Depletion Therapy Research Articles

Multifaceted Roles of Copper ions in Anticancer Nanomedicine.

The significantly increased copper level in tumor tissues and serum indicates the close association of copper ions with tumor development, making copper ions be attractive targets in the development of novel tumor treatment methods. The advanced nanotechnology developed in the past decades provides great potential for tumor therapy, among which Cu-based nanotherapeutic systems have received greater attention. In this review, the multifaceted roles of copper ions in cancer progression would be summarized and the recent advances in the copper-based nanostructures or nanomedicines for different kinds of tumor therapies including copper depletion therapy, copper-based cytotoxins, copper ions-based chemodynamic therapy and its combination with other treatments and copper ions-induced ferroptosis and cuproptosis activation would be discussed. Furthermore, the perspectives for the further development of copper ions-based nanomedicines for tumor therapy and clinic translation are presented by the authors. This article is protected by copyright. All rights reserved.

Early B cell tolerance defects in anti-neurofascin 155 mediated chronic inflammatory demyelinating polyneuropathy (S40.005)

Early B cell tolerance defects in anti-neurofascin 155 mediated chronic inflammatory demyelinating polyneuropathy (S40.005)

Influence of Body Mass Index on B Lymphocyte Repopulation in Multiple Sclerosis Patients Treated with Anti-CD20 Therapy (P7-3.016)

<h3>Objective:</h3> Investigate an association with BMI and early B cell repopulation in a large cohort of multiple sclerosis (MS) patients treated with CD20-depleting therapy <h3>Background:</h3> Findings from a prior retrospective cohort of 45 patients indicated larger body surface area (BSA) was associated with faster repopulation of B cells after CD20 depletion, attributed to underestimation of CD20-depleting therapy dosing for patients with high BSA. Body mass index (BMI) is also associated with increased MS risk and radiographic markers of disease in relapsing-remitting disease. We aimed to confirm an association with BMI and early B cell repopulation after CD20 depletion therapy in an approximately 4-fold larger sample of patients than prior data. <h3>Design/Methods:</h3> This is a retrospective cohort study at a single academic referral center. Patients were identified through chart review using ICD billing codes. Normal BMI was defined 18.5–25. Overweight/obese BMI was defined as 25 or greater. The outcome of interest was early B cell repopulation defined as presence of greater than or equal to 1% CD19 cells on serum lymphocyte subset profile. Logistic regression was used to compare the categorical outcome on the normal vs overweight/obese BMI groups. <h3>Results:</h3> An initial 405 patients were identified. After excluding patients with missing ocrelizumab infusion and lymphocyte subset data, a total sample size of 157 patients were analyzed. The mean age and female sex of the cohort were 51.8 years (SD 12.9) and 99 (63.1%), respectively. 67 (42.7%) patients were categorized having normal BMI (18.5–25) and 90 (57.3%) patients as overweight/obese BMI (&gt;25). The model revealed an effect of BMI: patients who were overweight/obese showed an increase in repopulation [Coef=0.49, SE=0.22, p=0.03]. There was no effect of sex or age. <h3>Conclusions:</h3> Our study provides supportive evidence that greater BMI is associated with B cell repopulation after CD20-depleting therapy. <b>Disclosure:</b> An immediate family member of Dr. Loeffler has received research support from National Science Foundation. The institution of an immediate family member of Dr. Loeffler has received research support from Amazon. Dr. Han has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Han has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arena Pharmaceuticals.

OA11 Juvenile Sjögren’s syndrome is characterised by dysregulated of B and T memory cell frequencies: a pilot immunophenotyping analysis of this rare disease phenotype

Abstract Background/Aims Sjögren’s syndrome (SS) is an autoimmune rheumatic disease characterised by dryness resulting from chronic lymphocytic infiltration of the exocrine glands and extra glandular manifestations such as arthritis, anemia, and fatigue. The disease is more frequent in women aged 30-50. However, in rare cases, the disease starts in childhood, known as juvenile SS (jSS). Children have different clinical manifestations compared to adults, with dryness being less common, making the diagnosis very challenging. Our aim is to investigate in depth the immune cell profile of patients with jSS and their cytokine profile for better understanding of disease pathogenesis. Methods Peripheral blood was collected from a cohort of patients with jSS (n = 10) and age and sex-matched healthy controls (HC) (n = 10). None of the patients had received B-cell depletion therapy. Peripheral blood immune-phenotyping of 29 immune-cell subsets, including B and T cells, was performed using flow cytometry as we have reported previously for patients with adult-onset SS. Data were analyzed using multiple t-tests and compared with the adult SS immune phenotype. A panel of 15 serum cytokines associated with SS pathology were measured by Luminex, multiple t-tests were performed to detect statistically significant differences between jSS and HCs. Results Patients with jSS had an average age of 18 years (range 16-21) with an average age of disease onset at 14 years (range 12-18). 60% of patients had anti-Ro autoantibodies and 50% had anti-La autoantibodies. Patients with jSS had an altered immune profile compared to age-matched healthy controls (HCs) (mean age = 18 years, range 15-25). In the B cell compartment, jSS patients had higher frequencies of total CD19+ B cells (p = 0.0044), naïve B cells (CD19+IgD+CD27-) (p = 0.0183) and bm2 (CD19+IgD+CD38+) (p = 0.0490) whereas memory B cell subsets such as early bm5 (CD19+IgD-CD38+) and late bm5 (CD19+IgD-CD38-) were significantly reduced (p = 0.0249 and p = 0.0117, respectively). Interestingly, in the CD4+ T cell compartment, central memory T cells (CD4+CD27+CD45RA-) were significantly reduced (p = &amp;lt;0.0001) but effector memory (CD4+CD27-CD45-) and effector memory-re-expressing-CD45RA (EMRA, CD4+CD27-CD45RA+) T-cell subsets were significantly elevated (p = 0.0171 and p = 0.0002 respectively). There was also a significant increase in CD8+CD25-CD127+ responders T cells (p = 0.0392) in jSS patients versus HCs. Serum cytokines levels of APRIL and CCL8 were significantly elevated in jSS. Conclusion This is the first pilot study investigating the immune profile of patients with jSS. In line with our previous studies in adults we detected elevated naïve and reduced frequencies of memory B cells, suggesting an immunological rationale for the use of similar therapies across age. However, we also found a specific dysregulation of the responder CD8+ T cell subpopulation in jSS versus HCs, which requires further investigation. Our cytokine data could indicate an ongoing dysregulation of the homeostasis of mature B-cells and activation of different immune cells. Disclosure L. Martin-Gutierrez: None. H. Peckham: None. A. Radziszewska: None. J. Peng: None. O. Nettey: None. E. Jury: None. C. Ciurtin: None.

B-Cell–Derived TGF-β1 Inhibits Osteogenesis and Contributes to Bone Loss in Periodontitis

B cells play a vital role in the elimination of periodontal pathogens, the regulation of the immune response, and the induction of tissue destruction. However, the role of B cells in the dysfunction of mesenchymal stem cell (MSC) differentiation to osteoblasts in periodontitis (PD) has been poorly studied. Here we show that the frequency of CD45−CD105+CD73+ MSCs in inflamed periodontal tissues is significantly decreased in patients with PD compared with that of healthy controls. CD19+ B cells dominate the infiltrated immune cells in periodontal tissues of patients with PD. Besides, B-cell depletion therapy reduces the alveolar bone loss in a ligature-induced murine PD model. B cells from PD mice express a high level of TGF-β1 and inhibit osteoblast differentiation by upregulating p-Smad2/3 expression and downregulating Runx2 expression. The inhibitory effect of PD B cells on osteoblast differentiation is reduced by TGF-β1 neutralization or Smad2/3 inhibitor. Importantly, B-cell–specific knockout of TGF-β1 in PD mice significantly increases the number of CD45−CD105+Sca1+ MSCs, ALP-positive osteoblast activity, and alveolar bone volume but decreases TRAP-positive osteoclast activity compared with that from control littermates. Lastly, CD19+CD27+CD38− memory B cells dominate the B-cell infiltrates in periodontal tissues from both patients with PD and patients with PD after initial periodontal therapy. Memory B cells in periodontal tissues of patients with PD express a high level of TGF-β1 and inhibit MSC differentiation to osteoblasts. Thus, TGF-β1 produced by B cells may contribute to alveolar bone loss in periodontitis, in part, by suppressing osteoblast activity.

Tumor progression is independent of tumor-associated macrophages in cell lineage-based mouse models of glioblastoma.

Macrophage targeting therapies have had limited clinical success in glioblastoma (GBM). Further understanding the GBM immune microenvironment is critical for refining immunotherapeutic approaches. Here, we use genetically engineered mouse models and orthotopic transplantation-based GBM models with identical driver mutations and unique cells of origin to examine the role of tumor cell lineage in shaping the immune microenvironment and response to tumor-associated macrophage (TAM) depletion therapy. We show that oligodendrocyte progenitor cell lineage-associated GBMs (Type 2) recruit more immune infiltrates and specifically monocyte-derived macrophages than subventricular zone neural stem cell-associated GBMs (Type 1). We then devise a TAM depletion system that offers a uniquely robust and sustained TAM depletion. We find that extensive TAM depletion in these cell lineage-based GBM models affords no survival benefit. Despite the lack of survival benefit of TAM depletion, we show that Type 1 and Type 2 GBMs have unique molecular responses to TAM depletion. In sum, we demonstrate that GBM cell lineage influences TAM ontogeny and abundance and molecular response to TAM depletion.

IL-15-producing splenic B cells play pathogenic roles in the development of autoimmune hepatitis

Background & AimsB-cell depletion therapy with an anti-CD20 is an effective treatment strategy for patients with refractory autoimmune hepatitis (AIH). However, the mechanisms underlying B-cell action are unclear. MethodsHerein, we used the adeno-associated virus IL-12 model, in which hepatic IL-12 expression triggers liver injuries characteristic of AIH. We also analysed the clinical samples of patients with AIH. ResultsB-cell depletion using anti-CD20 or splenectomy was found to improve liver functions and decrease the cytotoxic CD8+ T-cell (cytotoxic T lymphocyte [CTL]) count in the liver. This improvement was reversed by the adoptive transfer of splenic B cells derived from AAV IL-12-treated mice to splenectomised mice as it caused the hepatic CTL count to increase. RNA-sequencing analysis identified IL-15 as a key factor in pathogenic B cells, which promotes CTL expansion and subsequent migration to the liver via the CXCL9/CXCR3 axis. Indeed, IL-15 neutralisation ameliorated hepatitis by suppressing splenic and hepatic CTLs in vivo. The close distribution of B220+ B cells and CD8+ T cells in the spleen of AIH mice suggested mutual interactions. Mechanistically, IFNγ and CD40L/CD40 signalling were indispensable for the expression of IL-15 in B cells, and in vitro co-culture experiments revealed that splenic CD40L+CD8+ T cells promoted IL-15 production in B cells, which led to CTL expansion. In patients with AIH, high serum IL-15 concentration and IL-15+ B-cell counts, positively correlating with serum alanine aminotransferase levels, support translation and potential therapeutic targeting in human AIH. ConclusionsThis investigation elucidated the roles of IL-15-producing splenic B cells that occur in concert with pathogenic CD8+ T cells during the development of AIH. Impact and ImplicationsIL-15-producing B cells were shown to exacerbate experimental AIH via cytotoxic T lymphocyte expansion. CD40L+CD8+ T cells promoted IL-15 expression in B cells, indicating the mutual interaction of both cells. High serum IL-15 concentrations, IL-15+ B-cell counts, and CD40L+IL-15Rα+CD8+ T-cell counts were confirmed in the blood of patients with AIH.

Abstract NG07: Targeting polyamines metabolism in acute myeloid leukemia stem cells

Abstract NG07: Targeting polyamines metabolism in acute myeloid leukemia stem cells

Abstract 4720: Chromatin conformation alterations in prostate cancer progression and formation of castration resistance

Abstract Introduction: Prostate cancer (PC) is the most common cancer in men and second in cancer related deaths. Aggressive prostate cancer is typically treated with androgen depletion therapy which often results in the formation of castration resistant prostate cancer (CRPC). Androgen receptor (AR) is a transcription factor that regulates hundreds of target genes and is responsible for the differentiation and function of normal prostate epithelial cells. In addition to AR, multiple other TFs that bind to distal enhancers have been implicated in PC, such as FOXA1, MYC and HOXB13. Understanding the role of these distal regulators is paramount in PC. Methods: To study the changes in chromatin conformation in prostate cancer progression, we have sequenced clinical benign prostatic hyperplasia (BPH), PC and CRPC samples using Hi-C sequencing. From each group 6 samples were sequenced with a total of 18 samples in the cohort. In addition, we have combined a multi omics cohort consisting of chromatin accessibility, transcriptome and methylome sequencing data from matching samples. Together these data types allow us to map out the regulatory networks in PC and CRPC by probing the distal active regulatory sites and their interactions. To account for artifacts caused by genomic aberrations in cancer samples we have established a pipeline for normalizing these effects in HiC-data. Results: Overall topologically associated domains (TADs) and A/B-compartments remain stable between the groups. However, local changes of compartments in loci of key genes, such as AKR1C3 and FOXA1 correlate with their gene expression. We detect differential loops between sample groups and these changes are associated with gene expression alterations in PCs. Distal enhancers of PC up-regulated genes are enriched for FOXA1 and HOXB13. Interestingly, up-regulated loops in CRPC are enriched for FOXA1 and HOXB13, while no systematic effect on gene expression is seen on a genome wide scale, apart from genes such as AR and CENPE whose expression correlates strongly with their association to distal enhancers. We also detect enhancer hijacking events in driver genes. One example is the recurrent ETV1-MIPOL1 fusion, where promoter of ETV1 forms contacts with FOXA1 enhancer regions. Conclusions: Alterations in loop structures are strongly associated with regulatory programs that have been previously implicated in PC, including regulation by FOXA1, HOXB13 and other transcription factors. This highlights the importance of chromatin conformation in facilitating the effects of regulatory programs that rely on distal enhancers in PC. These changes appear more systematic in untreated PCs, whilst CRPCs exhibit more heterogeneity in chromatin conformation across the samples. Citation Format: Tuomo Virtanen, Ebrahim Afyounian, Riikka Nurminen, Teuvo Tammela, Tapio Visakorpi, Juha Kesseli, Kirsi Rautajoki, Matti Nykter. Chromatin conformation alterations in prostate cancer progression and formation of castration resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4720.

Intra-articular Injection of a B Cell Depletion Antibody Enhances Local Exposure to the Joint-Draining Lymph Node in Mice with Collagen-Induced Arthritis.

Changes to the number, type, and function of immune cells within the joint-draining lymphatics is a major contributor to the progression of inflammatory arthritis. In particular, there is a significant expansion in pathogenic B cells in the joint-draining lymph node (jdLN). These B cells appear to clog the lymphatic sinuses in the lymph node, inhibit lymph flow, and therefore, reduce the clearance of inflammatory fluid and cells from the joint. Taken together, there is potential to treat inflammatory arthritis more effectively, as well as reduce off-target side effects, with localized delivery of B-cell depleting therapies to the jdLNs. We recently reported that joint-draining lymphatic exposure of biologic disease-modifying anti-rheumatic drugs (DMARDs), including the B cell depletion antibody rituximab, is increased in healthy rats following intra-articular (IA) compared to subcutaneous (SC) or intravenous (IV) administration. This suggests that IA administration of B cell depleting antibodies may increase delivery to target cells in the jdLN and increase the effectiveness of B cell depletion compared to standard SC or IV administration. However, whether enhanced local delivery of DMARDs to the jdLN is also achieved after IA injection in the setting of inflammatory arthritis, where there is inflammation in the joint and jdLN B cell expansion is unknown. We, therefore, assessed the lymph node distribution, absorption and plasma pharmacokinetics, and B cell depletion at different sites after IA, SC, or IV administration of a fluorescently labeled mouse anti-CD20 B cell depleting antibody (Cy5-αCD20) in healthy mice compared to mice with collagen-induced arthritis (CIA). The absorption and plasma pharmacokinetics of Cy5-αCD20 appeared unaltered in mice with CIA whereas distribution of Cy5-αCD20 to the jdLNs was generally increased in mice with CIA, regardless of the route of administration. However, IA administration led to greater and more specific exposure to the jdLNs. Consistent with increased Cy5-αCD20 in the jdLNs of CIA compared to healthy mice, there was a greater reduction in jdLN weight and a trend toward greater jdLN B cell depletion at 24 h compared to 4 h after IA compared to SC and IV administration. Taken together, this data supports the potential to improve local efficacy of B cell depletion therapies through a jdLN-directed approach which will enable a reduction in dose and systemic toxicities.

Gene Expression and Autoantibody Analysis Revealing Distinct Ancestry-Specific Profiles Associated With Response to Rituximab in Refractory Systemic Lupus Erythematosus.

Gene expression profiles are associated with the clinical heterogeneity of systemic lupus erythematosus (SLE) but are not well studied as biomarkers for therapy. We studied gene expression and response to rituximab in a multiethnic UK cohort who were refractory to standard therapy. We evaluated baseline expression levels of transcripts known to associate with clinical features of SLE using a 96-probe TaqMan array and whole blood samples from 213 patients with active SLE who had been prospectively enrolled in the British Isles Lupus Assessment Group (BILAG) Biologics Register. We measured autoantibodies using immunoprecipitation and enzyme-linked immunosorbent assays. We determined responses to first-cycle rituximab at 6 months from treatment start in 110 SLE patients by assessing BILAG 2004 disease activity. Interferon gene expression scores were lower in patients of European ancestry than in all other ancestry groups. The relationship between blood interferon gene expression scores and scores annotated to plasmablasts, neutrophils, myeloid lineage, inflammation, and erythropoiesis differed between patients of European and non-European ancestries. Hierarchical clustering revealed 3 distinct non-European ancestry patient subsets with stratified responses to rituximab that were not explained by sociodemographic and clinical variables, with responses lowest in an interferon-low, neutrophil-high cluster and highest in a cluster with high expression levels across all signatures (P < 0.001). Clusters in European ancestry patients did not predict response to rituximab but segregated patients by global disease activity and renal involvement. In both ancestral groups, interferon-high clusters were associated with U1 RNP/Sm antibodies. Ancestry appears central to the immunologic and clinical heterogeneity in SLE. These results suggest that ancestry, disease activity, and transcriptional signatures could each assist in predicting the effectiveness of B cell depletion therapies.

Regulation of CD8 T cell by B-cells: A narrative review.

Activation of CD4 T cells by B cells has been extensively studied, but B cell-regulated priming, proliferation, and survival of CD8 T cells remains controversial. B cells express high levels of MHC class I molecules and can potentially act as antigen-presenting cells (APCs) for CD8 T cells. Several in vivo studies in mice and humans demonstrate the role of B cells as modulators of CD8 T cell function in the context of viral infections, autoimmune diseases, cancer and allograft rejection. In addition, B-cell depletion therapies can lead to impaired CD8 T-cell responses. In this review, we attempt to answer 2 important questions: 1. the role of B cell antigen presentation and cytokine production in the regulation of CD8 T cell survival and cell fate determination, and 2. The role of B cells in the formation and maintenance of CD8 T cell memory.

Consensus Statement on the definition and classification of metabolic hyperferritinaemia.

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.

B cell depletion therapies in autoimmune diseases: Monoclonal antibodies or chimeric antigen receptor-based therapy?

Immune system detects foreign pathogens, distinguishes them from self-antigens and responds to defend human body. When this self-tolerance is disrupted, the overactive immune system attacks healthy tissues or organs and the autoimmune diseases develop. B cells and plasma cells contribute a lot to pathogenesis and persistence of autoimmune diseases in both autoantibody-dependent and autoantibody-independent ways. Accumulating data indicates that treatments aiming to eliminate antibody-secreting cells (B cells or plasma cells) are effective in a wide spectrum of autoimmune diseases. Monoclonal antibodies (mAbs) deplete B cell lineage or plasma cells by signaling disruption, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Engineered-T cells armed with chimeric antigen receptors (CARs) have been adopted from field of hematological malignancies as a method to eliminate B cells or plasma cells. In this review, we update our understanding of B cell depletion therapies in autoimmune diseases, review the mechanism, efficacy, safety and application of monoclonal antibodies and CAR-based immunotherapies, and discuss the strengths and weaknesses of these treatment options for patients.

Role of [18F] FDG PET-CT in detection of COVID-19 vaccine-associated hypermetabolic lymphadenopathy (VAHL) in lymphoma patients: with serologic testing correlation

BackgroundCOVID-19 vaccination of the population has a great importance, especially in oncological patients. The high incidence of vaccine-associated hypermetabolic lymphadenopathy (VAHL) makes a difficulty in the diagnosis of PET-CT of oncological patients. They should be vaccinated in the side opposite to the expected malignant LNs to avoid unnecessary biopsy and change in therapy. The aim of this study was to assess the role of PET-CT in detection of VAHL after the 2nd dose of Pfizer-BioNTech vaccine in lymphoma patients and compare the incidence of VAHL among lymphoma patients treated with B cell depletion therapy during the 6 months prior to vaccination and those treated > 6 months before vaccination.ResultsThis study comprised 120 lymphoma patients, referred for FDG PET/CT 1–3 weeks after the 2nd dose of Pfizer-BioNTech COVID-19 vaccine. Hypermetabolic LNs were identified in 55%. The incidence of VAHL in lymphoma patients treated with anti-CD20 antibody rituximab during the 6 months prior to vaccination (9%) was significantly lower compared with other lymphoma patients treated with anti-CD20 antibody rituximab > 6 months before vaccination (91%). The incidence and grades of VAHL are significantly high within the 1st week after the 2nd dose of Pfizer-BioNTech vaccine in patients younger than 60 years of age. Only 7 of 37 patients with negative serology had VAHL on PET-CT, whereas 10 of 26 patients with decreased anti-spike titers and 49 of 57 patients with increased anti-spike titers had VAHL on PET-CT.ConclusionsVAHL makes challenges in the interpretation of FDG PET/CT in oncology patients. Accurate data collection, regarding the time and site of COVID vaccination, is important to help radiologists in identifying the cause of abnormal nodal FDG uptake. We suggest to schedule FDG PET-CT for lymphoma patients at least 3 weeks after the 2nd dose of Pfizer-BioNTech vaccine.

IgG4-related autoimmune liver disease.

The term IgG4-related autoimmune liver disease (AILD) refers to hepato-biliary manifestations of Immunoglobin G4-related disease (IgG4-RD) including IgG4-related sclerosing cholangitis and IgG4-related pseudotumor. The association of some forms of autoimmune hepatitis to IgG4-RD remains controversial. Although autoimmune phenomena have not been clearly observed in IgG4-AILD, perturbation of the adaptive immune system and activation of the humoral response represent established pathophysiological hallmarks and potential therapeutic targets. Clinical manifestations of IgG4-AILD are virtually indistinguishable from bile duct cancer or primary sclerosing cholangitis and are due to mass forming lesions and thickening of the biliary tract that progressively lead to biliary ducts obstruction. There are no current reliable biomarkers for IgG4-AILD and diagnosis should rely on the integration of clinical, serological, radiological, and histological findings. In analogy to most IgG4-RD manifestations, and in contrast to its major mimickers, IgG4-AILD promptly responds to glucocorticoids but frequently relapses, thus requiring long-term maintenance therapy to avoid progressive fibrosclerotic disease and liver cirrhosis. Accumulating evidence on the efficacy of B-cell depletion therapy in patients with systemic IgG4-RD is gradually changing the treatment paradigm of IgG4-AILD and biologics will be increasingly used also for gastroenterological manifestations of IgG4-RD to spare glucocorticoids and traditional immunosuppressive agents. Looking ahead, identification of reliable biomarkers and of mini-invasive strategies to obtain informative biopsies from the biliary tree represent unavoidable priorities to optimize diagnosis and management of IgG4-AILD.

CEACAM1 Marks Highly Suppressive Intratumoral Regulatory T Cells for Targeted Depletion Therapy.

Regulatory T cells (Tregs) exert immunosuppressive functions and hamper antitumor immune responses in the tumor microenvironment. Understanding the heterogeneity of intratumoral Tregs, and how it changes with tumor progression, will provide clues regarding novel target molecules of Treg-directed therapies. From 42 patients with renal cell carcinoma and 5 patients with ovarian cancer, immune cells from tumor and peripheral blood were isolated. We performed multicolor flow cytometry and RNA-sequencing to characterize the phenotypes and heterogeneity of intratumoral Tregs. In vitro functional assays were performed to evaluate suppressive capacity of Tregs and effect of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-mediated depletion. The CT26 tumor model was used to evaluate the association between intratumoral Tregs and tumor growth, and examine the in vivo role of CEACAM1+ intratumoral Tregs on antitumor immunity. We found that CEACAM1 was selectively expressed on intratumoral Tregs, whereas its expression on peripheral Tregs or other immune cells was low. The CEACAM1+ intratumoral Tregs accumulated with tumor progression, whereas the CEACAM1- subset did not. Notably, we found that CEACAM1 marked intratumoral Tregs that exhibited highly suppressive and activated phenotypes with substantial clonal expansion. Depletion of CEACAM1-expressing cells from tumor-infiltrating leukocytes led to increased effector functions of tumor-infiltrating T cells. Moreover, CEACAM1+ cell depletion further enhanced anti-PD-1-mediated reinvigoration of exhausted CD8+ T cells. CEACAM1 marks highly suppressive subset of intratumoral Tregs, and can be a target for selective depletion of intratumoral Tregs. These results may inform future studies on CEACAM1-mediated depletion in patients with cancer.

Commentary: Case report: Daratumumab treatment in pre-transplant alloimmunization and severe hemolytic anemia.

Pereda et al. recently reported three cases in which daratumumab was utilized to reduce the 36 burden of red blood cell (RBC) and human leukocyte antigen (HLA) alloantibodies (1). These 37 cases support the need for further investigation into the potential use of daratumumab and related 38 plasma cell depletion therapies for patients with significant alloimmunization. However, the 39 authors' cases, particularly cases 1 and 2 in which the authors describe patients with sickle cell 40 disease (SCD) and multiple RBC antibodies, lack sufficient immunohematology and transfusion 41 details to reliably conclude the effectiveness and safety of daratumumab to reduce and existing alloantibodies can persist despite daratumumab treatment (3-6). Secondly, the 80 authors fail to acknowledge the possibility that the alloantibodies may have disappeared naturally 81 through the phenomenon of evanescence. Numerous studies have shown that many patients' 82 RBC alloantibodies will decline in titer to levels below a detectable threshold without further 83 exposure (7-9). Though the loss of all antibodies due to evanescence may be less likely, not 84 accounting for this potential mechanism of a waning antibody is concerning. 85 86 Furthermore, literature demonstrates that even if these antibodies have become undetectable, 87 these patients may still be at risk for DHTRs (10-13).

The Amyloid Cascade Hypothesis 2.0: Generalization of the Concept.

Recently, we proposed the Amyloid Cascade Hypothesis 2.0 (ACH2.0), a reformulation of the ACH. In the former, in contrast to the latter, Alzheimer's disease (AD) is driven by intraneuronal amyloid-β (iAβ) and occurs in two stages. In the first, relatively benign stage, Aβ protein precursor (AβPP)-derived iAβ activates, upon reaching a critical threshold, the AβPP-independent iAβ-generating pathway, triggering a devastating second stage resulting in neuronal death. While the ACH2.0 remains aligned with the ACH premise that Aβ is toxic, the toxicity is exerted because of intra- rather than extracellular Aβ. In this framework, a once-in-a-lifetime-only iAβ depletion treatment via transient activation of BACE1 and/or BACE2 (exploiting their Aβ-cleaving activities) or by any means appears to be the best therapeutic strategy for AD. Whereas the notion of differentially derived iAβ being the principal moving force at both AD stages is both plausible and elegant, a possibility remains that the second AD stage is enabled by an AβPP-derived iAβ-activated self-sustaining mechanism producing a yet undefined deleterious "substance X" (sX) which anchors the second AD stage. The present study generalizes the ACH2.0 by incorporating this possibility and shows that, in this scenario, the iAβ depletion therapy may be ineffective at symptomatic AD stages but fully retains its preventive potential for both AD and the aging-associated cognitive decline, which is defined in the ACH2.0 framework as the extended first stage of AD.

Review of an Anti-CD20 Monoclonal Antibody for the Treatment of Autoimmune Diseases of the Skin.

Biologic therapies targeting B-cells are emerging as an effective strategy to treat a variety of immune-mediated diseases. One of the most studied B-cell-targeted therapies is rituximab, an anti-CD20 monoclonal antibody that exemplifies B-cell depletion therapy and has served as the prototype for other anti-CD20 monoclonal antibodies and the development of biosimilars. While there are multiple studies on the use of rituximab in dermatology, a comprehensive review of rituximab therapy in autoimmune skin conditions is lacking. In this literature review, we summarize indications, treatment efficacy, and safety of rituximab among common autoimmune diseases of the skin: pemphigus vulgaris, cutaneous lupus erythematous, dermatomyositis, systemic sclerosis, thyroid dermopathy, autoimmune pemphigoid diseases, and cutaneous vasculitis diseases. Existing data on rituximab support the approach of rituximab, biosimilars, and newer B-cell-targeting therapies in immune-mediated cutaneous diseases. Overall, rituximab, which targets CD20, provides an effective alternative or concomitant option to traditional immunosuppressants in the management of various autoimmune diseases of the skin. Further studies are necessary to expand the understanding and possible utility of B-cell-targeted therapies among autoimmune skin diseases.