Search

The extracellular matrix (ECM) is known to regulate innate immune cells but its role in T cell functions is poorly understood. Here, we show a protective role for ECM proteoglycans, lumican and biglycan in hapten-induced contact dermatitis that is achieved through limiting proinflammatory CD4 + T cells. Lumican and biglycan-null mice develop significant inflammation with greater numbers of CD4 + T cells in hapten-challenged ear pinnae, while their draining lymph nodes show increased T-bet-STAT1 signaling, Th1 commitment, and IFN-γ secreting CD4 + T cell proliferation. Wild type mouse lymph node fibroblastic reticular cells secrete lumican, biglycan and decorin, a related proteoglycan, while none are expressed by naive or activated T cells. In vitro , lumican and biglycan co-localize with LFA-1 on T cell surfaces, and all three proteoglycans suppress LFA-1 mediated T cell activation. Overall, this study elucidates a novel paracrine regulation of Th1 cells by ECM proteoglycans to limit inflammation and tissue damage.

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients., (© 2024. The Author(s).)

Infections and inflammation are profoundly influenced by the extracellular matrix (ECM), but their molecular underpinnings are ill defined. Here, we demonstrate that lumican, an ECM protein normally associated with collagens, is elevated in sepsis patients' blood, while lumican-null mice resolve polymicrobial sepsis poorly, with reduced bacterial clearance and greater body weight loss. Secreted by activated fibroblasts, lumican promotes Toll-like receptor (TLR) 4 response to bacterial lipopolysaccharides (LPS) but restricts nucleic acid-specific TLR9 in macrophages and dendritic cells. The underlying mechanism involves lumican attachment to the common TLR coreceptor CD14 and caveolin 1 (Cav1) in lipid rafts on immune cell surfaces via two epitopes, which may be cryptic in collagen-associated lumican. The Cav1 binding epitope alone is sufficient for cell surface enrichment of Cav1, while both are required for lumican to increase cell surface TLR4, CD14, and proinflammatory cytokines in response to LPS. Endocytosed lumican colocalizes with TLR4 and LPS and promotes endosomal induction of type I interferons. Lumican-null macrophages show elevated TLR9 in signal-permissive endolysosomes and increased response, while wild types show lumican colocalization with CpG DNA but not TLR9, consistent with a ligand sequestering, restrictive role for lumican in TLR9 signaling. In vitro, lumican competes with CD14 to bind CpG DNA; biglycan, a lumican paralog, also binds CpG DNA and suppresses TLR9 response. Thus, lumican and other ECM proteins, synthesized de novo or released from collagen association during ECM remodeling, may be internalized by immune cells to regulate their transcriptional programs and effector responses that may be harnessed in future therapeutics., Competing Interests: The authors declare no competing interest.

The median survival for glioblastoma patients is ~15 months despite aggressive surgery and radio-chemotherapy approaches. Thus, developing new therapeutics is necessary to improve the treatment of these invasive brain tumors, which are known to show high levels of the eukaryotic initiation factor, eIF4E, a potent oncogene. Ribavirin, the only clinically approved drug known to target eIF4E, is an anti-viral molecule currently used in hepatitis C treatment. Here, we report the effect of ribavirin on proliferation, cell cycle, cell death and migration of several human and murine glioma cell lines, as well as human glioblastoma stem-like cells, in vitro. In addition, we tested ribavirin efficacy in vivo, alone and in combination with temozolomide and radiation. Our work showed that ribavirin inhibits glioma cell growth and migration, and increases cell cycle arrest and cell death, potentially through modulation of the eIF4E, EZH2 and ERK pathways. We also demonstrate that ribavirin treatment in combination with temozolomide or irradiation increases cell death in glioma cells. Finally and most importantly, ribavirin treatment in vivo significantly enhances chemo-radiotherapy efficacy and improves survival of rats and mice orthotopically implanted with gliosarcoma tumors or glioma stem-like cells, respectively. On the basis of these results, we propose that ribavirin represents a new therapeutic option for glioblastoma patients as an enhancer of the cytotoxic effects of temozolomide and radiotherapy.

Purpose: Functions of antimicrobial peptidoglycan recognition proteins (Pglyrp1-4) at the ocular surface are poorly understood. Earlier, we reported an antibacterial role for Pglyrp-1 in Pseudomonas aeruginosa keratitis. Here we investigated functions of three other related genes Pglyrp-2, -3 and -4 in a mouse model of P. aeruginosa keratitis., Methods: Wild type (WT) and each of the Pglyrp-null genotypes were challenged with P. aeruginosa keratitis. The eyes were scored in a blinded manner 24 and 48h post infection. Viable bacterial counts and inflammatory factors (IL-12, TNF-α, IFN-γ, CCL2, IL-6 and IL-10) were measured in whole eye homogenates using cytometric bead arrays. Expressions of Pglyrp-1-4, mouse beta defensins (mBD)-2,-3, cathelicidin-related antimicrobial peptide (CRAMP) were determined by qRTPCR in total RNA extracts of uninfected and infected eyes of WT and each of the Pglyrp-null mouse types., Results: The Pglyrp-2-/- mice showed reduced disease and lower induction of pro-inflammatory TNF-α (p = 0.02) than WT or the other Pglyrp null mice. Viable bacterial yield was significantly lower in the Pglyrp-2-/- (p = 0.0007) and the Pglyrp-4-/- (p = 0.098) mice. With regards to expression of these antimicrobial genes, Pglyrp-2 expression was induced after infection in WT mice. Pglyrp-3 expression was low before and after infection in WT mice, while Pglyrp-4 expression was slightly elevated after infection in WT, Pglyrp-2 and -3 null mice. Pglyrp-1 expression was slightly elevated after infection in all genotypes without statistical significance. Transcripts for antimicrobial peptides mBD2, mBD3 and CRAMP were elevated in infected Pglyrp-2-/- males without statistical significance., Conclusions: Efficient resolution of keratitis in the Pglyrp-2-/- mice may be due to a reduced pro-inflammatory microenvironment and synergistic antibacterial activities of defensins, CRAMP and Pglyrp-1. Therefore, in ocular infections the pro-inflammatory functions of Pglyrp-2 must be regulated to benefit the host.

Histone deacetylase inhibitors are presently used in the routine clinic treatment against cancers. Recent data have established that some of these treatments have potent anti-inflammatory or immunomodulatory effects at noncytotoxic doses that might be of benefit in immuno-inflammatory disorders or post-transplantation. At least some of these effects result from the ability of histone deacetylase inhibitors to modulate the immune system. Dendritic cells are professional antigen presenting cells that play a major role in this immune system. Data summarized in this review brings some novel information on the impact of histone deacetylase inhibitors on dendritic cell functions, which may have broader implications for immunotherapeutic strategies., (Copyright © 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Recent evidence suggested that 5-azacytidine (5-aza) can impact important immune functions via epigenetic modifications, making it an attractive candidate for pharmacologic manipulation of the immune system. The aim of this work was to study the effects of 5-aza on human dendritic cells (DC) generated from peripheral blood monocytes, and to test the type of immune response induced in patients treated with 5-aza. On the phenotypic level, CD40 and CD86 expression was significantly increased on mature DC exposed to 5-aza (5-aza-DC), compared with control untreated DC. Mature control DC and mature 5-aza-DC secreted comparable amounts of interleukin (IL)-6, IL-12p70, IL-23, and tumor necrosis factor-α. However, mature 5-aza-DC secreted significantly lower levels of IL-10 and IL-27 compared to mature control DC (p = 0.04 and p = 0.005, respectively). In the peripheral blood of 14 patients (7 males and 7 females; age range, 53-81 years) with advanced myeloid malignancies (8 acute myeloid leukemia and 6 myelodysplastic syndrome) treated with 5-aza, there was a significant decrease of IL-4-secreting CD4(+) T cells (p = 0.001), and a significant increase of IL-17A- and IL-21-secreting CD4(+) T cells (p = 0.003 and p = 0.01, respectively, compared to 5 healthy donors) suggesting a Th17 response pattern in the blood of patients receiving 5-aza. In all, these data suggest potentially novel mechanisms of action of epigenetic therapies, such as 5-aza, which may have broader implications for immunotherapeutic strategies., (Copyright © 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)