an-adoptive-transfer-model-of-rheumatoid-arthritis-in-mice

An Adoptive Transfer Model of Rheumatoid Arthritis in Mice

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disorder that may result in joint damage, deformities, disability, and even ...

Fujian Medical University Union Hospital

Huazhong University of Science and Technology

Ministry of Education

Multiple sclerosis (MS) has been considered as a T cell-mediated autoimmune disease. However, the signaling pathways regulating effector T cells in MS have yet to be elucidated. Janus kinase 2 (JAK2) plays a crucial role in hematopoietic/immune cytokine receptor signal transduction. Here, we tested the mechanistic regulation of JAK2 and the therapeutic potential of pharmacological JAK2 inhibition in MS. Both inducible whole-body JAK2 knockout and T cell-specific JAK2 knockout completely prevented the onset of experimental autoimmune encephalomyelitis (EAE), a widely used MS animal model. Mice with JAK2 deficiency in T cells exhibited minimal demyelination and minimal CD45 leukocyte infiltration in the spinal cord, accompanied by a remarkable reduction of T helper cell type 1 (T1) and type 17 (T17) in the draining lymph nodes and spinal cord. In vitro experiments showed that disruption of JAK2 markedly suppressed T1 differentiation and IFNγ production. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) was reduced in JAK2 deficient T cells, while STAT5 overexpression significantly increased T1 and IFNγ production in STAT5 transgenic mice. Consistent with these results, JAK1/2 inhibitor baricitinib or selective JAK2 inhibitor fedratinib attenuated the frequencies of T1 as well as T17 in the draining lymph nodes and alleviated the EAE disease activity in mice. Our findings suggest that overactive JAK2 signaling in T lymphocytes is the culprit in EAE, which may serve as a potent therapeutic target for autoimmune disease.

JAK2/STAT5 inhibition protects mice from experimental autoimmune encephalomyelitis by modulating T cell polarization.

The spotlight in recent years has increasingly focused on inducible regulatory T cells 35 (iTr35), a novel subpopulation of regulatory T cells characterized by phenotypic stability, heightened reactivity, and potent immunosuppressive function through the production of IL-35. Despite being in the exploratory phase, research on iTr35 has garnered significant interest. In this review, we aim to consolidate our understanding of the biological characteristics and immunomodulatory mechanisms of iTr35, offering fresh perspectives that may pave the way for its potential applications in disease diagnosis and treatment.

Immunomodulatory effects of iTr35 cell subpopulation and its research progress.

In the era of precision medicine, antibody-drug conjugates (ADCs) have emerged as a cutting-edge therapeutic strategy. These innovative compounds combine the precision of monoclonal antibodies with the potent cell-killing or immune-modulating abilities of attached drug payloads. This unique strategy not only reduces off-target toxicity but also enhances the therapeutic effectiveness of drugs. Beyond their well established role in oncology, ADCs are now showing promising potential in addressing the unmet needs in the therapeutics of rheumatic diseases. Rheumatic diseases, a diverse group of chronic autoimmune diseases with varying etiologies, clinical presentations, and prognoses, often demand prolonged pharmacological interventions, creating a pressing need for novel, efficient, and low-risk treatment options. ADCs, with their ability to precisely target the immune components, have emerged as a novel therapeutic strategy in this context. This review will provide an overview of the core components and mechanisms behind ADCs, a summary of the latest clinical trials of ADCs for the treatment of rheumatic diseases, and a discussion of the challenges and future prospects faced by the development of next-generation ADCs. SIGNIFICANCE STATEMENT: There is a lack of efficient and low-risk targeted therapeutics for rheumatic diseases. Antibody-drug conjugates, a class of cutting-edge therapeutic drugs, have emerged as a promising targeted therapeutic strategy for rheumatic disease. Although there is limited literature summarizing the progress of antibody-drug conjugates in the field of rheumatic disease, updating the advancements in this area provides novel insights into the development of novel antirheumatic drugs.

Precision Medicine in Rheumatic Diseases: Unlocking the Potential of Antibody-Drug Conjugates.

Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed.

Mid1 promotes synovitis in rheumatoid arthritis via ubiquitin-dependent post-translational modification.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by severe inflammation and pulmonary dysfunction. Despite advancements in critical care, effective pharmacological interventions for ARDS remain elusive. While Janus kinase 2 (JAK2) inhibitors have emerged as an innovative treatment for numerous autoinflammatory diseases, their therapeutic potential in ARDS remains unexplored. In this study, we investigated the contribution of JAK2 and its underlying mechanisms in ARDS utilizing myeloid-specific JAK2 knockout murine models alongside a pharmacological JAK2 inhibitor. Notably, myeloid-specific JAK2 knockout led to a notable attenuation of ARDS induced by intratracheal administration of LPS, accompanied by reduced levels of neutrophils and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and lung tissue. Intriguingly, the ameliorative effects were abolished upon the depletion of monocyte-derived alveolar macrophages (Mo-AMs) rather than tissue-resident alveolar macrophages (TR-AMs). JAK2 deficiency markedly reversed LPS-induced activation of STAT5 in macrophages. Remarkably, pharmacological JAK2 inhibition using baricitinib failed to substantially alleviate neutrophils infiltration, implying that specific inhibition of JAK2 in Mo-AMs is imperative for ARDS amelioration. Collectively, our data suggest that JAK2 may mitigate ARDS progression through the JAK2 pathway in Mo-AMs, underscoring JAK2 in alveolar macrophages, particularly Mo-AMs, as a promising therapeutic target for ARDS treatment.

Article	Year
JAK2/STAT5 inhibition protects mice from experimental autoimmune encephalomyelitis by modulating T cell polarization. International immunopharmacology\| PubMed ID: 37269741	2023
Immunomodulatory effects of iTr35 cell subpopulation and its research progress. Clinical and experimental medicine\| PubMed ID: 38386086	2024
Precision Medicine in Rheumatic Diseases: Unlocking the Potential of Antibody-Drug Conjugates. Pharmacological reviews\| PubMed ID: 38622001	2024
Mid1 promotes synovitis in rheumatoid arthritis via ubiquitin-dependent post-translational modification. Pharmacological research\| PubMed ID: 38777113	2024
Deciphering the therapeutic potential of Myeloid-Specific JAK2 inhibition in acute respiratory distress syndrome. Mucosal immunology\| PubMed ID: 39173745	2024

Jixin Zhong

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