mc mice, treatment with a CD200R1 agonist promoted an immunoregulatory signature associated with PD-L1 expression, whereas CD200 blockade reversed the phenotype. Following adoptive transfer of G-MDSC precursor cells into arthritic mice, administration of a CD200-blocking antibody impaired the differentiation of PD-L1 ⁺ G-MDSCs and exacerbated disease severity. These findings reveal a tissue-intrinsic program that facilitates resolution of inflammation through fibroblast-myeloid crosstalk that enhances G-MDSC function.

Introduction: Psoriatic arthritis is a chronic inflammatory disease that can affect the axial skeleton as well as the joints and enthesis. Following the failure of conventional synthetic disease-modifying antirheumatic drugs (DMARDs), numerous biological DMARDs (b-DMARDs) or targeted synthetic DMARDs are now available, although current guidelines do not recommend a specific mode of action in the absence of comorbidities or contraindications. The aim of the study is to identify markers associated with the achievement of Minimal Disease Activity (MDA) at week 16 in patients treated with tumour necrosis factor inhibitors (TNFi), interleukin-17 inhibitors (IL-17i) or interleukin-23 inhibitors (IL-23i). Methods and analysis: A total of 100 patients with active psoriatic arthritis (PsA) with a clinical indication for treatment escalation of methotrexate (MTX) (ie, non-response or intolerance to MTX) to a b-DMARD are to be included in the prospective observational cohort study. Patients are escalated according to physician’s choice to one of the following modes of action: TNFi, IL-23i or IL-17i. Participant recruitment is currently ongoing and is expected to be completed in July 2026. This protocol was finalised prior to database lock and before any outcome analyses were conducted. The primary endpoint is achieving MDA at 16 weeks. Secondary endpoints include changes in clinical scores: Psoriasis Area and Severity Index 75% improvement, Disease Activity in Psoriatic Arthritis, Nail Psoriasis Severity Index and biomarker evaluation from blood and skin biopsy samples. Machine learning techniques will be applied to identify marker patterns associated with treatment response, while treatment-specific marker interactions will be explored on a hypothesis-generating basis. Ethics and dissemination: Ethics approval was obtained from the Ruhr University Bochum Ethics Committee (no. 23-7918) on 1 December 2024 for study protocol number 2.0 (30 October 2024). Study results will be published in an international journal, regardless of whether the results are positive or negative. Results will be communicated to the scientific community and healthcare professionals at the conference. Trial registration number: DRKS00032573.

Summary: Ankylosing spondylitis is the main entity of a family of inflammatory diseases affecting many musculoskeletal (sacroiliac joints, spine, and peripheral joints) and extra-musculoskeletal sites, termed spondyloarthritis. While it is debated whether disease onset is primarily driven by autoimmune or autoinflammatory processes, what is certain is that both innate and adaptive immune responses orchestrate local and systemic inflammation, which leads to chronic pain and immobility. Immune checkpoint signals are one key player in keeping the immune system in check and in balance, but their role in disease pathogenesis is still rather elusive. Therefore, we ran a MEDLINE search utilizing the PubMed platform for a variety of immune checkpoint signals in regard to ankylosing spondylitis. In this review, we summarize the experimental and genetic data available and evaluate the relevance of immune checkpoint signalling in the pathogenesis of ankylosing spondylitis. Markers such as PD-1 and CTLA-4 have been extensively studied and facilitate the concept of an impaired negative immune regulation in ankylosing spondylitis. Other markers are either neglected completely or insufficiently examined, and the data is conflicting. Still, some of those markers remain interesting targets to decipher the pathogenesis of ankylosing spondylitis and to develop new treatment strategies.

Purpose: Artificial antigen-presenting cells, aAPC, have successfully been used to stimulate antigen-specific T-cell responses in vitro as well as in vivo. Although aAPC compare favorably with autologous dendritic cells in vitro, their effect in vivo might be diminished through rapid clearance by macrophages. Therefore, to prevent uptake and minimize clearance of aAPC by macrophages, thereby increasing in vivo functionality, we investigated the efficiency of “don't eat me” three-signal aAPC compared with classical two-signal aAPC. Experimental Design: To generate “don't eat me” aAPC, CD47 was additionally immobilized onto classical aAPC (aAPC^CD47+). aAPC and aAPC^CD47+ were analyzed in in vitro human primary T-cell and macrophage cocultures. In vivo efficiency was compared in a NOD/SCID T-cell proliferation and a B16-SIY melanoma model. Results: This study demonstrates that aAPC^CD47+ in coculture with human macrophages show a CD47 concentration–dependent inhibition of phagocytosis, whereas their ability to generate and expand antigen-specific T cells was not affected. Furthermore, aAPC^CD47+-generated T cells displayed equivalent killing abilities and polyfunctionality when compared with aAPC-generated T cells. In addition, in vivo studies demonstrated an enhanced stimulatory capacity and tumor inhibition of aAPC^CD47+ over normal aAPC in conjunction with diverging biodistribution in different organs. Conclusions: Our data for the first time show that aAPC functionalized with CD47 maintain their stimulatory capacity in vitro and demonstrate enhanced in vivo efficiency. Thus, these next-generation aAPC^CD47+ have a unique potential to enhance the application of the aAPC technology for future immunotherapy approaches. Clin Cancer Res; 21(9); 2075–83. ©2015 AACR.