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Keywords = B cell-depleting therapy

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21 pages, 358 KiB  
Review
Infectious Complications in Patients with B-Cell Non-Hodgkin Lymphoma Treated with Bispecific Antibodies
by Agnieszka Szymczyk, Joanna Drozd-Sokołowska and Iwona Hus
Cancers 2025, 17(15), 2426; https://doi.org/10.3390/cancers17152426 - 22 Jul 2025
Viewed by 306
Abstract
Bispecific antibodies (BsABs) have become a new standard of treatment of refractory/relapsed patients with diffuse large B-cell lymphoma and follicular lymphoma, being also intensively studied in other types of B-cell non-Hodgkin lymphoma (B-NHL). Since the therapy with BsABs results in profound B-cell depletion [...] Read more.
Bispecific antibodies (BsABs) have become a new standard of treatment of refractory/relapsed patients with diffuse large B-cell lymphoma and follicular lymphoma, being also intensively studied in other types of B-cell non-Hodgkin lymphoma (B-NHL). Since the therapy with BsABs results in profound B-cell depletion and T-cell exhaustion, it is associated with significantly increased risk of infections. Additional risk factors involve immune disorders caused by lymphoma itself and previous lines of therapy. In this review, we focus on the infectious complications in B-NHL patients treated BsABs, presenting their incidence in clinical trials, admittedly performed to a large extent during the COVID-19 pandemic, as well as the proposals of infection prophylaxis. Full article
(This article belongs to the Special Issue Targeted Therapies for B-Cell Leukemia and Lymphoma)
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31 pages, 2674 KiB  
Review
Clinical Insights and Therapeutic Strategies for the Treatment of Interstitial Lung Disease in Patients with Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: Current Trends and Future Directions
by Justyna Fijolek and Anna Sniady
J. Clin. Med. 2025, 14(13), 4631; https://doi.org/10.3390/jcm14134631 - 30 Jun 2025
Viewed by 904
Abstract
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and interstitial lung disease (ILD) represent a complex interplay between autoimmune and fibrotic processes that poses significant diagnostic and therapeutic challenges. The distinction between isolated ANCA-ILD and AAV-ILD remains a subject of ongoing debate, with some researchers [...] Read more.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and interstitial lung disease (ILD) represent a complex interplay between autoimmune and fibrotic processes that poses significant diagnostic and therapeutic challenges. The distinction between isolated ANCA-ILD and AAV-ILD remains a subject of ongoing debate, with some researchers proposing that ANCA-ILD may be an early or restricted form of systemic vasculitis. Immunosuppressive therapy is the cornerstone of treatment for both diseases. However, there is increasing evidence that supports the potential role of antifibrotic agents in the management of progressive fibrosis. Management of these diseases requires a personalized approach that incorporates evaluation of biomarkers, imaging findings, and clinical risk factors to guide treatment decisions. Although current therapeutic strategies primarily target systemic inflammation, addressing the fibrotic components of these diseases is crucial for improving outcomes. Furthermore, emerging therapeutic options, such as B-cell depletion and antifibrotic therapies, offer promising outcomes. However, their roles in the treatment of AAV-ILD require further exploration. In this review, we discuss clinical insights and evolving therapeutic strategies for managing AAV and ANCA-positive ILD. In addition, we highlight the importance of early diagnosis and individualized treatment plans in improving the prognosis and quality of life of affected patients. Full article
(This article belongs to the Special Issue Interstitial Lung Diseases: New Treatments and Future Directions)
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31 pages, 2104 KiB  
Review
Balancing Regeneration and Resistance: Targeting DCLK1 to Mitigate Gastrointestinal Radiation Injury and Oncogenesis
by Landon L. Moore, Jerry Jaboin, Milton L. Brown and Courtney W. Houchen
Cancers 2025, 17(12), 2050; https://doi.org/10.3390/cancers17122050 - 19 Jun 2025
Viewed by 788
Abstract
Ionizing radiation (IR) poses a dual challenge in medicine; while essential for cancer therapy, it inflicts collateral damage to normal tissues, particularly the gastrointestinal (GI) tract. High-dose IR triggers acute radiation syndrome (ARS), characterized by crypt stem cell depletion, mucosal barrier disruption, inflammation, [...] Read more.
Ionizing radiation (IR) poses a dual challenge in medicine; while essential for cancer therapy, it inflicts collateral damage to normal tissues, particularly the gastrointestinal (GI) tract. High-dose IR triggers acute radiation syndrome (ARS), characterized by crypt stem cell depletion, mucosal barrier disruption, inflammation, and potential progression to fibrosis and secondary malignancy. Emerging evidence identifies the epithelial kinase doublecortin-like kinase 1 (DCLK1)—highly expressed in GI tuft cells and cancer stem-like cells—as a master regulator of post-IR responses. DCLK1 integrates DNA repair (via p53/ATM), and survival signaling (via NF-κB, TGF-β, and MAPK) to promote epithelial regeneration, yet these same mechanisms contribute to therapy resistance and oncogenesis. DCLK1 further modulates the immune microenvironment by skewing macrophages toward an immunosuppressive M2 phenotype, enhancing tissue remodeling, angiogenesis, and immune evasion. Preclinical studies demonstrate that DCLK1 inhibition sensitizes tumors to radiotherapy while preserving mucosal repair. Therapeutic strategies targeting DCLK1, alongside radioprotective agents, immunomodulators, and senolytics, may enhance regeneration, limit fibrosis, and eradicate therapy-resistant cancer stem cells. This review highlights DCLK1’s dual role in regeneration and tumorigenesis and evaluates its potential as a therapeutic target and biomarker in IR-induced GI damage. Full article
(This article belongs to the Section Cancer Biomarkers)
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17 pages, 2596 KiB  
Article
Low-Dose Salinomycin Alters Mitochondrial Function and Reprograms Global Metabolism in Burkitt Lymphoma
by Aleksandra Zdanowicz, Oleksandr Ilchenko, Andrzej Ciechanowicz, Haoyu Chi, Marta Struga and Beata Pyrzynska
Int. J. Mol. Sci. 2025, 26(11), 5125; https://doi.org/10.3390/ijms26115125 - 27 May 2025
Viewed by 621
Abstract
Salinomycin (SAL), originally identified for its potent antibacterial properties, has recently garnered attention for its remarkable activity against a variety of cancer types. Beyond its direct cytotoxic effects on cancer cells, SAL can also enhance the efficacy of anti-CD20 immunotherapy in B-cell malignancies, [...] Read more.
Salinomycin (SAL), originally identified for its potent antibacterial properties, has recently garnered attention for its remarkable activity against a variety of cancer types. Beyond its direct cytotoxic effects on cancer cells, SAL can also enhance the efficacy of anti-CD20 immunotherapy in B-cell malignancies, both in vitro and in vivo. Despite these promising findings, the precise molecular mechanisms underlying SAL’s anticancer action remain poorly understood. Here, we demonstrate that even at low concentrations (0.25–0.5 mM), SAL disrupts mitochondrial membrane potential and induces oxidative stress in Burkitt lymphoma. Further investigations uncovered that SAL shifts cellular metabolism from mitochondrial respiration to aerobic glycolysis. Additionally, metabolomic profiling identified SAL-induced arginine depletion as a key metabolic alteration. These findings provide new insights into SAL’s multifaceted mechanisms of action and support its potential as an adjunctive therapy in cancer treatment. Full article
(This article belongs to the Special Issue Oxidative Stress and Mitochondria in Human Diseases)
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20 pages, 3326 KiB  
Article
Increased STAT3 Phosphorylation in CD4+ T-Cells of Treated Patients with Chronic Lymphocytic Leukemia and Changes in Circulating Regulatory T-Cell Subsets Relative to Tumor Mass Distribution Value and Disease Duration
by Mojca Dreisinger, Zlatko Roškar, Aleš Goropevšek, Andreja Zakelšek, Sara Čurič, Nada Živko, Sebastjan Bevc and Evgenija Homšak
Biomedicines 2025, 13(5), 1204; https://doi.org/10.3390/biomedicines13051204 - 15 May 2025
Viewed by 668
Abstract
Introduction: In mouse models of chronic lymphocytic leukemia (CLL), an effective anti-leukemia immune response was obtained by depleting a specific regulatory T-cell (Treg) subset. While STAT5 signaling could alter the homeostasis of naïve (nTreg) and activated (aTreg) subsets, which are capable of [...] Read more.
Introduction: In mouse models of chronic lymphocytic leukemia (CLL), an effective anti-leukemia immune response was obtained by depleting a specific regulatory T-cell (Treg) subset. While STAT5 signaling could alter the homeostasis of naïve (nTreg) and activated (aTreg) subsets, which are capable of suppressing also CLL patients’ responses to microbial antigens, perturbed STAT3 signaling could drive CXCR5 expression in circulating T-follicular regulatory cells (Tfr) and their entry into the lymph node/tumor microenvironment. Materials and Methods: By using phospho-specific flow cytometry, we monitored STAT signaling/phosphorylation (pSTAT), in vitro responses to Sars-Cov2-antigen-specific stimulation, and circulating Treg subsets in relation to Binet stage and total tumor mass/tumor distribution (TTM/TD) scoring in 62 patients with CLL. Results: The percentage of CXCR5+ Treg significantly increased in patients with Binet stage B disease, and Tfr-like subsets were associated with higher TTM and lower TD. The pSTAT3 levels in CD4+ T-cells were only significantly increased in patients undergoing therapy. Lower nTreg percentages correlated with increased disease duration, and an increased aTreg/nTreg ratio correlated with SARS-CoV-2-antigen-induced STAT5 signaling responses. Conclusions: The results show increased amounts of circulating CXCR5+ Tfr-like subsets in patients with extensive lymph node involvement and augmented STAT3 signaling in patients on therapy. While STAT5 responses may drive nTreg differentiation into aTreg, nTreg decline is associated with increased disease duration. Full article
(This article belongs to the Section Cancer Biology and Oncology)
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27 pages, 707 KiB  
Review
Single-Agent and Associated Therapies with Monoclonal Antibodies: What About Follicular Lymphoma?
by Gabriella Cancemi, Chiara Campo, Santino Caserta, Iolanda Rizzotti and Donato Mannina
Cancers 2025, 17(10), 1602; https://doi.org/10.3390/cancers17101602 - 8 May 2025
Cited by 1 | Viewed by 1152
Abstract
Monoclonal antibodies (mAbs) have become a cornerstone in the treatment of follicular lymphoma (FL), offering highly specific therapeutic targeting that enhances efficacy while minimizing systemic toxicity. Their mechanisms of action include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptotic signaling, effectively [...] Read more.
Monoclonal antibodies (mAbs) have become a cornerstone in the treatment of follicular lymphoma (FL), offering highly specific therapeutic targeting that enhances efficacy while minimizing systemic toxicity. Their mechanisms of action include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptotic signaling, effectively mediating malignant B-cell depletion. Anti-CD20 mAbs, such as rituximab and obinutuzumab, have significantly improved progression-free survival (PFS) and overall survival (OS), establishing immunochemotherapy as the standard of care for FL. However, the emergence of treatment resistance, often characterized by CD20 antigen downregulation or immune escape, has prompted the development of next-generation mAbs with enhanced effector functions. Bispecific antibodies (BsAbs), which simultaneously engage CD20-expressing tumor cells and CD3-positive cytotoxic T cells, have emerged as a novel immunotherapeutic strategy, redirecting T-cell activity to eliminate malignant B cells independently of major histocompatibility complex (MHC) antigen presentation. Additionally, antibody–drug conjugates (ADCs) offer a targeted cytotoxic approach by delivering potent chemotherapeutic payloads directly to tumor cells while limiting off-target effects. The integration of mAbs with immune checkpoint inhibitors and immunomodulatory agents is further enhancing treatment outcomes by overcoming immunosuppressive mechanisms within the tumor microenvironment. Despite these advancements, challenges remain, including optimizing the treatment sequence, mitigating immune-related toxicities—particularly cytokine release syndrome (CRS)—and identifying predictive biomarkers to guide patient selection. As the role of monoclonal antibodies continues to expand, their integration into therapeutic regimens is transforming the management of FL, paving the way for chemotherapy-free treatment approaches and long-term disease control. This review provides an updated overview of mAbs therapies for FL, emphasizing the advances brought by BsAbs and ADCs toward more tailored and effective treatments. Full article
(This article belongs to the Special Issue Monoclonal Antibodies in Lymphoma)
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18 pages, 9773 KiB  
Article
Cucurbitacin B Exhibits Antitumor Effects on Chordoma Cells via Disruption of Brachyury
by Carolin Seeling, Johannes Neumahr, Fabian Häberle, André Lechel, Peter Möller, Nadine T. Gaisa, Thomas F. E. Barth and Kevin Mellert
Int. J. Mol. Sci. 2025, 26(8), 3864; https://doi.org/10.3390/ijms26083864 - 18 Apr 2025
Viewed by 610
Abstract
Chordomas are rare malignant tumors of the bone, originating from remnants of notochordal cells. The transcription factor brachyury, encoded by TBXT, serves as a critical diagnostic marker and is essential for tumor growth. While brachyury’s role in regulating the cytoskeleton during embryogenesis [...] Read more.
Chordomas are rare malignant tumors of the bone, originating from remnants of notochordal cells. The transcription factor brachyury, encoded by TBXT, serves as a critical diagnostic marker and is essential for tumor growth. While brachyury’s role in regulating the cytoskeleton during embryogenesis and tumorigenesis is well understood, the reverse—whether cytoskeletal alterations can influence brachyury levels—remains unclear. Despite advances in understanding chordoma biology, there are currently no approved targeted therapies, underscoring the need for novel therapeutic approaches. Three chordoma cell lines were treated with cytoskeletal inhibitors, including the actin-targeting compounds Cucurbitacin B (CuB) and Latrunculin B (LatB). Morphological changes, TBXT expression, and cell viability were analyzed. The effects of CuB were examined over time and across concentrations, with cell viability assessed via apoptosis and cytotoxicity assays. Microarray gene expression profiling of ten chordoma cell lines was performed to explore CuB-mediated transcriptional changes. Rescue experiments using a TBXT open reading frame vector and co-treatments with autophagy and proteasome inhibitors were conducted to elucidate the mechanisms of brachyury depletion. Both CuB and LatB induced significant morphological changes, but only CuB caused near-complete depletion of brachyury. This effect was time- and concentration-dependent, correlating with reduced cell viability driven primarily by apoptosis. Microarray analysis revealed that CuB treatment upregulated protein refolding pathways and downregulated protein glycosylation. Notably, TBXT transcription was only slightly suppressed, indicating that brachyury depletion was largely post-transcriptional. Rescue experiments and co-treatments implicated dysregulated protein refolding and endoplasmic reticulum (ER) stress as key mechanisms underlying CuB-mediated brachyury loss. This study demonstrates that actin cytoskeleton disruption by CuB depletes brachyury in chordoma cells, primarily through dysregulated protein refolding and ER stress rather than transcriptional repression. These findings suggest that targeting actin cytoskeleton dynamics or protein unfolding pathways may provide novel therapeutic approaches for chordoma treatment. Full article
(This article belongs to the Special Issue Molecular Research in Bone and Soft Tissue Tumors)
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7 pages, 488 KiB  
Case Report
Selective IgM Hypogammaglobulinemia and Multiple Sclerosis Treated with Natalizumab and Ofatumumab: A Case Report
by Francesco Crescenzo, Michelangelo Turazzini and Francesca Rossi
J. Pers. Med. 2025, 15(4), 155; https://doi.org/10.3390/jpm15040155 - 17 Apr 2025
Viewed by 702
Abstract
Background: B-cell-depleting drugs targeting the CD20 antigen have been increasingly implemented as an “exit strategy” from natalizumab for relapsing–remitting multiple sclerosis (RRMS) patients due to the increased risk of progressive multifocal leukoencephalopathy. Data on recently approved anti-CD20 drugs, such as ofatumumab serving as [...] Read more.
Background: B-cell-depleting drugs targeting the CD20 antigen have been increasingly implemented as an “exit strategy” from natalizumab for relapsing–remitting multiple sclerosis (RRMS) patients due to the increased risk of progressive multifocal leukoencephalopathy. Data on recently approved anti-CD20 drugs, such as ofatumumab serving as a natalizumab “exit strategy”, are lacking. Furthermore, due to their immunosuppressive mechanism of action, prolonged use of these “highly effective” drugs is associated with the development of hypogammaglobulinemia and, consequently, a higher risk of infections. There are no guidelines for monitoring serum immunoglobulin levels in individuals undergoing “highly effective” multiple sclerosis treatment. Methods: We present a case of a 26-year-old male RRMS patient with selective IgM deficiency and multiple sclerosis initially treated with natalizumab and later ofatumumab. Results: The patient achieved “no evident disease activity “status while undergoing treatment with natalizumab and ofatumumab, but these therapies, especially ofatumumab, greatly impacted further drops in IgM levels. However, no significant decrease in IgG levels was observed, and no infectious events occurred. In addition, the patient did not show signs of disease activity while on ofatumumab, which also offered a more convenient mode of administration. Conclusions: Our experience points to the need to further explore benefit–risk ratios of highly effective treatments, even in cases with low immunoglobulin levels. However, closely monitoring immunoglobulin levels and conducting clinical follow-ups to ensure prompt recognition of potential infectious complications constitute approaches that have been thought of for such patients. Full article
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15 pages, 951 KiB  
Review
Allergen Immunotherapy: Pitfalls, Perks and Unexpected Allies
by Tudor Paul Tamaș and Elena Ciurariu
Int. J. Mol. Sci. 2025, 26(8), 3535; https://doi.org/10.3390/ijms26083535 - 9 Apr 2025
Viewed by 943
Abstract
Allergen immunotherapy (AIT) is a well-established treatment aimed at reducing allergen sensitivity by gradually exposing the immune system to increasing doses of allergens. This promotes desensitization and immune tolerance through multiple mechanisms. AIT offers long-term immune modulation and is considered a potentially curative [...] Read more.
Allergen immunotherapy (AIT) is a well-established treatment aimed at reducing allergen sensitivity by gradually exposing the immune system to increasing doses of allergens. This promotes desensitization and immune tolerance through multiple mechanisms. AIT offers long-term immune modulation and is considered a potentially curative certain forms of allergic diseases. Altered antibody responses is a key mechanism of AIT in the production of allergen-specific IgG4 antibodies, which act as blocking antibodies to prevent allergen binding to IgE on mast cells (MCs) and basophils. However, IgG4 responses are sometimes ineffective due to variations in antibody affinity and epitope targeting. Reverse class switching from IgE to IgG4 and selective depletion of IgE-producing B cells represent potential strategies to improve AIT efficacy. Tregs play a central role in AIT by suppressing Th2-driven allergic responses and promoting immune tolerance through anti-inflammatory cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β. However, genetic and environmental factors may impair Treg function, leading to AIT failure. AIT reduces MC and basophil activation, leading to long-term suppression of allergic inflammation. It modulates IgE-FcεRI interactions and cytokine signaling pathways, but in some cases, anaphylactic reactions or resistance to MC desensitization may occur. Discussion and conclusions: While AIT is a highly effective allergy treatment, variability in immune responses can impact its success. Advances in biologic therapies offer potential synergies with AIT. Understanding these interactions will help refine AIT strategies and improve patient outcomes. Full article
(This article belongs to the Special Issue Allergic Diseases: Molecular Insights into Immunotherapy)
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21 pages, 4544 KiB  
Article
Injectable Magnetic-Nanozyme Based Thermosensitive Hydrogel for Multimodal DLBCL Therapy
by Min Yan, Jingcui Peng, Haoan Wu, Ming Ma and Yu Zhang
Gels 2025, 11(3), 218; https://doi.org/10.3390/gels11030218 - 20 Mar 2025
Viewed by 717
Abstract
Diffuse large B-cell lymphoma (DLBCL), accounting for 31% of non-Hodgkin lymphomas, remains recalcitrant to conventional therapies due to chemoresistance, metastatic progression, and immunosuppressive microenvironments. We report a novel injectable Fe3O4@DMSA@Pt@PLGA-PEG-PLGA hydrogel system integrating magnetothermal therapy (MHT), chemodynamic therapy (CDT), [...] Read more.
Diffuse large B-cell lymphoma (DLBCL), accounting for 31% of non-Hodgkin lymphomas, remains recalcitrant to conventional therapies due to chemoresistance, metastatic progression, and immunosuppressive microenvironments. We report a novel injectable Fe3O4@DMSA@Pt@PLGA-PEG-PLGA hydrogel system integrating magnetothermal therapy (MHT), chemodynamic therapy (CDT), and immunomodulation. Under alternating magnetic fields (AMF), the system achieves rapid therapeutic hyperthermia (50 °C within 7 min) while activating pH/temperature-dual responsive peroxidase (POD) -like activity in Fe3O4@DMSA@Pt nanoparticles. Catalytic efficiency under tumor-mimetic conditions was significantly higher than Fe3O4@DMSA controls, generating elevated reactive oxygen species (ROS). Flow cytometry revealed 75.9% apoptotic cell death in A20 lymphoma cells at 50 °C, significantly surpassing CDT alone (24.5%). Importantly, this dual mechanism induced immunogenic cell death (ICD) characterized by 4.1-fold CRT externalization, 68% HMGB1 nuclear depletion, and 40.74 nM ATP secretion. This triggered robust dendritic cell maturation (92% CD86+/CD80+ DCs comparable to LPS controls) and T cell activation (16.9% CD25+/CD69+ ratio, 130-fold baseline). Our findings validate the therapeutic potential of magnetothermal-chemodynamic synergy for DLBCL treatment, paving the way for innovative multi-mechanism therapeutic strategies against DLBCL with potential clinical translation prospects. Full article
(This article belongs to the Special Issue Recent Advances in Gels Engineering for Drug Delivery (2nd Edition))
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14 pages, 773 KiB  
Article
Advancing the Treatment of Adult Steroid-Resistant Nephrotic Syndrome: The Role of Rituximab
by Dmytro Ivanov, Mariia Ivanova, Olga Chub, Iryna Zavalna, Natalia Biljak, Yelizaveta Lagodych and Isa Jabbarli
Kidney Dial. 2025, 5(1), 10; https://doi.org/10.3390/kidneydial5010010 - 17 Mar 2025
Viewed by 1224
Abstract
Background: Steroid-resistant nephrotic syndrome (SRNS) in adults presents a significant therapeutic challenge, often leading to end-stage kidneys. This study aims to evaluate the clinical outcomes of rituximab (RTX) administration as an alternative to traditional cytostatic therapy in adults with SRNS, focusing on its [...] Read more.
Background: Steroid-resistant nephrotic syndrome (SRNS) in adults presents a significant therapeutic challenge, often leading to end-stage kidneys. This study aims to evaluate the clinical outcomes of rituximab (RTX) administration as an alternative to traditional cytostatic therapy in adults with SRNS, focusing on its effectiveness and safety profile. Methods: This multicenter, randomized study evaluates the effects of RTX for SRNS treatment, analyzing its clinical outcomes, safety, and efficacy across 52 adults (median age 47, 52% male) over 36 months. Amyloidosis and proliferative diseases were excluded by a kidney biopsy. Results: Complete remission rates improved from 50% to 66.7% by 36 months, with variations based on the morphological types of nephrotic syndrome experienced. The number needed to treat (NNT) for complete remission decreased from indeterminate to 12 by 36 months. RTX was well tolerated, with 17.3% experiencing allergic reactions and 25% developing hypogammaglobulinemia after one year. Severe infusion reactions were managed with omalizumab. Hypogammaglobulinemia and recurrent respiratory infections (21.5%) required additional treatments. Conclusions: RTX shows promise in achieving sustained remission in SRNS, especially in MN and FSGS, with increasing effectiveness over time. While its safety profile is encouraging, extended monitoring is essential for accurate treatment assessments. Further studies are needed to refine RTX protocols and outcomes. Full article
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22 pages, 5842 KiB  
Article
Axl Regulation of NK Cell Activity Creates an Immunosuppressive Tumor Immune Microenvironment in Head and Neck Cancer
by Kourtney L. Kostecki, Regan L. Harmon, Mari Iida, Madelyn A. Harris, Bridget E. Crossman, Justine Yang Bruce, Ravi Salgia and Deric L. Wheeler
Cancers 2025, 17(6), 994; https://doi.org/10.3390/cancers17060994 - 15 Mar 2025
Viewed by 995
Abstract
Background: Head and neck cancer (HNC) evades immune responses by manipulating the tumor immune microenvironment (TIME). Tumor-bound Axl has been implicated in promoting an immunosuppressive TIME in HNC, though its precise role remains unclear. Understanding Axl’s contribution to immune evasion in HNC [...] Read more.
Background: Head and neck cancer (HNC) evades immune responses by manipulating the tumor immune microenvironment (TIME). Tumor-bound Axl has been implicated in promoting an immunosuppressive TIME in HNC, though its precise role remains unclear. Understanding Axl’s contribution to immune evasion in HNC could lead to the identification of new therapeutic targets; therapies directed at these targets could be combined with and thereby enhance immunotherapies. Results: Using Axl knockout (Axl KO) cell lines derived from the immunologically “cold” MOC2 mouse model, we found that Axl loss delayed tumor growth in immunocompetent mice. This was accompanied by reduced immunosuppressive cells, including MDSCs, Tregs, B cells, and neutrophils, and increased infiltration of cytotoxic CD8 T cells and NK cells. To identify the immune population(s) responsible for these changes, Axl KO tumors were implanted in immune-deficient mice. Axl KO tumor growth in athymic nude mice (which lack T cells) was unchanged, whereas tumor growth in NCG mice (which lack NK cells) was rescued, suggesting that NK cells mediate the Axl KO tumor growth delay. Further, Axl loss enhanced NK cell cytotoxicity in vitro and in vivo, and NK cell depletion reversed delayed Axl KO tumor growth. Mechanistically, Axl KO tumors showed decreased expression of CD73 and CCL2, which inhibit NK cells, and increased expression of CCL5 and CXCL10, which promote NK cell recruitment and activation. Conclusions: These novel findings suggest that tumor-bound Axl fosters an immunosuppressive TIME by inhibiting NK cell recruitment and function, thereby promoting tumor growth. Targeting Axl may enhance NK cell-mediated tumor killing and improve immunotherapy efficacy in HNC. Full article
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14 pages, 250 KiB  
Review
Memory Cells in Infection and Autoimmunity: Mechanisms, Functions, and Therapeutic Implications
by Shilpi Giri and Lalit Batra
Vaccines 2025, 13(2), 205; https://doi.org/10.3390/vaccines13020205 - 19 Feb 2025
Cited by 3 | Viewed by 1895
Abstract
Memory cells are central to the adaptive immune system’s ability to remember and respond effectively to previously encountered pathogens. While memory cells provide robust protection against infections, they can also contribute to autoimmunity when regulation fails. Here, we review the roles of memory [...] Read more.
Memory cells are central to the adaptive immune system’s ability to remember and respond effectively to previously encountered pathogens. While memory cells provide robust protection against infections, they can also contribute to autoimmunity when regulation fails. Here, we review the roles of memory T and B cells in infection and autoimmunity, focusing on their differentiation, activation, effector functions, and underlying regulatory mechanisms. We elaborate on the precise mechanisms by which memory cells contribute to autoimmune diseases, highlighting insights from current research on how pathogenic memory responses are formed and sustained in autoimmunity. Finally, we explore potential therapeutic strategies aimed at modulating memory cells to prevent or treat autoimmune disorders, including B cell-depleting therapies (e.g., Rituximab), T cell-targeting agents (e.g., Abatacept), and cytokine inhibitors (e.g., IL-17 or IL-23 blockers) that are currently used in diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis. Full article
(This article belongs to the Special Issue Viral Infections, Host Immunity and Vaccines)
10 pages, 215 KiB  
Review
B-Cell-Depleting Immune Therapies as Potential New Treatment Options for Systemic Sclerosis
by Gerhard Zugmaier, Matthias Klinger, Marion Subklewe, Faraz Zaman and Franco Locatelli
Sclerosis 2025, 3(1), 5; https://doi.org/10.3390/sclerosis3010005 - 26 Jan 2025
Cited by 2 | Viewed by 2275
Abstract
Background: Systemic sclerosis (SSc), also known as scleroderma, is a complex, chronic autoimmune disease characterized by fibrosis of the skin and internal organs, vasculopathy, and immune system dysregulation. The treatment of SSc has historically focused on symptom management and slowing down disease progression [...] Read more.
Background: Systemic sclerosis (SSc), also known as scleroderma, is a complex, chronic autoimmune disease characterized by fibrosis of the skin and internal organs, vasculopathy, and immune system dysregulation. The treatment of SSc has historically focused on symptom management and slowing down disease progression through conventional immune-suppressive agents. New therapeutic approaches have been emerging due to advances in understanding of the disease mechanisms, particularly in the areas of fibrosis, vascular involvement, and immune dysregulation. Methods: In this review of the literature, we discuss the current stage of development of B-cell-depleting immune therapies in SSc. Results: B-cell depletion therapy has become an area of growing interest in the treatment of SSc due to the role played by B cells in the pathogenesis of the disease. There is increasing evidence that B cells contribute to disease progression through multiple mechanisms. B cells in SSc are implicated in autoantibody production, cytokine production, and fibroblast activation. B cells are responsible for producing autoantibodies, such as anti-topoisomerase I (Scl-70) and anti-centromere antibodies, which are hallmarks of SSc. B cells release pro-inflammatory cytokines (such as interleukin-6 [IL-6] and transforming growth factor β [TGF-β]), which promote fibrosis and inflammation, they also contribute to the activation of fibroblasts, the cells responsible for excessive collagen production and fibrosis, a key feature of SSc. Conclusions: In light of these findings, therapies that target B cells are being investigated for their potential to modify the disease course in SSc, particularly by reducing autoantibody production, inflammation, and fibrosis. Full article
(This article belongs to the Special Issue Recent Advances in Understanding Systemic Sclerosis)
16 pages, 1200 KiB  
Article
The Secondary Resistome of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics
by Nader Abdelmalek, Sally Waheed Yousief, Martin Saxtorph Bojer, Mosaed Saleh A. Alobaidallah, John Elmerdahl Olsen and Bianca Paglietti
Antibiotics 2025, 14(2), 112; https://doi.org/10.3390/antibiotics14020112 - 21 Jan 2025
Cited by 2 | Viewed by 1681
Abstract
Background: Therapeutic strategies for methicillin-resistant Staphylococcus aureus (MRSA) are increasingly limited due to the ability of the pathogen to evade conventional treatments such as vancomycin and daptomycin. This challenge has shifted the focus towards novel strategies, including the resensitization of β-lactams, which [...] Read more.
Background: Therapeutic strategies for methicillin-resistant Staphylococcus aureus (MRSA) are increasingly limited due to the ability of the pathogen to evade conventional treatments such as vancomycin and daptomycin. This challenge has shifted the focus towards novel strategies, including the resensitization of β-lactams, which are still used as first-line treatments for methicillin-susceptible Staphylococcus aureus (MSSA). To achieve this, it is essential to identify the secondary resistome associated with the clinically relevant β-lactam antibiotics. Methods: Transposon-Directed Insertion Site Sequencing (TraDIS) was employed to assess conditional essentiality by analyzing the depletion of mutants from a highly saturated transposon library of MRSA USA300 JE2 exposed to ½ minimal inhibitory concentration (MIC) of oxacillin or cefazolin. Results: TraDIS analysis led to the identification of 52 shared fitness genes involved in β-lactam resistance that are primarily linked to cell wall metabolism and regulatory systems. Among these, both known resistance factors and novel conditionally essential genes were highlighted. As proof of concept, transposon mutants corresponding to nine genes (sagB, SAUSA300_0657, SAUSA300_0957, SAUSA300_1683, SAUSA300_1964, SAUSA300_1966, SAUSA300_1967, SAUSA300_1692, and mazF) were grown in the presence of β-lactam antibiotics and their MICs were determined. All mutants showed significantly reduced resistance to β-lactam antibiotics. Conclusions: This comprehensive genome-wide investigation provides novel insights into the resistance mechanisms of β-lactam antibiotics, and suggests potential therapeutic targets for combination therapies with helper drugs. Full article
(This article belongs to the Section Mechanism and Evolution of Antibiotic Resistance)
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