Rituximab‐induced interleukin‐15 reduction associated with clinical improvement in rheumatoid arthritis

Bucchia

Arthritis & Rheumatology

et al. 2019

Objective. To compare the effects of rituximab (RTX) and conventional immunosuppressants (CIs) on CD4+ T cells, Treg cells, and CD8+ T cells in antineutrophil cytoplasmic antibody-associated vasculitis (AAV).Methods. A thorough immunophenotype analysis of CD4+, Treg, and CD8+ cells from 51 patients with AAV was performed. The production of cytokines and chemokines by CD8+ T cells stimulated in vitro was assessed using a multiplex immunoassay. The impact of AAV B cells on CD8+ T cell response was assessed using autologous and heterologous cocultures.Results. CD4+ and Treg cell subsets were comparable among RTX-treated and CI-treated patients. In contrast, within the CD8+ T cell compartment, RTX, but not CIS, reduced CD45RA+CCR7-(TEMRA) cell frequency (from a median of 39% before RTX treatment to 10% after RTX treatment [P < 0.01]) and efficiently dampened cytokine/chemokine production (e.g., the median macrophage inflammatory protein 1α level was 815 pg/ml in patients treated with RTX versus 985 pg/ml in patients treated with CIs versus 970 pg/ml in those with active untreated AAV [P < 0.01]). CD8+ T cell subsets cocultured with autologous B cells produced more proinflammatory cytokines in AAV patients than in controls (e.g., for tumor necrosis factor-producing effector memory CD8+ T cells: 14% in AAV patients versus 9.2% in controls [P < 0.05]). In vitro disruption of AAV B cell-CD8+ T cell cross-talk reduced CD8+ T cell cytokine production, mirroring the reduced CD8+ response observed ex vivo after RTX treatment.Conclusion. The disruption of a pathogenic B cell/CD8+ T cell axis may contribute to the efficacy of RTX in AAV. Further studies are needed to determine the value of CD8+ T cell immunomonitoring in B cell-targeted therapies.

Section: Discussionmentioning

confidence: 99%

Dampening of CD8+ T Cell Response by B Cell Depletion Therapy in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Bucchia

Arthritis & Rheumatology

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

“…+ T and NK cell responses in other diseases such as rheumatoid arthritis (44)(45)(46) and multiple sclerosis (47), suggesting that the enlarged infarct size seen in GFAP-IL-15 tg mice may result from the enhanced CD8 + T and NK responses. This notion is supported by the observation of an astrocytic IL-15-induced increase of activated CD8 + T and NK cells, which suggests the involvement of direct cytotoxicity by CD8 + T and NK cells in postischemic lesion enlargement.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

Yao

et al. 2016

156

148

Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) Infiltrating leukocytes such as lymphocytes are major effectors of postischemic brain inflammation (1-6). The phenotype and function of infiltrating lymphocytes are largely dictated by organspecific intrinsic factors during inflammatory responses (7-9), and such factors in the brain are unique in terms of cellular constituents, blood-brain barrier (10-12), and microenvironment (1-3, 7). As the most abundant cell type in the CNS, astrocytes constitute nearly 50% of the human brain's volume. Astrocytes contribute to the regulation of neural transmission, survival of neurons and other glia cells, and integrity of the blood-brain barrier. In the inflamed CNS, astrocytes engage in significant cross-talk with CNS-infiltrating immune cells by providing a major source of the proinflammatory cytokines and chemokines, thereby activating infiltrating lymphocytes. Evidence has shown that astrocytes can exert potent proinflammatory functions by producing factors including monocyte chemotactic protein-1 (MCP-1/CCL2), interleukin 1 beta (IL-1β), interleukin-6 (IL-6), etc., as their primary mode of action after CNS injury. In addition, astrocytes are considered as important nonprofessional antigen-presenting cells. Depending on the stage of brain pathology, astrocytes also possess antiinflammatory properties such as scar formation and restriction of inflammation by producing transforming growth factor-β (13,14). Recent studies have shown that the inhibition of astrocytes correlates with decreased infarct size (15,16) and that treatments capable of decreasing infarct size are often accompanied by attenuated astrocyte responses. These findings suggest a detrimental role for astrocytes after brain ischemia (15-18). However, still unknown are whether and how astrocytes shape acute CNS immune responses in the context of a postischemic brain and whether this process has any clinical significance.IL-15 belongs to a family of cytokines using the common γ-chain as a component of their receptors (19,20). IL-15 interacts specifically with the high-affinity IL-15 receptor α (IL-15Rα) and binds to IL-2/IL-15Rβ and a common γ-chain expressed by target cells (21-23). In the periphery, monocytes and dendritic cells are the main sources of 25). IL-15 maintains homeostasis and cytotoxic activities of lymphocytes that bear its receptor [i.e., natural killer (NK) and CD8 + T cells] (19,20). Some studies have demonstrated that IL-15 contributes to the immunopathology of several inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease (26,27). Despite recent studies suggesting astrocytes as a major...

“…IL-15 is an inflammatory cytokine with a function on a wide range of immune cells ( 27 , 28 ). Much evidence demonstrated that IL-15 can boost immune cells to exacerbate disease progression such as rheumatoid arthritis and stroke ( 13 – 15 , 29 ). However, there are still documents, which demonstrated that IL-15 is beneficial to experimental autoimmune encephalomyelitis ( 17 , 18 ).…”

Section: Discussionmentioning

confidence: 99%

Astrocytic Interleukin-15 Reduces Pathology of Neuromyelitis Optica in Mice

Han

Ren

et al. 2018

Front. Immunol.

Astrocyte loss induced by neuromyelitis optica (NMO)-IgG and complement-dependent cytotoxicity (CDC) is the hallmark of NMO pathology. The survival of astrocytes is thought to reflect astrocyte exposure to environmental factors in the CNS and the response of astrocytes to these factors. However, still unclear are how astrocytes respond to NMO-IgG and CDC, and what CNS environmental factors may impact the survival of astrocytes. In a murine model of NMO induced by intracerebral injection of NMO-IgG and human complement, we found dramatic upregulation of IL-15 in astrocytes. To study the role of astrocytic IL-15 in NMO, we generated a transgenic mouse line with targeted expression of IL-15 in astrocytes (IL-15tg), in which the expression of IL-15 is controlled by a glial fibrillary acidic protein promoter. We showed that astrocyte-targeted expression of IL-15 attenuates astrocyte injury and the loss of aquaporin-4 in the brain. Reduced blood–brain barrier leakage and immune cell infiltration are also found in the lesion of IL-15tg mice subjected to NMO induction. IL-15tg astrocytes are less susceptible to NMO-IgG-mediated CDC than their wild-type counterparts. The enhanced resistance of IL-15tg astrocytes to cytotoxicity and cell death involves NF-κB signaling pathway. Our findings suggest that IL-15 reduces astrocyte loss and NMO pathology.