Treatment Of Autoimmune Diseases Research Articles

The immunoregulatory effects of total glucosides of peony in autoimmune diseases

Abstract Total glucoside of peony and its main active ingredient paeoniflorin, extracted from the Chinese herb Paeonia lactiflora Pallas, exhibit potent immunomodulatory effects. Total glucoside of peony has been shown to inhibit inflammatory responses and disease progression in experimental models of multiple autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, psoriasis, and so on. Total glucoside of peony shows broad immunomodulatory effects on many immune cells, such as T cells, macrophages, and dendritic cells, by regulating their activation, proliferation, differentiation, and production of effector molecules. Mechanistically, total glucoside of peony modulates intracellular signaling transductions, including JAK/STAT, NF-κB, MAPK, and PI3K/AKT/mTOR pathways. Moreover, total glucoside of peony has been applied in the clinical treatment of various autoimmune diseases with satisfactory therapeutic outcomes and minor side effects. Thus, available studies have demonstrated that total glucoside of peony and its bioactive constituents exhibit anti-inflammatory and immunomodulatory functions and may have extensive applications in the treatment of autoimmune diseases.

A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease.

IRAK4 is a critical mediator in NF-κB-regulated inflammatory signaling and has emerged as a promising therapeutic target for the treatment of autoimmune diseases; however, none of its inhibitors have received FDA approval. In this study, we identified a novel small-molecule IRAK4 kinase inhibitor, DW18134, with an IC50 value of 11.2 nM. DW18134 dose-dependently inhibited the phosphorylation of IRAK4 and IKK in primary peritoneal macrophages and RAW264.7 cells, inhibiting the secretion of TNF-α and IL-6 in both cell lines. The in vivo study demonstrated the efficacy of DW18134, significantly attenuating behavioral scores in an LPS-induced peritonitis model. Mechanistically, DW18134 reduced serum TNF-α and IL-6 levels and attenuated inflammatory tissue injury. By directly blocking IRAK4 activation, DW18134 diminished liver macrophage infiltration and the expression of related inflammatory cytokines in peritonitis mice. Additionally, in the DSS-induced colitis model, DW18134 significantly reduced the disease activity index (DAI) and normalized food and water intake and body weight. Furthermore, DW18134 restored intestinal damage and reduced inflammatory cytokine expression in mice by blocking the IRAK4 signaling pathway. Notably, DW18134 protected DSS-threatened intestinal barrier function by upregulating tight junction gene expression. In conclusion, our findings reported a novel IRAK4 inhibitor, DW18134, as a promising candidate for treating inflammatory diseases, including peritonitis and IBD.

Current Pathogenesis and Treatment of Autoimmune Diseases

Nowadays, autoimmune diseases(AD) still torment many people and they always suffer from severe symptoms and complications. However, the pathogenesis of AD is still unclear and needs more research. Also, there are shortages of treatments which can totally cure AD. This research mainly focuses on current findings of possible pathogenesis and treatments for AD by discussing and analyzing two of most famous AD: rheumatoid arthritis and systemic lupus erythematosus (SLE). This essay discusses pathogenesis of RA and SLE from three aspects: genes, immune systems and environmental factors, and then concludes current medications and therapies as well as their drawbacks. This study finds that susceptible genes, abnormal immune responses and environmental stimulation can synergistically lead to autoimmune diseases, and existing treatments are mainly composed of symptomatic treatments and modifying treatments. But each medication has its inevitable side effects. Furthermore, more research should focus on systematic treatments with fewer drawbacks in order to truly cure AD.

CD19-directed T cell-engaging antibodies for the treatment of autoimmune disease.

Jennifer S. Michaelson, Chief Scientific Officer at Cullinan Oncology, and Patrick A. Baeuerle, scientific advisor to Cullinan Oncology and honorary professor in immunology at Ludwig Maximilians University Munich, discuss the use of CD19-specific T cell-engaging antibody therapies (TCEs) as therapeutics for autoimmune diseases.

Toosendanin inhibits T-cell proliferation through the P38 MAPK signalling pathway

In recent years, immunosuppressants have shown significant success in the treatment of autoimmune diseases. Therefore, there is an urgent need to develop additional immunosuppressants that offer more options for patients. Toosendanin has been shown to have immunosuppressive activity in vitro as well as effects on autoimmune hepatitis (AIH) in vivo. Toosendanin did not induce apoptosis in activated T-cells and affect the survival rate of naive T-cells. Toosendanin did not affect the expression of CD25 or secretion of IL-2 by activated T-cells, and not affect the expression of IL-4 and INF-γ. Toosendanin did not affect the phosphorylation of STAT5, ERK, AKT, P70S6K. However, toosendanin inhibited proliferation of anti-CD3/anti-CD28 mAbs-activated T-cells with IC50 of (10 ± 2.02) nM. Toosendanin arrested the cell cycle in the G0/G1 phase, significantly inhibited IL-6 and IL-17A secretion, promoted IL-10 expression, and inhibited the P38 MAPK pathway. Finally, toosendanin significantly alleviated ConA-induced AIH in mice. In Summary, toosendanin exhibited immunosuppressive activity in vivo and in vitro. Toosendanin inhibits the proliferation of activated T-cells through the P38 MAPK signalling pathway, significantly suppresses the expression of inflammatory factors, enhances the expression of anti-inflammatory factors, and effectively alleviates ConA-induced AIH in mice, suggesting that toosendanin may be a lead compound for the development of novel immunomodulatory agents with improved efficacy and reduced toxicity.

The Value of Traditional Medicine Should not be Underestimated—Traditional Chinese Medicine in Treatment of Autoimmune Diseases

Abstract Autoimmune diseases of the nervous system (ADNS) are characterized by the formation of a pronounced neurologic deficit and often lead to disability. The attention of doctors and researchers is increasingly attracted by complementary medicine as adjuvant or preventive therapy for various diseases, including autoimmune diseases. Traditional Chinese medicine (TCM) is a combination of treatment methods that include acupuncture, herbal medicine, dietetics, physical exercises, and other methods that are often used in conjunction with recognized approaches of official medical science. The article describes the application of TCM techniques in autoimmune diseases of the nervous system, and demonstrates clinical experience in the use of acupuncture, herbal medicine, diets and physical exercises. Traditional and complementary medicine is an important and often underestimated healthcare resource, especially in the prevention and treatment of autoimmune diseases of the nervous system.

Regulatory role of PI16 in autoimmune arthritis and intestinal inflammation: implications for Treg cell differentiation and function

BackgroundRegulatory T cells (Tregs) are crucial in maintaining immune homeostasis and preventing autoimmunity and inflammation. A proportion of Treg cells can lose Foxp3 expression and become unstable under inflammation conditions. The precise mechanisms underlying this phenomenon remain unclear.MethodsThe PI16 gene knockout mice (PI16fl/flFoxp3Cre) in Treg were constructed, and the genotypes were identified. The proportion and phenotypic differences of immune cells in 8-week-old mice were detected by cell counter and flow cytometry. Two groups of mouse Naïve CD4+T cells were induced to differentiate into iTreg cells to observe the effect of PI16 on the differentiation and proliferation of iTreg cells, CD4+CD25+Treg and CD4+CD25− effector T cells (Teff) were selected and co-cultured with antigen presenting cells (APC) to observe the effect of PI16 on the inhibitory ability of Treg cells in vitro. The effects of directed knockout of PI16 in Treg cells on inflammatory symptoms, histopathological changes and immune cell expression in mice with enteritis and autoimmune arthritis were observed by constructing the model of antigen-induced arthritis (AIA) and colitis induced by dextran sulfate sodium salt (DSS).ResultsWe identified peptidase inhibitor 16 (PI16) as a negative regulator of Treg cells. Our findings demonstrate that conditional knock-out of PI16 in Tregs significantly enhances their differentiation and suppressive functions. The conditional knockout of the PI16 gene resulted in a significantly higher abundance of Foxp3 expression (35.12 ± 5.71% vs. 20.00 ± 1.61%, p = 0.034) in iTreg cells induced in vitro compared to wild-type mice. Mice with Treg cell-specific PI16 ablation are protected from autoimmune arthritis (AIA) and dextran sulfate sodium (DSS)-induced colitis development. The AIA model of PI16CKO is characterized by the reduction of joint structure and the attenuation of synovial inflammation and in DSS-induced colitis model, conditional knockout of the PI16 reduce intestinal structural damage. Additionally, we found that the deletion of the PI16 gene in Treg can increase the proportion of Treg (1.46 ± 0.14% vs. 0.64 ± 0.07%, p < 0.0001) and decrease the proportion of Th17 (1.00 ± 0.12% vs. 3.84 ± 0.64%, p = 0.001). This change will enhance the shift of Th17/Treg toward Treg cells in AIA arthritis model (0.71 ± 0.06% vs. 8.07 ± 1.98%, p = 0.003). In DSS-induced colitis model of PI16CKO, the proportion of Treg in spleen was significantly increased (1.40 ± 0.15% vs. 0.50 ± 0.11%, p = 0.003), Th17 (2.18 ± 0.55% vs. 6.42 ± 1.47%, p = 0.017), Th1 (3.42 ± 0.19% vs. 6.59 ± 1.28%, p = 0.028) and Th2 (1.52 ± 0.27% vs. 2.76 ± 0.38%, p = 0.018) in spleen was significantly decreased and the Th17/Treg balance swift toward Treg cells (1.44 ± 0.50% vs. 24.09 ± 7.18%, p = 0.012).ConclusionPI16 plays an essential role in inhibiting Treg cell differentiation and function. Conditional knock out PI16 gene in Treg can promote the Treg/Th17 balance towards Treg dominance, thereby alleviating the condition. Targeting PI16 may facilitate Treg cell-based therapies for preventing autoimmune diseases and inflammatory diseases. The research provides us with novel insights and future research avenues for the treatment of autoimmune diseases, particularly arthritis and colitis.

Exploring the anti-inflammatory activity of the plant-derived phytochemical sulforaphane from cruciferous vegetables

Dysregulation of immune responses results in the development of chronic inflammatory conditions. The current frontline therapy, glucocorticoids, are effective immunosuppressive drugs but come with a trade-off of cumulative, debilitating side effects with sustained use. Clearly, alternative drug options with improved safety profiles are urgently needed. Macrophage Migration Inhibitory Factor (MIF) is a pleotropic pro-inflammatory cytokine and integral component of immune and inflammatory responses. MIF counter-regulates the immunosuppressive effects of glucocorticoids and promotes NLRP3 inflammasome activation.1, 2 Elevated MIF is a feature of multiple diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous. Given the association of increased MIF in serum with multiple disease models, it is considered MIF may be a plausible, specific druggable target in treatment of chronic inflammatory and autoimmune diseases, particularly as a target for glucocorticoid-sparing therapy to reduce the dose or duration of glucocorticoid treatment. The organosulfur isothiocyanate phytochemical sulforaphane (SFN) is extracted from cruciferous vegetables, including broccoli and Brussel sprouts following hydrolysis of its inactive precursor, glucoraphanin. SFN has antioxidant and cancer chemoprotective properties, and promotes NRF2 antioxidant signalling to upregulate the expression of numerous antioxidant enzymes. SFN has been shown to covalently modify MIF with high reactivity and is a potent inhibitor of MIF tautomerase activity. However, to date, no such study has evaluated the role of SFN as a novel inhibitor of MIF-mediated inflammatory pathway activation. Using cell-based assays, we have sought to investigate the role of SFN as an inhibitor of multiple inflammatory pathways which have previously implicated MIF as a possible regulator. Our initial work has examined SFN as an inhibitor of NF-κB activity, inflammasome activation, and evaluated if MIF is required for this effect. RAW264.7 murine macrophage cells stably expressing NF-κB-luciferase reporter construct were pre-treated with SFN (2.5 µM) before the induction of inflammation, via LPS (100ng/mL). For NLRP3 inflammasome activation, cells were subsequently treated with the NLRP3-specific inflammasome activator, nigericin (10 µM). TNF, IFN-β and IL-1β cytokine expression was measured by ELISA and NF-κB activity by luciferase reporter assay. We found SFN is a potent inhibitor of NF-κB activity and inhibits release of the pro-inflammatory cytokine IL-1β through inhibition of NLRP3 inflammasome activation. Finally, co-incubation of SFN with the glucocorticoid dexamethasone significantly suppressed TNF and IFN-β expression, demonstrating steroid sparing activity of SFN in vitro. Thus, SFN may be a suitable treatment for disruption of inflammatory pathways and suggest some of these effects may be mediated through direct interactions with MIF.

Screening, Deconvolution and Parallel Synthesis of Trisubstituted Piperazine and Trisubstituted 2,3-diketopierazine Libraries for the Rapid Identification of Antagonists of the Nuclear Retinoic Acid Receptor-related Orphan Receptor Gamma (RORγ)

Background: Genetic studies support a key role for RORγ and RORα in the differentiation of proinflammatory Th17 cells, and a growing body of evidence suggests a pathogenic role for Th17 in several autoimmune diseases, including MS, rheumatoid arthritis, inflammatory bowel disease, type I diabetes, and psoriasis. RORγ antagonists have been shown to suppress Th17 differentiation and delay the onset of disease in an experimental autoimmune encephalomyelitis mouse model of MS. Objective: Given the high therapeutic interest of RORγ antagonists and the promising activity of currently known ligands, small molecules with higher potency and receptor selectivity (in particular within the ROR family) are highly desirable. We used our small molecule compound library to discover, characterize, and optimize novel RORγ antagonists for the treatment of autoimmune diseases from Mixture-based Combinatorial Chemical Libraries. Methods: We screened the FIU collection of small molecule libraries (&gt;30 million compounds) composed of 75 molecular scaffolds systematically arranged in positional scanning and scaffold ranking formats. We identified scaffolds that selectively inhibit the binding of RORγ, RORγ, and RORβ but not RORα, and others that function as antagonists of all three receptors. Results: The deconvolution of selected PS-SCL mixtures led to the identification of novel chemical entities, trisubstituted piperazine and diketopiperazine that function as RORγ antagonists. Conclusion: The screening of a large complex library led to the rapid identification of novel trisubstituted piperazine and diketopiperazine antagonists of the nuclear retinoic acid receptor-related orphan receptor gamma (RORγ).

A Review on Nanosystem-Based Delivery of Tofacitinib for Enhanced Treatment of Autoimmune Diseases and Inflammation

A Review on Nanosystem-Based Delivery of Tofacitinib for Enhanced Treatment of Autoimmune Diseases and Inflammation

Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases.

The salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 belong to the adenosine monophosphate-activated protein kinase (AMPK) family of serine/threonine kinases. SIK inhibition represents a new therapeutic approach modulating pro-inflammatory and immunoregulatory pathways that holds potential for the treatment of inflammatory diseases. Here, we describe the identification of GLPG3970 (32), a first-in-class dual SIK2/SIK3 inhibitor with selectivity against SIK1 (IC50 of 282.8 nM on SIK1, 7.8 nM on SIK2 and 3.8 nM on SIK3). We outline efforts made to increase selectivity against SIK1 and improve CYP time-dependent inhibition properties through the structure-activity relationship. The dual activity of 32 in modulating the pro-inflammatory cytokine TNFα and the immunoregulatory cytokine IL-10 is demonstrated in vitro in human primary myeloid cells and human whole blood, and in vivo in mice stimulated with lipopolysaccharide. Compound 32 shows dose-dependent activity in disease-relevant mouse pharmacological models.

AxoDetect: an automated nerve image segmentation and quantification workflow for computational nerve modeling

Objective. Bioelectronic treatments targeting near-organ innervation have unprecedented clinical applications. Particularly in the spleen, the inhibition of the cholinergic inflammatory response by near-organ nerve stimulation has potential to replace pharmacological treatments in chronic and autoimmune diseases. A caveat is that the optimization of therapeutic stimulation parameters relies on in vivo experimentation, which becomes challenging due to the small nerve diameters (2 μ m), complex anatomy, and mixed axon type composition of the autonomic nerves. Effective development of in silico models requires tools which allow for fast and efficient quantification of axonal composition of specific nerves. Current approaches to generate such information rely on manual image segmentation and quantification. Approach. We developed a combined image-segmentation and model-generation software called AxoDetect: a target- and format-agnostic computer vision algorithm which can segment myelin, endo/epineurium, and both myelinated and unmyelinated fibers from a nerve image without training. Main results. AxoDetect is over 10 times faster on average when compared with current automatic methods while maintaining flexibility through the use of tunable pixel threshold filters to detect different types of tissue. When compared to a distribution-based and a manually segmented model of the splenic nerve terminal branch 1, the model generated with AxoDetect had comparable threshold prediction and was able to accurately detect an increase in activation threshold caused by the addition of surrounding fat tissue to the modeled nerve. Significance. AxoDetect contributes to the acceleration of neuromodulation treatment development through faster model design and iteration without requiring training. Furthermore, the computer vision approach and tunable nature of the filters in our method allow for its use in a variety of histological applications. Our approach will impact not only the study of nerves but also the design of implantable neural interfaces to enhance bioelectronic therapeutic options.

A Systematic Review of the Novel Targeted Immunobiological Medications in Rheumatoid Arthritis: Efficacy, Safety, and Innovation

Introduction: Over the last half-century, the treatment and management of autoimmune rheumatic diseases have progressively improved, particularly with the contribution of immunobiological or biological therapies known as disease-modifying antirheumatic drugs. Although these agents have been generally efficient in the management of rheumatoid arthritis (RA), some patients experience limited efficacy and non-responsiveness to treatment. In addition, they may cause adverse clinical effects, further aggravating the disease. Objectives: Despite advancements in biological therapies, significant clinical needs persist. This review aims to discuss novel treatments, guiding future guidelines and drug discoveries for rheumatoid arthritis. Methods: This review follows the 2020 PRISMA statement, utilising PubMed and Google Scholar for literature search and emphasizing recent meta-analyses on the safety and efficacy of targeted immunobiological medications. Results: Small molecule inhibitors, whether utilised independently or in conjunction with Methotrexate, have been shown to contribute to effective disease management and have the potential for better adherence to the American College of Rheumatology criteria. Tocilizumab therapy demonstrates a significant reduction in disease activity and improves rates of disease remission when combined with Methotrexate. Investigations of mesenchymal stromal cell therapies have had promising outcomes, improving both cartilage quality (as evaluated by Macroscopic Cartilage Repair Assessment) and joint tenderness and swelling in clinical joint counts. Intra-articular administration of tolerogenic dendritic cells has displayed a capacity to alleviate pain, as measured by Visual Analog Scale scores, and enhance the Disease Activity Score across 28 joints. Resveratrol capsules supplemented with allopathic therapy show potential in reducing TNF-α and interleukin-6 serum levels. Conclusion: More investigations and their analysis will improve patient outcomes and reduce adverse effects and the costs involved in developing and obtaining immunobiological drugs. Moreover, assessing the safety and efficacy of anti-RA properties of the bioactive compounds could offer less toxic and more cost-effective natural treatment options.

Modern aspects of external application and prospects of using the secretome of mesenchymal stem cells (review)

Introduction. The secretome of mesenchymal stem cells (SMSC) is widely used in medicine. It is most often used due to its immune-modulating and regenerative properties in the treatment of autoimmune, immuno-mediated and other diseases due to its anti-inflammatory, neuroprotective and regenerating action. In many studies, exosomes isolated from SMSC are used as a therapeutic agent. In recent years, the interest in the development of products containing SMSC for external use has increased. Similar drugs are planned to be used in the treatment of diabetic wounds, for skin regeneration, the treatment of inflammatory diseases, as well as alopecia. There are multiple studies on increasing collagen secretion and reducing skin photosensitivity in preclinical studies, which confirms the significant potential for the use of SMSC in dermatology and cosmetology. The purpose of this review was to study the potential of using conditioned medium in medicines for external use, approaches to standardization of SMSC as a pharmaceutical substance and methods of increasing percutaneous delivery.Text. SMSC as an active pharmaceutical ingredient is a transparent liquid from yellow to orange in color with a characteristic odor. The pH of the ready-to-use SMSC composition ranges from 7.0 to 7.5, which allows it to be used in topical and external applications without the addition of stabilizers or pH correctors. Problems of delivery of SMSC through the epidermis are most often solved by placing the secretome in hydrogels, using exosomes or technology using microneedles. Since 2022, after legislative changes, measures have been taken to register and introduce into clinical practice domestic drugs based on cellular products. However, as the analysis showed, it will take some time before the appearance of original medicines based on SMSC, and today in the Russian Federation only products related to cosmetics and veterinary drugs, as well as zoocosmetics, are produced so far.Conclusion. SMSC may also prove to be a safer and more effective substance for the potential treatment of a wide range of acute and chronic diseases. But despite the large number of positive results of using SMSC for wound healing in animals, as well as clinical studies on skin regeneration, there are no studies of its safety and effectiveness, as well as standardization of the production process.

Abstract 5254: The “off-the-shelf ”CD19-CAR-Vδ1T cells demonstrated an enhanced therapeutic effect on B-cell malignancy models

Abstract Background: The commercialization of autologous chimeric antigen receptor T cell (CAR-T) is hindered by the expensive and time-consuming manufacturing process, presenting major challenges. The development of allogeneic products is proposed as an alternative strategy to overcome these obstacles. Vδ1T cells, possessing active homing capability, are known to infiltrate tumor tissues and have been linked with favorable patient prognosis due to their direct killing effect via innate immunity and their sensitive T cell receptors that can broadly recognize tumor antigens. Unlike conventional αβ T cells, Vδ1 TCRs are not restricted by major histocompatibility complexes (MHCs), thus preventing the development of graft-versus-host disease (GVHD). Therefore, Vδ1T cells were hypothesized to be a superior candidate for universal CAR-T cells. Nevertheless, the small portion of Vδ1T cells (less than 1%) in peripheral blood posts a significant challenge for CMC and production. Here we present the successful development of CD19-CAR-Vδ1T cells, which demonstrate enhanced therapeutic efficacy on B-cell malignancy models. Methods: High-purity CD19-CAR-Vδ1T cells were prepared using PersonGen's proprietary platform technology. Multiple CAR structures were tested for cytotoxicity, and the fourth-generation CAR-transduced Vδ1 cells designated as UTAA09 exhibited sustained killing of CD19+ target cells. UTAA09 underwent in-depth research regarding its anti-tumor efficacy and safety. Results: The Vδ1T cell purity exceeded 95%, while the residual TCRαβ count remained under 1%. The CAR transduction efficiency remained stable across batches, with medium CAR+~30%, and up to 2×1011 UTAA09 cells were harvested in compliance with GMP standards. The presence of secreted IL-2 significantly increased the persistence of UTAA09 in vitro, and UTAA09 showed comparable anti-tumor activity and expansion rates to CD19-CAR-αβT cells. Notably, no exhaustion phenotype was detected for UTAA09 after multiple antigen stimulation processes. Moreover, UTAA09 lacked detectable IL-17A, indicating a non-promoting characteristic in tumor growth. In the xenograft model, significant inhibition of tumor growth was observed in all mice, of which 40% achieved long-term disease-free survival (p&amp;lt;0.01) . On days 5, 12, and 19 after the administration of UTAA09, Vδ1T cells underwent significant expansion in all 5 mice tested. Subsequent analysis confirmed that the majority of these expanded Vδ1T cells were CAR+ cells, indicating the specific and long-lasting expansion of CD19-CAR+ Vδ1T cells in vivo. Importantly, none of the mice experienced significant weight loss, demonstrating the safety and outstanding in vivo effectiveness of UTAA09. Conclusion: UTAA09 shows potential as an off-the-shelf allogeneic cellular therapy for the treatment of B-cell malignancies and autoimmune diseases derived from B cells. Citation Format: Dan Chen, Fengtao You, Cheng Chen, Shufen Xiang, Ping Zhang, Hai Wu, Zhong Zheng, Min Wang, Xingbing Wang, Huimin Meng, Nan Yang, Bozhen Zhang, Lin Yang. The “off-the-shelf ”CD19-CAR-Vδ1T cells demonstrated an enhanced therapeutic effect on B-cell malignancy models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5254.

Abstract 1405: Development of a humanized anti-IL-22 antibody for cancer and inflammation therapy

Abstract Interleukin-22 (IL-22) is an inflammatory cytokine involved in the pathology of autoimmune diseases such as psoriasis, atopic dermatitis, and ulcerative colitis. IL-22 has also been shown to promote epithelial cell proliferation, stemness and tumorigenesis in cancer, and is associated with a more aggressive phenotype in a variety of cancers including inflammatory colon cancer models. IL-22 plays a central role in this pathogenic process by driving activation of STAT3 and other signaling cascades. Recent studies demonstrated that neutralization of IL-22 reduced dysplasia and tumor development in preclinical models. However, there has not been a clear application for anti-IL-22 therapy for cancer and autoimmune diseases, likely due to identifying the right disease indication and their low potency and efficacy. Thus, there remains an opportunity to explore the potential of more potent anti-IL-22 therapeutics. We have developed humanized anti-IL-22 antibodies with high affinities to human, cynomolgus and mouse IL-22 using BioAtla’s proprietary antibody discovery and engineering platforms. In vitro data demonstrated that our anti-IL-22 antibodies inhibited IL-22-induced p-STAT3 activities. In addition, our antibodies showed a 10-fold increased binding activity to human IL-22 compared to Fezakinumab, which was previously developed by Pfizer for the treatment of autoimmune diseases. To test the functions of our antibodies in vivo, we established an inflammation-driven sporadic colitis-associated colorectal (CAC) cancer mouse model. Our humanized anti-IL-22 antibody, a potent, species cross-reactive anti-IL-22 blocking antibody, significantly reduced tumor progression in CAC model. These data suggest that targeting IL-22 reduces tumor occurrence by reducing inflammation-induced tumorigenesis. In addition, we evaluated our anti-IL22 antibodies in an imiquimod-induced psoriasiform skin inflammation mouse model. The mice treated with anti-IL22 antibodies had significantly reduced skin lesions compared to isotype antibody-treated mice. Q-PCR analysis of the mouse skin demonstrated that treatment with our anti-IL-22 antibody led to significantly decreased RNA levels of the imiquimod-induced inflammatory marker CXCL3. In conclusion, the development of a potent, species cross-reactive anti-IL-22 antibody using BioAtla’s antibody discovery and engineering platforms addresses the past challenges of anti-IL-22 therapeutics and allows for translational studies in relevant animal efficacy and safety models. Citation Format: Jian Chen, Cathy Chang, Gerhard Frey, Haizhen Liu, Jing Wang, William J. Boyle, Jay M. Short. Development of a humanized anti-IL-22 antibody for cancer and inflammation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1405.

Manic Episode Due to Steroid Use in Pemphigus Vulgaris Patient: Case Report

Corticosteroids are used in the treatment of numerous diseases, primarily in the treatment of autoimmune diseases. They have various side-effects. Although the pathophysiology of psychiatric side-effects have not clearly been revealed, the various risk factors leading to these have been defined. In the treatment of psychiatric symptoms which emerge after steroid treatments, it is firstly advised to discontinue the use of the steroid and initiate the use of an antipsychotic medicine together with a mood regulator or single-handedly. It is aimed at discussing the manic attack which took place after corticosteroid use in our patient diagnosed with pemphigus vulgaris, the risk factors leading to this situation and the course of the disease only with olanzapine.

Mycobacterium xenopi vertebral osteomyelitis in a patient with systemic lupus erythematosus: illustrative case.

Mycobacterium xenopi is a common nontuberculous Mycobacterium (NTM) that is slow growing and an infrequent cause of infection. When infections do occur, it is by exposure to contaminated soil or water or to infectious aerosols. Nontuberculous mycobacterial infections in the spine are exceedingly rare. Risk factors can include immunosuppression, particularly human immunodeficiency virus; however, other systemic diseases such as systemic lupus erythematosus (SLE) have been reported. The authors report a case of cord compression due to M. xenopi vertebral osteomyelitis with an epidural abscess in a patient with SLE on hydroxychloroquine and recent steroid use. The authors explore the presentation of a patient who developed acute neurological deficits concerning for spinal pathology secondary to NTM. Although considered a rare occurrence, patients with autoimmune pathologies are susceptible to infection by unusual organisms. Standard treatment of autoimmune diseases can predispose patients to infection and warrant surgical correction to prevent long-term neurological deficits. There is still much work and research to be done in the exploration and understanding of nontuberculous mycobacterial infection, pathophysiology, and treatment in the immunocompetent population and in patients with autoimmune disorders.

Mathematical modeling in autoimmune diseases: from theory to clinical application.

The research & development (R&D) of novel therapeutic agents for the treatment of autoimmune diseases is challenged by highly complex pathogenesis and multiple etiologies of these conditions. The number of targeted therapies available on the market is limited, whereas the prevalence of autoimmune conditions in the global population continues to rise. Mathematical modeling of biological systems is an essential tool which may be applied in support of decision-making across R&D drug programs to improve the probability of success in the development of novel medicines. Over the past decades, multiple models of autoimmune diseases have been developed. Models differ in the spectra of quantitative data used in their development and mathematical methods, as well as in the level of "mechanistic granularity" chosen to describe the underlying biology. Yet, all models strive towards the same goal: to quantitatively describe various aspects of the immune response. The aim of this review was to conduct a systematic review and analysis of mathematical models of autoimmune diseases focused on the mechanistic description of the immune system, to consolidate existing quantitative knowledge on autoimmune processes, and to outline potential directions of interest for future model-based analyses. Following a systematic literature review, 38 models describing the onset, progression, and/or the effect of treatment in 13 systemic and organ-specific autoimmune conditions were identified, most models developed for inflammatory bowel disease, multiple sclerosis, and lupus (5 models each). ≥70% of the models were developed as nonlinear systems of ordinary differential equations, others - as partial differential equations, integro-differential equations, Boolean networks, or probabilistic models. Despite covering a relatively wide range of diseases, most models described the same components of the immune system, such as T-cell response, cytokine influence, or the involvement of macrophages in autoimmune processes. All models were thoroughly analyzed with an emphasis on assumptions, limitations, and their potential applications in the development of novel medicines.

A type I interferon regulatory network for human plasmacytoid dendritic cells based on heparin, membrane-bound and soluble BDCA-2

Plasmacytoid dendritic cells (pDCs) produce type I interferons (IFNs) after sensing viral/bacterial RNA or DNA by toll-like receptor (TLR) 7 or TLR9, respectively. However, aberrant pDCs activation can cause adverse effects on the host and contributes to the pathogenesis of type I IFN-related autoimmune diseases. Here, we show that heparin interacts with the human pDCs-specific blood dendritic cell antigen 2 (BDCA-2) but not with related lectins such as DCIR or dectin-2. Importantly, BDCA-2-heparin interaction depends on heparin sulfation and receptor glycosylation and results in inhibition of TLR9-driven type I IFN production in primary human pDCs and the pDC-like cell line CAL-1. This inhibition is mediated by unfractionated and low-molecular-weight heparin, as well as endogenous heparin from plasma, suggesting that the local blood environment controls the production of IFN-α in pDCs. Additionally, we identified an activation-dependent soluble form of BDCA-2 (solBDCA-2) in human plasma that functions as heparin antagonist and thereby increases TLR9-driven IFN-α production in pDCs. Of importance, solBDCA-2 levels in the serum were increased in patients with scrub typhus (an acute infectious disease caused by Orientia tsutsugamushi) compared to healthy control subjects and correlated with anti-dsDNA antibodies titers. In contrast, solBDCA-2 levels in plasma from patients with bullous pemphigoid or psoriasis were reduced. In summary, this work identifies a regulatory network consisting of heparin, membrane-bound and solBDCA-2 modulating TLR9-driven IFN-α production in pDCs. This insight into pDCs function and regulation may have implications for the treatment of pDCs-related autoimmune diseases.