Therapy Of Autoimmune Diseases Research Articles

High-throughput screening identification of novel immunomodulatory combinations for the generation of tolerogenic dendritic cells.

Tolerogenic Dendritic Cells (tolDCs) have an exceptional promise as a potential therapy for autoimmune disease and transplantation rejection. TolDCs are a unique phenotype of antigen presenting cells (APCs) that can influence naïve T cells into antigen specific T regulatory cells (Tregs), which can re-establish tolerance against auto/allo-antigens in the long term. Despite their promise, tolDCs have not found clinical success. Most strategies seek to generate tolDCs ex vivo by differentiating naïve dendritic cells (DCs) with immunosuppressive agents. Recently, we developed a tolDC generation strategy, which we call Push/Pull Immunomodulation (PPI). In PPI, DCs are treated with combinations of toll-like-receptor (TLR) agonists and immunomodulatory agents, which generate more robust, Treg-inducing tolDCs than previous strategies. Here, we seek to identify more potent and clinically viable PPI formulations using data from a high-throughput screening project. Over 40,000 combinations of pathogen-associated molecular patterns (PAMPs) and immunomodulatory small molecules were screened using a modified murine macrophage line, RAW dual cells, to observe the effect of these combinations on two major immune regulatory transcription factors, NF-κB and IRF. Combinations were further screened for inflammatory cytokine activity using a human monocyte cell line, THP-1, then on murine DCs. Leading candidates were co-cultured with T cells to assess antigen specific T cell responses. From this data, we identified 355 combinations that showed low or moderate IRF activity, low NF-κB activity, low inflammatory cytokine generation and good viability: all hallmarks of tolerogenic potential. We further screened these 355 combinations using bone marrow derived DCs (BMDCs) and identified 10 combinations that demonstrated high IL-10 (tolerogenic) and low TNF-α (inflammatory) secretion. After further optimizing these combinations, we identified two combinations that generate robust tolDCs from BMDCs ex vivo. We further show that these PPI-tolDCs can also generate antigen specific Tregs but do not increase overall Treg populations. These second-generation PPI formulations have significant potential to generate robust tolDCs and strong antigen specific Tregs.

Signaling Pathway Governed by Lipid Derived Molecules as Secondary Messenger

Research shown that the cell death, particularly apoptosis, can extend beyond single cell boundaries. Gap junctions IP3 diffusion, and sphingolipids play significant roles in membrane biology and regulation of cell function. S1P plays crucial role in the cardiovascular and immune systems, serving as a mediator of signaling during cell migration, differentiation, proliferation, and apoptosis. Intestinal phospholipid metabolism, including 1B phospholipase A2 and autotaxin-mediated pathways, contributes to cardiometabolic diseases through multiple mechanisms. A potential strategy for treating cardiovascular and metabolic diseases is the therapeutic suppression of1B phospholipase A2 and autotaxin in the gastrointestinal tract. Cellular stress signalling, inflammation, resolution, and host defence responses are all significantly influenced by lysophospholipids such LPA and S1P. New therapies for cancer, vascular diseases, fibrotic disorders, and autoimmune diseases have been made possible by developments in lysophospholipid research.

Lithocholic acid derivatives as potent modulators of the nuclear receptor RORγt.

Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor found in various tissues that plays a crucial role in the differentiation and proliferation of T helper 17 (Th17) cells, as well as in their generation of the pro-inflammatory cytokine IL-17A. RORγt represents a promising therapeutic target for autoimmune diseases, metabolic disorders, and multiple tumors. Despite extensive research efforts focused on the development of small molecule RORγt modulators, no drug candidates have advanced to phase 3 clinical trials owing to a lack of efficacy or safety margin. This outcome highlights the unmet need to optimize small molecule drug candidates targeting RORγt to develop effective therapies for autoimmune and inflammatory diseases. In this study, we synthesized and evaluated 3-oxo-lithocholic acid amidates as a new class of RORγt modulators. Our evaluation entailed biophysical screening, cellular screening in different platforms, molecular docking, and in vitro pharmacokinetic profiling. The top compound from our study (3-oxo-lithocholic acid amidate, A2) binds to RORγt at an equilibrium dissociation constant (KD) of 16.5 ± 1.34 nM based on microscale thermophoresis (MST). Assessment of the efficacy of A2 in the cellular RORγt reporter luciferase assay revealed a half-maximal inhibitory concentration (IC50) value of 225 ± 10.4 nM. Unlike 3-oxo-lithocholic acid, A2 demonstrated the ability to reduce the IL-17A mRNA expression levels in EL4 cells with RORγt expression using quantitative reverse transcriptase PCR (RT-PCR). Validation of the desirable physicochemical properties and stability of A2 sets the stage for the preclinical evaluation of this new class of RORγt modulators in animal models of autoimmune diseases.

Antibody therapies in cancer and autoimmune disease

Cancer and autoimmune diseases are gradually proven to be "two sides of the same coin". Many cancer patients develop manifestations of autoimmune diseases and rheumatism, especially those receiving immune checkpoint inhibitors. At the same time, patients with autoimmune diseases also have cancer combined, which may be related to chronic inflammation damage to DNA or clinical medication. Antibody therapies, pioneered by monoclonal antibody drugs, are now used extensively in the treatment of cancer and autoimmune diseases. The relationship between cancer and autoimmune diseases is gradually being discovered, and some antibody therapies have therapeutic effects on both types of diseases, perhaps because the two have common targets. In-depth study of the role of various targets in the occurrence and development of the two types of diseases, screen the common targets, and discover the antibody drugs that play an activation or inhibition role against the common targets, so as to achieve the effect of "same treatment for different diseases", which brings hope to patients with "cancer-autoimmune diseases". This paper discusses the relationship between the two types of diseases, summarizes the specific targets and corresponding diseases of some antibody therapies, and analyzes the current status of antibody therapy in the treatment of the two types of diseases, in order to explore the "dual therapy" potential of more antibody therapies in the future, and develop new targets and drugs.

Complement-targeted therapy for autoimmune diseases.

The success and safety seen in treating complement-mediated hemolysis conditions has sparked the development of targeted therapies for rare autoimmune diseases, with expansion to more common autoimmune conditions. Various classes of drugs, including small molecules, peptides, monoclonal antibodies, and small interfering RNA (siRNA), are undergoing development to specifically address complement activity. A dual approach targeting both complement and other immune components may be required for autoimmune diseases characterized by inflammation and complex pathogenic mechanisms. siRNA, which suppresses complement production, is emerging as a potent therapeutic tool. Combining a complement-blocking siRNA drug with a treatment that reduces autoantibodies could prove clinically feasible and impactful in managing these conditions.

Glabridin improves autoimmune disease in Trex1-deficient mice by reducing type I interferon production

BackgroundThe cGAS-STING signaling pathway is an essential section of the natural immune system. In recent years, an increasing number of studies have shown a strong link between abnormal activation of the cGAS-STING signaling pathway, a natural immune pathway mediated by the nucleic acid receptor cGAS, and the development and progression of autoimmune diseases. Therefore, it is important to identify an effective compound to specifically downregulate this pathway for disease.MethodsThe effect of Glabridin (Glab) was investigated in BMDMs and Peripheral blood mononuclear cell (PBMC) by establishing an in vitro model of cGAS-STING signaling pathway activation. An activation model stimulated by DMXAA was also established in mice to study the effect of Glab. On the other hand, we investigated the possible mechanism of action of Glab and the effect of Glab on Trex1-deficient mice.ResultsIn this research, we report that Glab, a major component of licorice, specifically inhibits the cGAS-STING signaling pathway by inhibiting the level of type I interferon and inflammatory cytokines (IL-6 and TNF-α). In addition, Glab has a therapeutic effect on innate immune diseases caused by abnormal cytoplasmic DNA in Trex1-deficient mice. Mechanistically, Glab can specifically inhibit the interaction of STING with IRF3.ConclusionGlab is a specific inhibitor of the cGAS-STING signaling pathway and may be used in the clinical therapy of cGAS-STING pathway-mediated autoimmune diseases.

An engineered Fc fusion protein that targets antigen-specific T cells and autoantibodies mitigates autoimmune disease

Current effective therapies for autoimmune diseases rely on systemic immunomodulation that broadly affects all T and/or B cell responses. An ideal therapeutic approach would combine autoantigen-specific targeting of both T and B cell effector functions, including efficient removal of pathogenic autoantibodies. Albeit multiple strategies to induce T cell tolerance in an autoantigen-specific manner have been proposed, therapeutic removal of autoantibodies remains a significant challenge. Here, we devised an approach to target both autoantigen-specific T cells and autoantibodies by producing a central nervous system (CNS) autoantigen myelin oligodendrocyte glycoprotein (MOG)-Fc fusion protein. We demonstrate that MOG-Fc fusion protein has significantly higher bioavailability than monomeric MOG and is efficient in clearing anti-MOG autoantibodies from circulation. We also show that MOG-Fc promotes T cell tolerance and protects mice from MOG-induced autoimmune encephalomyelitis. This multipronged targeting approach may be therapeutically advantageous in the treatment of autoimmunity.

Mechanism underlying polyvalent IgG-induced regulatory T cell activation and its clinical application: Anti-idiotypic regulatory T cell theory for immune tolerance.

The regulatory T (Treg) cells constitute a functionally defined subpopulation of T cells that modulate the immune system and maintain immune tolerance through suppression of the development of autoimmune responses to self-antigens and allergic reactions to external antigens. Reduction in the number or function of Treg cells has been suggested as a key immune abnormality underlying the development of autoimmune and allergic diseases. In vitro studies have demonstrated that purified polyvalent immunoglobulin G (IgG) from multiple healthy blood donors can exert immunomodulatory effects on Treg cells. Incubation of polyvalent human IgG with purified CD4+CD25high T cells increased the intracellular expression of interleukin (IL)-10. Intravenous administration of polyvalent human IgG induced significant expansions of CD4+ Foxp3+ Treg cells and clinical improvements in patients with autoimmune diseases. In human clinical trials, intramuscular administration of autologous total IgG significantly increased the percentage of IL-10-producing CD4+ Treg cells in the peripheral blood of healthy subjects and provided significant clinical improvements in patients with atopic dermatitis. These results suggest a clinical usefulness of polyvalent IgG-induced activation of Treg cells in human subjects. This review proposes a new hypothesis for immune tolerance mechanism by integrating the pre-existing "idiotypic network theory" and "Treg cell theory" into an "anti-idiotypic Treg cell theory." Based on this hypothesis, an "active anti-idiotypic therapy" for allergic and autoimmune diseases using autologous polyvalent IgG (as immunizing antigens) is suggested as follows: (1) Intramuscular or subcutaneous administration of autologous polyvalent IgG produces numerous immunogenic peptides derived from idiotypes of autologous IgG through processing of dendritic cells, and these peptides activate anti-idiotypic Treg cells in the same subject. (2) Activated anti-idiotypic Treg cells secrete IL-10 and suppress Th2 cell response to allergens and autoimmune T cell response to self-antigens. (3) These events can induce a long-term clinical improvements in patients with allergic and autoimmune diseases. Further studies are needed to evaluate the detailed molecular mechanism underlying polyvalent IgG-induced Treg cell activation and the clinical usefulness of this immunomodulatory therapy for autoimmune and allergic diseases.

The Therapeutic Efficacy of CD19 Chimeric Antigen Receptor T Cells in Immune Thrombocytopenia Model

Abstract Introduction: ITP is a hemorrhagic autoimmune disease characterized by excessive platelet destruction and impaired platelet production,resulting in a high risk of bleeding. The pathogenesis of ITP involves immune intolerance towards platelet antigen, with platelet autoantibodies produced by plasma cells playing a significant role. Current treatments targeting this pathogenesis mainly rely on CD20 monoclonal antibodies, such as rituximab. However, as CD20 expression is present at the pre-B cell and mature B cell stages but absent on the surface of mature plasma cells. This can explain why a subset of autoantibody-positive patients do not respond to B-cell depletion therapy. CAR-T cell therapy, a form of adoptive cellular immunotherapy, has shown great potential in hematological malignancies and solid tumors. Recent studies have demonstrated its potential effectiveness of CAR-T cell therapy in various autoimmune diseases. CD19, expressed at all stages of B cell differentiation, presents an opportunity for CAR-T cell therapy in ITP. This study aims to evaluate the efficacy of CD19 CAR-T cell immunotherapy in an active murine ITP model. Methods: CD42-knockout mice were immunized with wild type (WT) C57BL/6 mice and splenocytes from these immunized mice were transplanted into irradiated WT mice to construct a murine model of active ITP. The ITP mice were then randomized into two groups, with the experimental group receiving an intraperitoneal injection with 1×10 6 CD19 CAR-T cells. Platelet counts were monitored weekly, and after 3 weeks, the ITP mice were euthanized and sacrificed. Single-cell suspensions were prepared from harvested spleens for analysis. Anti-murine antibodies were analyzed using flow cytometry (Beckmann Coulter, Brea, CA, USA). All data were analyzed by Statistical Package for the Social Sciences (SPSS) software, version 25.0 (IBM Corp., Armonk, NY, USA). P < 0.05 was considered statistically significance. Results: Our results demonstrated that the platelet counts of ITP mice reached their lowest level on day 7 after spleen cell transplantation, gradually recovering within a week. Platelet counts were significantly higher in the CD19 CAR-T cell therapy group compared to the control group on day 7 and persisted until day 21. There were no significant differences in weight between two groups, indicating no severe complication or CRS were identified. In the third week CD19 CAR-T cell therapy, the proportion of plasma cells in the spleen was determined, showing a marked decrease in the percentage of CD138+ plasma cells in the CAR-T group compared to the control group. Additionally, at day 14, the titers of anti-platelet CD42-specific antibodies were significantly lower in the CAR-T cell treated group compared to the control group. Furthermore, the mean fluorescence intensity (MFI) of CD19+ B cells in the spleen cells of the CD19 CAR-T cell immunotherapy group was significantly decreased compared to the control group. Conclusion: This study demonstrates the effectiveness of CD19 CAR-T cell therapy in treating thrombocytopenia by suppressing plasma and B cells in a mouse model of active ITP. These findings provide valuable insights into the potential therapeutic application of CD19 CAR-T cell immunotherapy for immune thrombocytopenia. Disclosure: No conflict of interest.

Molecular Engineering of Interleukin-2 for Enhanced Therapeutic Activity in Autoimmune Diseases.

The interleukin-2 (IL-2) cytokine plays a crucial role in regulating immune responses and maintaining immune homeostasis. Its immunosuppressive effects have been harnessed therapeutically via administration of low cytokine doses. Low-dose IL-2 has shown promise in the treatment of various autoimmune and inflammatory diseases; however, the clinical use of IL-2 is complicated by its toxicity, its pleiotropic effects on both immunostimulatory and immunosuppressive cell subsets, and its short serum half-life, which collectively limit the therapeutic window. As a result, there remains a considerable need for IL-2-based autoimmune disease therapies that can selectively target regulatory T cells with minimal off-target binding to immune effector cells in order to prevent cytokine-mediated toxicities and optimize therapeutic efficacy. In this review, we discuss exciting advances in IL-2 engineering that are empowering the development of novel therapies to treat autoimmune conditions. We describe the structural mechanisms of IL-2 signaling, explore current applications of IL-2-based compounds as immunoregulatory interventions, and detail the progress and challenges associated with clinical adoption of IL-2 therapies. In particular, we focus on protein engineering approaches that have been employed to optimize the regulatory T-cell bias of IL-2, including structure-guided or computational design of cytokine mutants, conjugation to polyethylene glycol, and the development of IL-2 fusion proteins. We also consider future research directions for enhancing the translational potential of engineered IL-2-based therapies. Overall, this review highlights the immense potential to leverage the immunoregulatory properties of IL-2 for targeted treatment of autoimmune and inflammatory diseases.

Efficacy, Safety and the Lymphocyte Subset Changes of Low-Dose IL-2 in Patients with Autoimmune Rheumatic Diseases: A Systematic Review and Meta-Analysis.

Current therapies for autoimmune rheumatic diseases (ARDs) have limited efficacy in certain patients, highlighting the need for the development of novel treatment approaches. This meta-analysis aims to assess the efficacy and safety of low-dose interleukin-2 (LD-IL-2) and evaluate the alterations in lymphocyte subsets in various rheumatic diseases following administration of different dosages of LD-IL-2. A comprehensive search was conducted in PubMed, Web of Science, the Cochrane Library, Embase databases and CNKI to identify relevant studies. A total of 31 trials were included in this meta-analysis. The review protocols were registered on PROSPERO (CRD42022318916), and the study followed the PRISMA guidelines. Following LD-IL-2 treatment, patients with ARDs exhibited a significant increase in the number of Th17 cells and Tregs compared to their pre-treatment levels [standardized mean difference (SMD) = 0.50, 95% confidence interval (CI) (0.33, 0.67), P < 0.001; SMD = 1.13, 95% CI (0.97, 1.29), P < 0.001]. Moreover, the Th17/Tregs ratio showed a significant decrease [SMD = - 0.54, 95% CI (- 0.64, - 0.45), P < 0.001]. In patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), LD-IL-2 injection led to a significant increase in Treg numbers, and the Th17/Tregs ratio and disease activity scores, including Disease Activity Score-28 joints (DAS28), Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), were all significantly reduced. No serious adverse events were reported in any of the included studies. Additionally, 54.8% of patients with lupus nephritis achieved distinct clinical remission following LD-IL-2 treatment. Injection site reactions and fever were the most common side effects of LD-IL-2, occurring in 33.1% and 14.4% of patients, respectively. LD-IL-2 treatment showed promise and was well tolerated in the management of ARDs, as it effectively promoted the proliferation and functional recovery of Tregs. Retrospectively registered (CRD42022318916, 21/04/2022).

DG-Affinity: predicting antigen–antibody affinity with language models from sequences

BackgroundAntibody-mediated immune responses play a crucial role in the immune defense of human body. The evolution of bioengineering has led the progress of antibody-derived drugs, showing promising efficacy in cancer and autoimmune disease therapy. A critical step of this development process is obtaining the affinity between antibodies and their binding antigens.ResultsIn this study, we introduce a novel sequence-based antigen–antibody affinity prediction method, named DG-Affinity. DG-Affinity uses deep neural networks to efficiently and accurately predict the affinity between antibodies and antigens from sequences, without the need for structural information. The sequences of both the antigen and the antibody are first transformed into embedding vectors by two pre-trained language models, then these embeddings are concatenated into an ConvNeXt framework with a regression task. The results demonstrate the superiority of DG-Affinity over the existing structure-based prediction methods and the sequence-based tools, achieving a Pearson’s correlation of over 0.65 on an independent test dataset.ConclusionsCompared to the baseline methods, DG-Affinity achieves the best performance and can advance the development of antibody design. It is freely available as an easy-to-use web server at https://www.digitalgeneai.tech/solution/affinity.

New dawn of cellular therapies in autoimmune diseases

New dawn of cellular therapies in autoimmune diseases

Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis

B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell depletion, but allows for the survival of long-lived plasma cells. Therefore, there is an unmet need for more reversible and full B lineage cell targeting approaches. To find potential novel therapeutic targets, RNA sequencing of CD27+ memory B cells of patients with active AAV was performed, revealing an upregulated NF-κB-associated gene signature. NF-κB signaling pathways act downstream of various B cell surface receptors, including the BCR, CD40, BAFFR and TLRs, and are essential for B cell responses. Here we demonstrate that novel pharmacological inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signaling) and inhibitor-of-κB-kinase-β (IKKβ, canonical NF-κB signaling) can effectively inhibit NF-κB signaling in B cells, whereas T cell responses were largely unaffected. Moreover, both inhibitors significantly reduced B cell proliferation, differentiation and production of antibodies, including proteinase-3 (PR3) autoantibodies, in B lineage cells of AAV patients. These findings indicate that targeting NF-κB, particularly NIK, may be an effective, novel B lineage cell targeted therapy for AAV and other autoimmune diseases with prominent B cell involvement.

Mesenchymal Stem Cells in the Pathogenesis and Therapy of Autoimmune and Autoinflammatory Diseases.

Mesenchymal stem cells (MSCs) modulate immune responses and maintain self-tolerance. Their trophic activities and regenerative properties make them potential immunosuppressants for treating autoimmune and autoinflammatory diseases. MSCs are drawn to sites of injury and inflammation where they can both reduce inflammation and contribute to tissue regeneration. An increased understanding of the role of MSCs in the development and progression of autoimmune disorders has revealed that MSCs are passive targets in the inflammatory process, becoming impaired by it and exhibiting loss of immunomodulatory activity. MSCs have been considered as potential novel cell therapies for severe autoimmune and autoinflammatory diseases, which at present have only disease modifying rather than curative treatment options. MSCs are emerging as potential therapies for severe autoimmune and autoinflammatory diseases. Clinical application of MSCs in rare cases of severe disease in which other existing treatment modalities have failed, have demonstrated potential use in treating multiple diseases, including rheumatoid arthritis, systemic lupus erythematosus, myocardial infarction, liver cirrhosis, spinal cord injury, multiple sclerosis, and COVID-19 pneumonia. This review explores the biological mechanisms behind the role of MSCs in autoimmune and autoinflammatory diseases. It also covers their immunomodulatory capabilities, potential therapeutic applications, and the challenges and risks associated with MSC therapy.

CD19-Targeted CAR-T Cells in Refractory Systemic Autoimmune Diseases: A Monocentric Experience from the First Fifteen Patients

Background: CD19-targeting chimeric antigen receptor (CAR) T cells are highly efficient in B cell malignancies. However, CD19 CAR T cells also target autoreactive B cells that trigger autoimmune diseases (AID) including systemic lupus erythematosus (SLE), idiopahtic inflammatory myositis (IIM) and systemic sclerosis (SSc). Achieving long-term remission in AID with standard therapy remains challenging and usually necessitates long-term treatment. Aim: To test whether CD19 CAR T cells achieve a deeper reset of B cells, eradicate autoimmunity, and achieve lasting drug-free remission in autoantibody-dependent AID. Methods: Patients with treatment-refractory SLE, IIM and SSc were eligible if they had signs of active organ involvement, failure of multiple immunomodulatory therapies, and serious or immediately life-threatening disease. CAR T cell therapy was offered via an expanded access program. Autologous CD19 CAR T cells MB-CART19.1 were produced with the Miltenyi prodigy platform. After leukapheresis on day -13, manufacturing commenced in house and lymphodepletion was started with fludarabine 25 mg/m2/d intravenously (i.v.) on days -5 to -3 and cyclophosphamide 1000 mg/m2/d i.v. on day -3. On day 1, all patients received 1x106 CAR T cells / kg body weight. Results: 15 patients (8 SLE, 4 SSc, and 3 IIM) were apheresed and were treated with a single infusion of CD19 CAR T cells. Median disease duration before CAR T was 3 years [1-20], median follow-up after CAR T was 12 months [2-28]. All patients failed on a median of 5 [2-14] previous treatments. Except for a maximum of 10 mg prednisolone daily, all immunomodulatory drugs were stopped prior to leukapheresis. After infusion, CAR T cells rapidly expanded till day 8.6 ± 0.8. CD19+ B cells were rapidly eliminated from peripheral blood after a mean of 5.9 ± 2.2 days. In 12/15 patients, B cells reoccurred at day 111±50. The last three patients with 77, 51 and 16 days follow-up are still B cell aplastic. All 8 SLE patient reached a complete remission after 3 months and maintain a SLE Disease Activity Index (SLEDAI) of 0 since. 3/3 IIM patients experienced major improvement and normalization of CK after 3 months which is ongoing. Of 4 SSc patients, 3 patients with &amp;gt;3 months follow-up show a decreased disease activity by EULAR AI by -4.3 [-4.3; -3.6]. All 15 patients entirely stopped immunosuppressive drugs. Overall safety of CAR T Cell therapy in AID was very favourable with cytokine-release syndrome (CRS) of grade 0 in 4, grade 1 in 10, and grade 2 in 1 patient. 6/15 patients received tocilizumab. One grade 1 immune-effector cell associated neurotoxicity syndrome (ICANS) presented as vertigo two weeks after CAR T infusion. No prolonged (&amp;gt;28 days) bone marrow suppression occurred. The Five SLE patients with a follow-up of 14-24 months stayed in remission despite reconstitution of B cells. In line, complement factor C3 stayed normal, proteinuria remained absent or at very low levels, and autoantibody seroconversion persisted. IgG responses to standard vaccines remained stable up to month 24 and were boosted by re-vaccination. Total B cell numbers gradually increased to a median of 230 cells/µl [183; 886] at month 12 and were mostly of a naïve phenotype. The early drop of CD19+CD27+ memory B cells increased again at month 12 indicating maturation of the B cells emerging after CAR T treatment. Conclusion: CD19 CAR T cells induce persistent, drug-free remission in three distinct autoantibody dependent AID with very good tolerability. Though hypothetical cure appears possible, longer follow up is needed. This unprecedented drug-free remission is remarkable as B cells functionally reconstitute. An investigator-initiated trial is currently expanding our experience of efficacy and safety.

Clinical Research Progress of BTK Inhibitors in the Treatment of Autoimmune Diseases.

Bruton tyrosine kinase (BTK) is an important protein of the tyrosine kinase family and plays a key role in signal transduction, proliferation, migration, and survival in B lymphocytes. The inhibition of BTK is a promising therapy for various autoimmune diseases (AD) involving abnormal B cell function, such as rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). This article briefly summarizes the role of BTK in the BCR signaling pathway, the development process of BTK inhibitors, and especially the latest progress of their clinical trials for the treatment of AD.

MRNA Lipid Nanoparticles for Ex Vivo Engineering of Immunosuppressive T Cells for Autoimmunity Therapies.

Cell-based therapies for autoimmune diseases have gained significant traction, with several approaches centered around the regulatory T (Treg) cell─a well-known immunosuppressive cell characterized by its expression of the transcription factor Foxp3. Unfortunately, due to low numbers of Treg cells available in circulation, harvesting and culturing Treg cells remains a challenge. It has been reported that engineering Foxp3 expression in CD4+ T cells can result in a Treg-like phenotype; however, current methods result in the inefficient engineering of these cells. Here, we develop an ionizable lipid nanoparticle (LNP) platform to effectively deliver Foxp3 mRNA to CD4+ T cells. We successfully engineer CD4+ T cells into Foxp3-T (FP3T) cells that transiently exhibit an immunosuppressive phenotype and functionally suppress the proliferation of effector T cells. These results demonstrate the promise of an LNP platform for engineering immunosuppressive T cells with potential applications in autoimmunity therapies.

Therapy-Related Myeloid Neoplasms: Predisposition and Clonal Evolution.

Therapy-related Myeloid Neoplasm (t-MN) represents one of the worst long-term consequences of cytotoxic therapy for primary tumors and autoimmune disease. Poor survival and refractoriness to current treatment strategies characterize affected patients from a clinical point of view. In our aging societies, where newer therapies and ameliorated cancer management protocols are improving the life expectancy of cancer patients, therapy-related Myeloid Neoplasms are an emerging problem. Although several research groups have contributed to characterizing the main risk factors in t-MN development, the multiplicity of primary tumors, in association with the different therapeutic strategies available and the new drugs in development, make interpreting the current data still complex. The main risk factors involved in t-MN pathogenesis can be subgrouped into patient-specific, inherited, and acquired predispositions. Although t-MN can occur at any age, the risk tends to increase with advancing age, and older patients, characterized by a higher number of comorbidities, are more likely to develop the disease. Thanks to the availability of deep sequencing techniques, germline variants have been reported in 15-20% of t-MN patients, highlighting their role in cancer predisposition. It is becoming increasingly evident that t-MN with driver gene mutations may arise in the background of Clonal Hematopoiesis of Indeterminate Potential (CHIP) under the positive selective pressure of chemo and/or radiation therapies. Although CHIP is generally considered benign, it has been associated with an increased risk of t-MN. In this context, the phenomenon of clonal evolution may be described as a dynamic process of expansion of preexisting clones, with or without acquisition of additional genetic alterations, that, by favoring the proliferation of more aggressive and/or resistant clones, may play a crucial role in the progression from preleukemic states to t-MN.

Rituximab bij auto-immune blaarziekten

Rituximab for autoimmune bullous diseases For a long time, the treatment of autoimmune blistering diseases consisted of classical immunosuppressants. Recently, biologicals, including rituximab, directed against the pan B-cell marker CD20, are used. Currently, practical guidelines for the optimal use of rituximab in the treatment of autoimmune blistering diseases are still under discussion. This literature review provides an overview of the efficacy, side effects, indication, optimal dosage and administration interval of rituximab in this population. In total, 37 publications were included, based on a systematic search strategy and selection procedure. The reported efficacy of rituximab in pemphigoid, expressed as complete remission without further therapy, ranges from 20% to 79%. For pemphigus, this amounts to 89% in the RITUX-3 study, which formed the basis for approval as first-line therapy. Side effects occur in 24% to 85% of the cases. The most important are infusion-related reactions and infections. In general, the safety profile corresponds to the known side effects of rituximab in other indications. The evidence for the practical guidelines is mainly built around pemphigus. Currently, the ‘high-dose rheumatoid arthritis protocol’ is preferred, although randomised, comparative studies are lacking. The high relapse rate justifies the need for repeated administrations. Further research should clarify whether repeated administration should be done systematically or based on different parameters. Rituximab is an effective and relatively safe therapy in autoimmune blistering diseases in both first and second line. In terms of practical use, further research is recommended.