bims-hummad 2026-06-28 papers

Front Immunol. 2026 ;17 1813955

Tocilizumab but not Siltuximab prevents systemic inflammation in a humanized mouse model.

Liang Zhang, Jacqueline Wax, Torsten Goldmann, Afsaneh Mehrpouyan, Antje Müller, Frank Petersen, Gabriela Riemekasten, Xinhua Yu.

Objectives: The present study aimed to assess the therapeutic efficacy of neutralizing monoclonal antibodies targeting a prominent proinflammatory cytokine in a PBMC transfer-induced humanized mouse model of systemic inflammation.
Methods: Inflammatory cytokines were measured in human and murine sera using the LEGENDplex™ cytokine panel. Humanized mice were treated with neutralizing antibodies against human IL-6 (Siltuximab) or the human IL-6 receptor (Tocilizumab), along with matched IgG isotype controls.
Results: Cytokine responses in the humanized mouse model were predominantly of human, not murine, origin. Elevated levels of human IL-6 were observed in both SSc patients and their corresponding mouse models. Preventive administration of Tocilizumab reduced anti-nuclear antibody production and mitigated disease severity in the PBMCs-transfer-induced humanized mouse model. In contrast, treatment with Siltuximab, an antibody targeting human IL-6, did not prevent disease development in the humanized mouse model. The lack of efficacy of Siltuximab was associated with the accumulation of human IL-6/anti-human IL-6 monoclonal antibody immune complexes.
Conclusion: These findings highlight the pivotal role of IL-6 signaling in the SSc related systemic inflammation within the humanized mouse model and underscore the therapeutic potential of IL-6 receptor blockade. Furthermore, the PBMCs-based humanized mouse model offers a valuable preclinical platform for evaluating human-specific therapeutic interventions in systemic inflammation.

Keywords: Siltuximab; Tocilizumab; humanized mouse model; systemic inflammation; systemic sclerosis; therapeutic efficacy

DOI: https://doi.org/10.3389/fimmu.2026.1813955

J Transl Autoimmun. 2026 Dec;13 100380

SM03, a non-depleting anti-CD22 antibody, modulates B cell activation and immune crosstalk to attenuate autoimmunity.

Kin Lok Wong, Lung Hei Cheng, Cheuk Ling Chung, Pui Lam Ng, Shaik Abdullah Nawabjan, Muthu Iswarya Gandhi Sethuraman, Ka Kiu Luk, Wing Tung Tsoi, Billy Kwok Chong Chow, Shui On Leung.

Objective: To evaluate the disease-modifying potential of SM03, a novel humanized anti-CD22 monoclonal antibody, for B cell-mediated autoimmune diseases by investigating its mechanism for suppressing B cell dysregulation in autoimmune milieu.
Methods: SM03's mechanism was assessed in-vitro using functional assays on stimulated human PBMC from healthy donors and patients with Systemic Lupus Erythematosus (SLE)/Sjögren's Syndrome (SS). The efficacy of SM03 to attenuate autoimmunity was then evaluated in-vivo in a humanized pristane-induced SLE mouse model as well as a preventive collagen-induced Rheumatoid Arthritis (RA) model in cynomolgus monkeys. Disease-specific biomarkers, histopathology, and immune cell phenotypes were analyzed.
Results: SM03 attenuated T cell-dependent B cell activation by reducing class-switched B cells, plasmablast differentiation, and pro-inflammatory cytokine production in B cell lines, healthy and disease PBMCs, without inducing B cell depletion. In the SLE model, SM03 suppressed key disease manifestations (splenomegaly, anti-dsDNA, proteinuria, glomerular deposits) and reduced activated T cells without broad B cell depletion. In the RA model, SM03 dose-dependently suppressed joint scores, cartilage damage, synovial hyperplasia, anti-collagen II antibodies, and IL-6.
Conclusion: By enhancing CD22's inhibitory signalling to disrupt autoreactive B-T cell interactions, SM03 functions as a disease-modifying therapy that attenuates dysregulation of lymphocytes in autoimmunity. This non-depleting mechanism supports its translational potential for SLE and RA and implicates its broader utility for other B cell-driven autoimmune diseases.

Keywords: Antibody treatment; B cell therapy; CD22; Humanized murine model; Non-human primate collagen induced arthritis model; Rheumatoid arthritis; Systemic lupus erythematosus

DOI: https://doi.org/10.1016/j.jtauto.2026.100380

Adv Sci (Weinh). 2026 Jun 26. e24189

Optimization of B Cell Responses in Human Immune System Mice Through Organoid Based Screening.

Haiqiao Sun, He Li, Xu Zhu, Zijian Zhang, Deshan Ren, Shuai Ding, Yan Li.

B cells in the human immune system (HIS) mice exhibit weak responses to external antigens, characterized by insufficient antigen-specific B cell proliferation, low antibody titers, and a lack of differentiation into effector B cell subsets. We hypothesize that this failure is due to the absence of second signals provided by T cells following BCR stimulation. To address this, we developed an organoid screening system using HIS mouse splenocytes to identify missing signals. A combination of IL-4, IL-10, IL-21 together with CD40L was found to drive potent B cell proliferation and differentiation. Further organoid-based screening revealed that TNF-α and CpG synergistically promoted IgG class-switch, and that temporal separation of expansion and differentiation signals enhanced B cell responses. Translating these findings in vivo, CpG-adjuvanted vaccination followed by sequential i.v. delivery of expansion and differentiation cytokine mixtures induced antigen-specific B cell expansion, B cell differentiation, and IgG class-switch in HIS mice without affecting non-specific B cells. Sorting RBD-specific B cells from immunized mice yielded recombinant antibodies with high binding affinity and neutralizing activity against SARS-CoV-2 pseudovirus. Our study establishes a spleen organoid platform for screening factors that influence B cell responses in HIS mice and provides a generalizable strategy to obtain fully human antibodies for therapeutic development.

Keywords: B cells; antibody development; cytokines; human immune system mice; vaccines

DOI: https://doi.org/10.1002/advs.202524189

Nat Commun. 2026 Jun 26. pii: 5556. [Epub ahead of print]17(1):

Affinity- and epitope-dependent pathogenicity of GM-CSF autoantibodies in patients with autoimmune pulmonary alveolar proteinosis.

Shinji Futami, Chie Kawai, Jun-Ichi Kishikawa, Masaki Hirose, Hiroshi Kida, Po-Hung Wang, Kazuo Yamashita, Fumihiko Ishikawa, Takayuki Kato, Yoshikazu Inoue, Atsushi Kumanogoh, Tomohiro Kurosaki, Takeshi Inoue.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disease caused by autoantibodies targeting granulocyte-macrophage colony-stimulating factor (GM-CSF). Although serum GM-CSF autoantibody levels are markedly increased in aPAP patients, total antibody titer does not correlate with disease severity. Here, we characterize 186 monoclonal anti-GM-CSF autoantibodies derived from GM-CSF-specific B cells in 28 aPAP patients with varying disease severity, including three longitudinal cohorts, to determine whether epitope specificity and affinity of the autoantibodies contribute to disease pathophysiology. We classify these antibodies into two groups based on their epitopes: class 1 (targeting A, BD, or D epitopes) and class 2 (targeting B or C epitopes). In class 1 antibodies, affinity strongly correlates with neutralization activity, whereas this relationship is weak or absent in class 2 antibodies. High-affinity class 1 antibodies are present at higher levels in patients with more severe disease and are sufficient to induce PAP symptoms in a humanized mouse model. Thus, these findings identify epitope specificity and affinity as key determinants of pathogenicity and provide a mechanistic framework for understanding why total serum autoantibody levels fail to reflect disease severity in aPAP.

DOI: https://doi.org/10.1038/s41467-026-74717-2