Depletion Therapy Research Articles

Contribution of long-lived plasma cells to antibody-mediated allograft rejection.

Persistent alloantigens derived from allograft tissues can be recognized by the host's alloreactive immune system. This process enables cognate B cells to differentiate into plasma cells, which secrete donor-specific antibodies that are key drivers of antibody-mediated allograft rejection. A subset of these plasma cells can survive for extended periods in a suitable survival niche and mature into long-lived plasma cells (LLPCs), which are a cellular component of humoral memory. The current understanding of LLPCs is limited due to their scarcity, heterogeneity, and absence of unique markers. However, accumulating evidence indicates that LLPCs, unlike conventional short-lived plasma cells, can respond to extrinsic signals from their survival niches and can resist cell death associated with intracellular stress through cell-intrinsic mechanisms. Notably, they are refractory to traditional immunosuppressants and B cell depletion therapies. This resistance, coupled with their longevity, may explain why current treatments targeting antibody-mediated rejection are often ineffective. This review offers insights into the biology of LLPCs and discusses ongoing therapeutic trials that target LLPCs in the context of antibody-mediated allograft rejection.

The Role of Tumor-Associated Macrophages in Cancer Immunoevasion and Therapy Resistance

Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment, playing significant roles in cancer progression, immune evasion, and therapy resistance. Originating from circulating monocytes, TAMs can polarize into M1 and M2 phenotypes, with M2-like TAMs predominating in many cancers. This M2 polarization fosters an immunosuppressive environment that promotes tumor growth, metastasis, and resistance to therapies, including chemotherapy and immune checkpoint inhibitors. TAMs secrete various cytokines, chemokines, and growth factors that enhance tumor cell survival, promote angiogenesis, and recruit additional immunosuppressive cells such as regulatory T cells. They also express immune checkpoint molecules, further inhibiting effective anti-tumor immune responses. Given their dual role in supporting tumor survival and mediating immune evasion, TAMs represent an attractive target for therapeutic intervention. Current strategies to target TAMs include depletion, reprogramming, and combination therapies aimed at enhancing anti-tumor immunity. This review explores the complex biology of TAMs, their mechanisms of action in promoting cancer immunoevasion and therapy resistance, and the therapeutic strategies being developed to exploit their unique characteristics. By providing insights into the multifaceted roles of TAMs, this review aims to highlight potential avenues for improving cancer treatment outcomes and addressing the challenges posed by tumor-induced immune suppression. Keywords: Tumor-Associated Macrophages (TAMs), Immune Evasion, Therapy Resistance, Macrophage Polarization, Immunotherapy

Epidemiology of men with synchronous metastatic prostate cancer diagnosis – A nationwide 26-year temporal analysis

BackgroundEvolving imaging modalities, increased awareness, and prostate-specific antigen testing in men with synchronous metastatic prostate cancer (mHSPC) are expected to have prolonged survival. Here we analyze trends in survival among men diagnosed with synchronous metastatic prostate cancer in Denmark. MethodsHere, we included all men diagnosed with mHSPC (N = 12,017) in Denmark between January 1st, 1995, and December 31st, 2021. Men were followed until December 31st, 2022. Median time to death was calculated by the Kaplan Meier method and the 3-year risk of prostate cancer death per calendar year was estimated by the Aalen-Johansen estimator from time of diagnosis. FindingsMedian follow-up was 9 years (IQR: 4–15), from 2015 59 % of the men with mHSPC had treatment beyond androgen depletion therapy. Median survival increased from 1.7 years (IQR: 1·3–2·0) to 3.8 years (IQR: 3·3–4·2) in men diagnosed in 1995 and 2018, respectively (p < 0·001), after which median survival was not reached. The prostate cancer-specific mortality three years after diagnosis decreased from 66 % (95 %CI: 60–72) in 1995 to 28 % (95 %CI: 25–32) in 2019 (p < 0·001). From the period 1995–1999 to 2015–2021 median overall survival increased from 1·7 years (IQR: 0·8–3·7) to 4·5 years (IQR: 2·4-not reached; p < 0·001) in men age < 65 years and from 1·5 years (IQR: 0·7–2·9) to 3·1 years (IQR: 1·6–5·7; p < 0.001) in men older than 74 years at diagnosis. InterpretationThe improved survival suggests that, among other contributing factors, implementing novel therapies has likely been efficacious outside the clinical trial setting. Still, most men diagnosed with synchronous metastatic prostate cancer will die of prostate cancer. As such the need for life-prolonging and age-tailored treatment trials remains evident.

IgE immunoadsorption: technical background, functionality, and first clinical experience

Summary Background The prevalence of allergic diseases has risen in the 21st century, drawing attention to specific therapeutic and preventive strategies. Due to the key role of immunoglobulin E (IgE) in the development of allergic reactions, IgE represents a key target treatment. In this scenario, IgE immunoadsorption (IgE-IA) has been investigated as a procedure that selectively removes circulating IgE antibodies from the bloodstream of patients with atopy. Methods This narrative review aims to critically summarize the current insights regarding IgE-IA in the context of the management of allergic diseases, ranging from the rationale to the technical aspects, as well as the benefits and unmet needs. Results IgE-IA might be a treatment strategy in well-selected patients with allergic diseases. IgE depletion through sessions of IgE-IA results in immediate clinical improvement and might be useful in acute situations when a rapid clinical response is required or when classic approaches are contraindicated or ineffective. Due to the reduced effectiveness over time, IgE-IA could be a valid first approach before starting another IgE depletion therapy, such as omalizumab, when its commencement would otherwise be contraindicated by too-high serum IgE levels. Conclusion Overall, IgE-IA is safe and well tolerated; however, this procedure is currently difficult to implement in routine clinical practice because of costs, time demands, need for hospitalization, and the invasiveness of the procedure, with the associated risks related to the necessity of venous catheterization.

Pemphigus relapse: Mechanisms, risk factors, and agents associated with disease recurrence.

Pemphigus represents a spectrum of potentially life-threatening autoimmune-mediated skin blistering conditions caused by antibody production against desmoglein 1 and 3 (anti-DSG 1 and 3) in keratinocytes. Greater than 50% of pemphigus patients experience relapse, which complicates long-term medical management, including risks associated with re-treatment and complications such as infection and dehydration. This review aims to elucidate mechanisms, risk factors, and medications associated with pemphigus relapse. Mechanisms of relapse include the persistence of auto-reactive B-cell populations post-treatment and CD20- B-cell populations that reactivate after B-cell depletion therapy. Risk factors for relapse include high body surface area (BSA) of pemphigus involvement, high body mass index, high severity according to the Pemphigus Disease Area Index (PDAI) at onset, treatment delay, and high anti-DSG1 and DSG3 titers post-treatment. Targeted B-cell localization is associated with better clinical outcomes, including less frequent relapses. Rituximab is currently the gold standard of treatment for moderate-severe pemphigus and has relapse rates of 11%-44% in selected studies, with a mean time to relapse of 5.8 months to 36 months following treatment. Relapse rates across lymphoma dosing (375 mg/m2) versus rheumatoid arthritis dosing (1 g dosing weekly) was inconsistent; however, more frequent dosing, earlier treatment, and higher cumulative dosing were associated with lower relapse rates. Alternative agents that have clinical efficacy include corticosteroid monotherapy, mycophenolate mofetil, azathioprine, and intravenous immunoglobulin. Future studies should include head-to-head comparators over long follow-up periods to identify the best treatment agents associated with the least relapse risk.

Cutting-edge approaches to B-cell depletion in autoimmune diseases.

B-cell depletion therapy (BCDT) has been employed to treat autoimmune disease for ~20 years. Immunoglobulin G1 (IgG1) monoclonal antibodies targeting CD20 and utilizing effector function (eg, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis) to eliminate B cells have historically been the predominant therapeutic approaches. More recently, diverse BCDT approaches targeting a variety of B-cell surface antigens have been developed for use in hematologic malignancies, including effector-function-enhanced monoclonal antibodies, chimeric antigen receptor T-cell (CAR-T) treatment, and bispecific T-cell engagers (TCEs). The latter category of antibodies employs CD3 engagement to augment the killing of target cells. Given the improvement in B-cell depletion observed with CAR-T and TCEs compared with conventional monospecific antibodies for treatment of hematologic malignancies and the recent case reports demonstrating therapeutic benefit of CAR-T in autoimmune disease, there is potential for these mechanisms to be effective for B-cell-mediated autoimmune disease. In this review, we discuss the various BCDTs that are being developed in autoimmune diseases, describing the molecule designs, depletion mechanisms, and potential advantages and disadvantages of each approach as they pertain to safety, efficacy, and patient experience. Additionally, recent advances and strategies with TCEs are presented to help broaden understanding of the potential for bispecific antibodies to safely and effectively engage T cells for deep B-cell depletion in autoimmune diseases.

Follow Up of Total B Cells (CD 19) Count after B Cell Depleting Therapy in Relapse Remitting Multiple Sclerosis Disorder in Egyptian Patients

Abstract Background Multiple Sclerosis (MS) is a chronic neurological disorder affecting central nervous system. It is classified as the most common neurological cause of disability in young adults. However the aetiology is not well understood, but most propably multifactorial involvement is the most convenient theory till now. It is characterized by inflammation, demyelinaion, axonal loss and degeneration. Ocrelizumab (ocrevus®) (OCR) was approved as treatment for relapsing and progressive patients in 2017. It is a humanized IgG1 monoclonal antibody anti CD20, a cell surface antigen found on pre-B cells, mature B cells and memory B cells. Aim of the Work To follow up total B cell count along the course of B cell depletion therapy in MS patients, correlating it with disease activity, in an attempt to investigate whether routine measurement of B cell counts may serve for dosage and time-to-infusion decision making in those patients. Subjects and Methods It was a prospective cohort study carried on 30 Egyptian patients diagnosed with Relapse remitting multiple sclerosis according to McDonald criteria 2017. They were recruited from Multiple sclerosis unit at Ain Shams University Hospitals, both genders were included and age older than 18 years old. Results This study showed that most of patients were females by 73.3%, but males were 26.7%. The mean age at onset of illness was 29.93 ± 5.55 years and the mean duration of illness was 6.9 ± 4.96. 70% of patients had ≤3 relapses in previous 2 years, while 86.7% had improvement in the annual relapse rate. Regarding history of DMT most patients (66.7%) had two, but only 13.3% were naïve. The mean count of CD19 B cells was cells/µl 65.98 ± 79.04 and significantly depleted to, 3.59 ± 2.94, 25.6 ± 43.98 and 11.11 ± 19.53 cells/µl after 1, 6 and 12 months respectively. this was associated with significant decline in the median (IQR) ARR from 20 (66.67%) to 0 (0%) after 12 months of ocrelizumab therapy and the median (IQR) EDSS from 4.5 (3.5 – 5.5) pretreatment to 3.5 (2.5 - 4.5) and 2.5(2.5-4.5) after 6 and 12 months respectively. Most patients showed either stationary cerebral and cord lesions (as regards number and size of the lesions) and also as regard gadolinium enhanced cerebral lesions, there was a statistically significant decrease in number of patients after 1 year as p-value was &amp;lt;0.05. In our study, the changes in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition) show statistically significant improvement in all parameters of assessment across three time points. As long as, the depletion of CD19 B cell counts was associated with marked clinical and radiological improvement. We found statistically significant correlation between CD19 B cell counts and EDSS. Furthermore, there was no statistically significant correlation with changes in the multiple sclerosis functional composite score (a composite measure of walking speed, upper-limb movements, and cognition) and MRI Disease activity. Conclusion Ocrelizumab was highly efficacious in reducing relapses, preventing disability progression and reducing activity either clinically as EDSS and functional composite score or radiologically in Egyptian MS patients. A fixed-dose schedule of 6-monthly infusion achieved a good relapse free rate. Repeated treatment with ocrelizumab in patients with MS leads to sustained CD19 B cells depletion.

An endogenous oxygen self-supplied nanoplatform with GSH-depleted and NIR-II triggered electron-hole separation for enhanced photocatalytic anti-tumor therapy.

The use of artificial enzymes and light energy in photocatalytic therapy, a developing drug-free therapeutic approach, can treat malignant tumors in vivo. However, the relatively deficient oxygen concentration in the tumor microenvironment (TME) restrains their further tumor treatment capability. Herein, a novel nanoplatform with Cu7S4@Au nanocatalyst coated by MnO2 was successfully designed. After 1064 nm light irradiation, the designed nanocatalyst can promote the separation of light generated electron-hole pairs, resulting in ROS generation and tumor cell apoptosis. The MnO2 shelled nanoplatform can function as a TME-responsive oxygen self-supplied producer to improve photocatalyst treatment and GSH depletion. In summary, the designed novel nanoplatform shows efficient inhibition of tumor growth via GSH depletion and synergistic photocatalytic therapy, which is of great significance for improving the clinical tumor treatment effect.

B-cell Depletion Therapy in Pediatric Neuroinflammatory Disease.

B-cell depletion therapy, including anti-CD20 and anti-CD19 therapies, is increasingly used for a variety of autoimmune and conditions, including those affecting the central nervous system. However, B-cell depletion therapy use can be complicated by adverse effects associated with administration and immunosuppression. This review aims to summarize the application of anti-CD20 and anti-CD19 therapies for the pediatric neurologist and neuroimmunologist. Most existing literature come from clinical trials with adult patients, although more recent studies are now capturing the effects of these therapies in children. The most common side effects include infusion related reactions and increased infection risk from immunosuppression. Several strategies can mitigate infusion related reactions. Increased infections due to persistent hypogammaglobulinemia can benefit from replacement immunoglobulin. B-cell depletion therapies can be safe and effective in pediatric patients. Anticipation and mitigation of common adverse effects through primary prevention strategies, close monitoring, and appropriate symptomatic management can improve safety and tolerability.

Rational use of immunoglobulins (IVIgs and SCIgs) in secondary antibody deficiencies.

Immunoglobulins for intravenous use (IVIgs) and subcutaneous use (SCIgs) can prevent recurrent and severe infections in patients with secondary antibody deficiencies that are frequently linked to haematological/oncological malignancies as well as other clinical conditions and their respective treatments. Even so, as IVIgs and SCIgs are costly and their supply is limited, their clinical use must be optimised. The aim of this position paper is to provide structured practical guidance on the optimal use of IVIgs and SCIgs in secondary antibody deficiencies, particularly in haematological and oncological practice. The authors agree that the occurrence of severe infections is a prerequisite for the use of IVIgs. Serum IgG levels in general as well as IgG subclass levels can be additional indicators of whether a patient could benefit from IVIgs. Responsiveness to vaccines can help to identify immunodeficiency. Patients with chronic lymphocytic leukaemia or multiple myeloma who are receiving respective treatment, especially B-cell depletion therapy, but also some patients with autoimmune diseases are prone to antibody deficiencies and need IVIgs. For the optimal use of IVIgs and to maximise their potential benefit, the indication must be individually assessed for each patient. As a primary treatment goal, the authors define a sufficient prophylaxis of severe infections, which can be supported by normalising IgG levels. If the initiated treatment is insufficient or linked to intolerable adverse reactions, switching the product within the class of IVIgs or changing to a different batch of the same product can be considered. Pausing treatment can also be considered if there are no infections, which happens more frequently in summer, but treatment needs to be resumed once infections return. These structured recommendations for IVIg treatment in patients with secondary antibody deficiency may provide guidance for clinical practice and therefore help to allocate IVIgs to those who will benefit the most, without overusing valuable resources.

An “Iron-phagy” nanoparticle inducing irreversible mitochondrial damages for antitumor therapy

Cellular iron is inseparably related with the proper functionalities of mitochondria for its potential to readily donate and accept electrons. Though promising, the available endeavors of iron chelation antitumor therapies have tended to be adjuvant therapies. Herein, we conceptualized and fabricated an “iron-phagy” nanoparticle (Dp44mT@HTH) capable of inducing the absolute devastation of mitochondria via inhibiting the autophagy-removal of impaired ones for promoting cancer cell death. The Dp44mT@HTH with hyaluronic acid (HA) as hydrophilic shell can specifically target the highly expressed CD44 receptors on the surface of 4T1 tumor cells. After internalization and lysosomal escape, the nanoparticle disassembles in response to the reactive oxygen species (ROS), subsequently releasing the iron chelator Dp44mT and autophagy-inhibitory drug hydroxychloroquine (HCQ). Dp44mT can then seize cellular Fe2+ to trigger mitochondrial dysfunction via respiratory chain disturbance, while HCQ not only lessens Fe2+ intake, but also impedes fusions of autophagosomes and lysosomes. Consequentially, Dp44mT@HTH induces irreversible mitochondrial impairments, in this respect creating a substantial toxic stack state that induces apoptosis and cell death. Initiating from the perspective of endogenous substances, this strategy illuminates the promise of iron depletion therapy via irreversible mitochondrial damage induction for anticancer treatment.

Neutralizing Autoantibodies against Interleukin-10 in Inflammatory Bowel Disease

SummaryWe discovered high-titer neutralizing autoantibodies against interleukin-10 in a child with infantile-onset inflammatory bowel disease (IBD), a phenocopy of inborn errors of interleukin-10 signaling. After B-cell–depletion therapy and an associated decrease in the anti–interleukin-10 titer, conventional IBD therapy could be withdrawn. A second child with neutralizing anti–interleukin-10 autoantibodies had a milder course of IBD and has been treated without B-cell depletion. We conclude that neutralizing anti–interleukin-10 autoantibodies may be a causative or modifying factor in IBD, with potential implications for therapy. (Funded by the National Institute for Health and Care Research and others.)

A randomized cross-over trial of prebiotics and probiotics in multiple sclerosis: Trial feasibility, supplement tolerability and symptom abatement

BackgroundDietary supplements can modulate the gut microbial ecosystem and affect the immune system. This has potential implications for autoimmune diseases, including multiple sclerosis (MS). Prior studies explored tolerability, symptomatic improvement, and immunologic effects of probiotics in people with MS (pwMS), but no study has examined prebiotics in this population or compared prebiotics with probiotics. MethodsThis is a randomized, open-label trial of participants with relapsing-remitting MS on B-cell depletion therapy from two MS centers. 22 participants enrolled in the original cross-over study in which probiotic (Visbiome, containing Lactobacillus, Bifidobacterium and Streptococcus species) or prebiotic (Prebiotin, containing oligofructose enriched inulin) supplementation for 6 weeks was randomized, each followed by a washout period. Due to pandemic-related interruptions and expiration of the study supply of probiotics, another 15 participants enrolled in a single-arm study to receive prebiotic supplementation for 6 weeks followed by a washout period. We assessed supplement tolerability and patient-reported outcomes (PRO) relevant to MS (disability, fatigue, mood, and bowel symptoms) before and after each supplement administration period and each washout period. We bio-archived plasma, serum, peripheral blood mononuclear cells and stool samples at each timepoint for future multi-omic assessment. ResultsPrebiotics and probiotics had comparable adherence rates and both supplements were well tolerated in pwMS. Participants on either supplement reported minor adverse events, most of which were mild and self-limited. There was a subjective preference for prebiotics over probiotics. Comparing supplement-associated changes in PRO scores from baseline to 6 weeks post-supplementation, there were significant difference between prebiotics and probiotics for the change in patient-reported global symptom burden (MSRS-R Total) and bowel control (BWCS), but only probiotics statistically improved bowel control from baseline to post-supplementation. ConclusionSupplementation with either prebiotics or probiotics is reasonably well-tolerated and safe. Probiotics improved bowel control, but did not improve other PROs in a 6-week time frame. These data regarding feasibility, tolerability, adherence, and adverse events of supplements will inform future clinical trial designs to definitively compare the efficacy and safety of prebiotics and probiotics. The biological data that will be generated from this study in the future will provide mechanistic insights into the effects of these dietary supplements on MS pathophysiology.

European flow cytometry quality assurance guidelines for the diagnosis of primary immune deficiencies and assessment of immune reconstitution following B cell depletion therapies and transplantation.

Over the last 15 years activity of diagnostic flow cytometry services have evolved from monitoring of CD4 T cell subsets in HIV-1 infection to screening for primary and secondary immune deficiencies syndromes and assessment of immune constitution following B cell depleting therapy and transplantation. Changes in laboratory activity in high income countries have been driven by initiation of anti-retroviral therapy (ART) in HIV-1 regardless of CD4 T cell counts, increasing recognition of primary immune deficiency syndromes and the wider application of B cell depleting therapy and transplantation in clinical practice. Laboratories should use their experience in standardization and quality assurance of CD4 T cell counting in HIV-1 infection to provide immune monitoring services to patients with primary and secondary immune deficiencies. Assessment of immune reconstitution post B cell depleting agents and transplantation can also draw on the expertise acquired by flow cytometry laboratories for detection of CD34 stem cell and assessment of MRD in hematological malignancies. This guideline provides recommendations for clinical laboratories on providing flow cytometry services in screening for immune deficiencies and its emerging role immune reconstitution after B cell targeting therapies and transplantation.

Systemic lupus erythematosus and autoimmune hepatitis overlap disease in a hospitalized systemic lupus erythematosus cohort

Liver dysfunction in systemic lupus erythematosus (SLE) is caused by disease activity or secondary conditions like coexistent autoimmune liver diseases. In Taiwan, despite sporadically reported cases of SLE-autoimmune hepatitis (AIH) overlap disease, larger-scale monocentric investigations for such overlapping patients are not available. Retrospective analyses were performed in a hospitalized SLE cohort with 805 patients for identifying co-existent AIH from 2014 to 2023, focusing on distinct therapeutic modalities and differential diagnosis between SLE-AIH overlap and lupus hepatitis (LH). There were 5 cases (a 0.6% occurrence), all females aged 25–58 years (44 ± 13). Ages for the SLE diagnosis were 19–51 years (30 ± 13), while ages for the AIH diagnosis were 22–57 years (36 ± 14). Contradictory to interface hepatitis in SLE-AIH overlap, liver biopsy only demonstrated non-specific abnormalities in LH. Liver cirrhosis was identified in SLE-AIH overlap but not in LH. After corticosteroids/azathioprine therapy, there were normalized liver function in all LH. In 2 SLE-AIH overlap cases refractory to such therapy, one received B-cell depletion therapy (annual rituximab infusion, 375 mg/m2 weekly × 4) and another accepted living-donor liver transplantation from sibling due to advanced liver cirrhosis, leading to improved hepatic dysfunction in both.

B-cells depletion after treatment with rituximab predicts relapse of IgG4-related disease.

B cell depletion therapy with rituximab is effective in most patients with IgG4-related disease (IgG4-RD) but requires repeated cycles to prevent disease flares. We here aimed to assess B cells after rituximab to predict relapse of IgG4-RD and guide retreatment. Patients with active IgG4-RD included in this retrospective study fulfilled the ACR/EULAR Classification Criteria. Total CD19+ B cells, plasmablasts, naïve and memory B cells were measured on peripheral blood by flow-cytometry at baseline and six months after rituximab. All patients were treated with two 1 g infusions of rituximab 15 days apart and monitored for 48 months. Disease response was assessed using the IgG4-RD Responder Index. Thirty-three patients were included. Six months after rituximab, disease response was observed in all patients. Complete depletion of CD19+ B cells, plasmablasts, naïve and memory B cell depletion was achieved in 30%, 55%, 39%, and 42% of cases, respectively. Twenty-three relapses (70%) were observed at a median time of 24 months after rituximab. Relapse rate was significantly higher in patients who failed to achieve complete depletion of CD19+ cells (60% vs 17%, p= 0.02), naïve B cells (54% vs 15%, p= 0.01), or memory B cells (50% vs 16%, p= 0.03) six months after rituximab. The median relapse free survival time was shorter in patients who failed to achieve complete depletion of CD19+ cells (19 vs 38 months, p= 0.02), naïve B cells (16 vs 38 months, p= 0.01), or memory B cells (19 vs 38 months, p= 0.03) six months after rituximab. The degree of B cell depletion six months after rituximab may predict disease flare and may instruct on the pacing of B cell depletion therapy in IgG4-RD.

Iron promotes ovarian cancer malignancy and advances platinum resistance by enhancing DNA repair via FTH1/FTL/POLQ/RAD51 axis

Iron is crucial for cell DNA synthesis and repair, but an excess of free iron can lead to oxidative stress and subsequent cell death. Although several studies suggest that cancer cells display characteristics of ‘Iron addiction’, an ongoing debate surrounds the question of whether iron can influence the malignant properties of ovarian cancer. In the current study, we initially found iron levels increase during spheroid formation. Furthermore, iron supplementation can promote cancer cell survival, cancer spheroid growth, and migration; vice versa, iron chelators inhibit this process. Notably, iron reduces the sensitivity of ovarian cancer cells to platinum as well. Mechanistically, iron downregulates DNA homologous recombination (HR) inhibitor polymerase theta (POLQ) and relieves its antagonism against the HR repair enzyme RAD51, thereby promoting DNA damage repair to resist chemotherapy-induced damage. Additionally, iron tightly regulated by ferritin (FTH1/FTL) which is indispensable for iron-triggered DNA repair. Finally, we discovered that iron chelators combined with platinum exhibit a synergistic inhibitory effect on ovarian cancer in vitro and in vivo. Our findings affirm the pro-cancer role of iron in ovarian cancer and reveal that iron advances platinum resistance by promoting DNA damage repair through FTH1/FTL/POLQ/RAD51 pathway. Our findings highlight the significance of iron depletion therapy, revealing a promising avenue for advancing ovarian cancer treatment.

A new perspective on therapies involving B-cell depletion in autoimmune diseases.

It has been rediscovered in the last fifteen years that B-cells play an active role in autoimmune etiology rather than just being spectators. The clinical success of B-cell depletion therapies (BCDTs) has contributed to this. BCDTs, including those that target CD20, CD19, and BAFF, were first developed to eradicate malignant B-cells. These days, they treat autoimmune conditions like multiple sclerosis and systemic lupus erythematosus. Particular surprises have resulted from the use of BCDTs in autoimmune diseases. For example, even in cases where BCDT is used to treat the condition, its effects on antibody-secreting plasma cells and antibody levels are restricted, even though these cells are regarded to play a detrimental pathogenic role in autoimmune diseases. In this Review, we provide an update on our knowledge of the biology of B-cells, examine the outcomes of clinical studies employing BCDT for autoimmune reasons, talk about potential explanations for the drug's mode of action, and make predictions about future approaches to targeting B-cells other than depletion.

Mitigating adverse effects of B cell depletion therapy on acute respiratory virus infections through IFN-β intervention treatment.

Abstract In autoimmune patients, the use of disease-modifying therapies (DMTs) can compromise immunity to viral infections. The COVID-19 pandemic generated interest in the effects of two DMTs on acute viral infections:B cell depletion therapy (α-CD20) and Interferon-beta (IFN-β) therapy. Severe acute viral infections have been associated with B cell depletion therapy, while IFN-β is believed to provide protection due to its antiviral properties. The goal of our study is to elucidate the individual and combined effects of α-CD20 and IFN-β during acute respiratory viral infections in mice. In our study, B cell depletion was achieved by administering α-CD20 three times every 5 days, starting 7 days before influenza A virus (IAV) infection, while IFN-β was given on days 1 and 2 post-infection. When administered alone, α-CD20 resulted in increased weight loss, reduced viral clearance, heightened lung-infiltrating myeloid cells, and elevated inflammatory cytokines in the blood on day 9 post-infection. T cell responses to IAV were not inhibited by α-CD20. While IFN-β alone did not protect against IAV, co-administration of IFN-β with α-CD20 effectively mitigated adverse effects of B cell depletion, by reducing viral load, mitigating morbidity, and slowing the infiltration of myeloid cells into the lung. These data demonstrate IFN-β’s ability to counteract α-CD20’s negative impact on viral infections, providing insights for potential treatment strategies in autoimmunity during viral outbreaks.

Treatment Strategies for Anti-Synthetase Syndrome

Anti-aminoacyl tRNA synthetase (ARS) antibodies are the most frequent in idiopathic inflammatory myopathy, notably associated with anti-synthetase syndrome (ASyS), which is characterized by six clinical features: arthritis, myositis, interstitial lung disease (ILD), fever, Raynaud's phenomenon, and mechanical hands. Although patients with ASyS often respond well to initial glucocorticoid (GC) therapy, they tend to have a chronic, recurrent disease course. In anti-ARS-positive patients, the treatment goal involves suppressing disease recurrence and progression while achieving a minimal GC dose. In this regard, the administration and continuation of immunosuppressants, such as calcineurin inhibitors, have been suggested. B-cell depletion therapies are expected to be valuable in patients with refractory ASyS. Moreover, additional antifibrotic agents may be beneficial for patients with progressive fibrosing ILD.