Publications by authors named "Hongdi Ma"

Pancreatic cancer remains a challenging disease with limited treatment options, resulting in high mortality rates. The predominant approach to managing pancreatic cancer patients continues to be systemic cytotoxic chemotherapy. Despite substantial advancements in immunotherapy strategies for various cancers, their clinical utility in pancreatic cancer has proven less effective and durable.

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Objective: The human cluster of differentiation (CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer (NK) cells targeting hematologic malignancies (HMs).

Methods: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine (PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in and settings.

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Inflammatory bowel diseases (IBD) are known to have complex, genetically influenced etiologies, involving dysfunctional interactions between the intestinal immune system and the microbiome. Here, we characterized how the RNA transcript from an IBD-associated long non-coding RNA locus ("CARINH-Colitis Associated IRF1 antisense Regulator of Intestinal Homeostasis") protects against IBD. We show that CARINH and its neighboring gene coding for the transcription factor IRF1 together form a feedforward loop in host myeloid cells.

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Metabolic rewiring is essential for Th17 cells' functional identity to sense and interpret environmental cues. However, the environmental metabolic checkpoints with specific regulation of Th17 cells, manifesting potential therapeutic opportunities to autoimmune diseases, remain largely unknown. Here, by screening more than one hundred compounds derived from intestinal microbes or diet, we found that vitamin B5 (VB5) restrains Th17 cell differentiation as well as related autoimmune diseases such as experimental autoimmune encephalomyelitis and colitis.

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Food allergy is a growing concern due to its increasing world-wide incidence. Strict avoidance of allergens is a passive treatment strategy. Since the mechanisms responsible for the occurrence and development of food allergy have not yet been fully elucidated, effective individualized treatment options are lacking.

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Liver-resident NK cells are distinct from conventional NK cells and play an important role in the maintenance of liver homeostasis. How liver-resident NK cells participate in autoimmune cholangitis remains unclear. Here, we extensively investigated the impact of NK cells in the pathogenesis of autoimmune cholangitis utilizing the well-established dnTGFβRII cholangitis model, NK cell-deficient (Nfil3) mice, adoptive transfer and in vivo antibody-mediated NK cell depletion.

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Although lymphocytes are known to circulate throughout lymphoid tissues and blood, they also establish residency in nonlymphoid organs, most prominently in barrier tissues, such as the intestines. The adaptation of T lymphocytes to intestinal environments requires constant discrimination between natural stimulation from commensal flora and food and pathogens that need to be cleared. Genetic variations that cause a defective defense or a break in tolerance along with environmental cues, such as infection or imbalances in the gut microbiota known as dysbiosis, can trigger several immune disorders via the activation of T lymphocytes in the intestines.

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Article Synopsis
  • Gut microbiota and bacterial translocation are key factors influencing immune responses and tolerance, particularly relating to autoimmune conditions, though the exact mechanisms remain unclear.
  • Using a specific mouse model of autoimmune cholangitis, the study found that changes in gut microbiota composition can reduce immune-related damage when antibiotics are administered.
  • Additionally, mice lacking toll-like receptor 2 (TLR2) experienced worsened conditions due to compromised gut barrier function, highlighting the role of gut permeability and microbiota translocation in liver damage associated with the disease.
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  • Primary biliary cholangitis (PBC) is an autoimmune liver disease that leads to serious complications like liver failure due to the destruction of bile ductules.
  • The research introduced a new mouse model for PBC by immunizing with bile duct protein, showing that this approach effectively disrupts immune tolerance and mimics key aspects of the disease.
  • The findings revealed enhanced immune responses, such as increased T cell activity and the presence of anti-mitochondrial antibodies, which could provide insights into the mechanisms of PBC.
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Autoimmune diseases often induce dysregulated hematopoiesis with altered number and function of hematopoietic stem and progenitor cells (HSPCs). However, there are limited studies on the direct regulation of HSPCs on T cells, which are often detrimental to autoimmunity. Here, we found that in a murine model of Concanavalin A-induced autoimmune hepatitis, LSK (LineageSca-1c-Kit)-like cells accumulated in liver, spleen, and bone marrow (BM), which were myeloid progenitors (LineageSca-1c-Kit) that upregulated Sca-1 expression upon T cell-derived IFN-γ stimulation.

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Ten-Eleven-Translocation-2 (Tet2) is a DNA methylcytosine dioxygenase that functions as a tumor suppressor in hematopoietic malignancies. We examined the role of Tet2 in tumor-tissue myeloid cells and found that Tet2 sustains the immunosuppressive function of these cells. We found that Tet2 expression is increased in intratumoral myeloid cells both in mouse models of melanoma and in melanoma patients and that this increased expression is dependent on an IL-1R-MyD88 pathway.

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  • Molecular mechanisms controlling liver regeneration play a crucial role in various liver disorders, with Kupffer cells and natural killer (NK) cells being essential for this process.
  • The study highlights that deletion of PTEN leads to M2-like polarization in Kupffer cells, which hampers NK cell activation but promotes hepatocyte proliferation through the release of growth factors.
  • Targeting PTEN in Kupffer cells may offer new strategies to modify liver regeneration in patients who have undergone liver resection.
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  • CXCR3 is a pleiotropic receptor involved in immune processes like T cell differentiation and chemotaxis, especially significant in autoimmune cholangitis.
  • Researchers used a CXCR3 knockout mouse model to study its role in autoimmune cholangitis, revealing that CXCR3 deficiency leads to worse disease outcomes and increased effector memory T cells.
  • Gene analysis showed that CXCR3-deficient CD8 T cells have a strong pro-inflammatory profile, suggesting potential pathways for therapeutic interventions in autoimmune liver diseases.
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Understanding the mechanisms that lead to autoimmunity is critical for defining potential therapeutic pathways. In this regard there have been considerable efforts in investigating the interacting roles of TGF-β and IL-2 on the function regulatory T cells. We have taken advantage of dnTGF-βRII Il2ra (abbreviated as Il2raTg) mouse model, which allows a direct mechanistic approach to define the relative roles of TGF-β and IL-2 on Treg development.

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Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease with progressive cholestasis and liver fibrosis. Similar to human patients with PBC, p40-/-IL-2Rα-/- mice spontaneously develop severe autoimmune cholangitis. Although there has been considerable work on immune regulation and autoimmunity, there is a relative paucity of work directed at the functional implications of the key peritoneal cavity (PC) B cell subset, coined B1a cells in PBC.

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The functions of macrophages that lead to effective host responses are critical for protection against Staphylococcus aureus. Deep tissue-invading S. aureus initially countered by macrophages trigger macrophage accumulation and induce inflammatory responses through surface receptors, especially toll-like receptor 2 (TLR2).

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There is a significant unmet need in the treatment of primary biliary cirrhosis (PBC) despite significant data on the effector pathways that lead to biliary duct damage. We focused attention on a murine model of PBC, the dominant negative transforming growth factor β receptor II (Tg) mice. To further define the pathways that lead to biliary pathology in these mice, we developed Tg mice deleted of CD4 cells (CD4(-/-)Tg).

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Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that develops based upon the interaction of genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified dozens of predisposing variants including HLA, IL12A, and CTLA4 but have been disappointed in identifying a "smoking gun." These discoveries highlight the importance of the genetic background involved in immunological dysregulation.

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Thymic CD4(+) FoxP3(+) regulatory T (Treg) cells are critical for the development of immunological tolerance and immune homeostasis and requires contributions of both thymic dendritic and epithelial cells. Although B cells have been reported to be present within the thymus, there has not hitherto been a definition of their role in immune cell development and, in particular, whether or how they contribute to the Treg cellular thymic compartment. Herein, using both phenotypic and functional approaches, we demonstrate that thymic B cells contribute to the maintenance of thymic Treg cells and, using an in vitro culture system, demonstrate that thymic B cells contribute to the size of the thymic Treg compartment via cell-cell MHC II contact and the involvement of two independent co-stimulatory pathways that include interactions between the CD40/CD80/CD86 co-stimulatory molecules.

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The intestinal microbiome plays a significant role in the development of autoimmune diseases, in particular, inflammatory bowel diseases. But the interplay between the intestinal tract and the liver may explain the increased association with autoimmune liver diseases and inflammatory bowel diseases. The gut-liver axis involves multiple inflammatory cell types and cytokines, chemokines and other molecules which lead to the destruction of normal liver architecture.

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The IL-12 family modulates T cell mediated autoimmune diseases and GWAS in PBC have suggested a critical role of IL-12 and its subunits in modulating portal inflammation. We have taken advantage of an aggressive model of portal inflammation and colitis in IL-2Rα(-/-) mice to study the specific role of IL-12 and, in particular, the immunobiology of p40(-/-)IL-2Rα(-/-) mice. Colonies of IL-2Rα(+/-), IL-2Rα(-/-) and p40(-/-)IL-2Rα(-/-) mice were studied for the natural history of immunopathology in liver and colon using histology and immunohistochemistry.

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There have been major advances in defining the immunological events associated with fibrosis in various chronic liver diseases. We have taken advantage of this data to focus on the mechanisms of action of a unique multi-kinase inhibitor, coined sorafenib, on CCl4-induced murine liver fibrosis, including the effects of this agent in models of both acute and chronic CCl4-mediated pathology. Importantly, sorafenib significantly attenuated chronic liver injury and fibrosis, including reduction in liver inflammation and histopathology as well as decreased expression of liver fibrosis-related genes, including α-smooth muscle actin, collagen, matrix metalloproteinases and the tissue inhibitor of metalloproteinase-1.

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Traditional Chinese medicines (TCMs) have a long history in Asian countries and are traditionally used to prevent and treat a variety of diseases. The rising interest in TCMs in recent years is reflected in both the increase in their market demand as well as scientific research. Previous studies show that TCMs perform dual roles on immunological regulation: immunological activation and immunological suppression.

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