The anti-CD20 antibody rituximab reduces the Th17 cell response

Veerdonk, Frank L. van de; Lauwerys, Bernard; Marijnissen, Renoud J.; Timmermans, Kim; Padova, Franco Di; Koenders, Marije I.; Gutierrez-Roelens, Ilse; Durez, Patrick; Netea, Mihai G.; Meer, J.W.M. van der; Berg, Wim B. van den; Joosten, Leo A. B.

doi:10.1002/art.30314

Cited by 162 publications

(113 citation statements)

References 34 publications

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“…Our findings are therefore consistent with demonstrations that B-cell depletion in lupus or rheumatoid arthritis patients dramatically decreases T-cell inflammation, including Th17 function (34,35). Our data also indicate myeloid cells play supportive, albeit disease-independent, roles in overall levels of T-cell inflammation.…”

Section: Discussionsupporting

confidence: 91%

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

DeFuria

Belkina

Jagannathan-Bogdan

et al. 2013

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

449

442

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Patients with type 2 diabetes (T2D) have disease-associated changes in B-cell function, but the role these changes play in disease pathogenesis is not well established. Data herein show B cells from obese mice produce a proinflammatory cytokine profile compared with B cells from lean mice. Complementary in vivo studies show that obese B cell-null mice have decreased systemic inflammation, inflammatory B-and T-cell cytokines, adipose tissue inflammation, and insulin resistance (IR) compared with obese WT mice. Reduced inflammation in obese/insulin resistant B cell-null mice associates with an increased percentage of anti-inflammatory regulatory T cells (Tregs). This increase contrasts with the sharply decreased percentage of Tregs in obese compared with lean WT mice and suggests that B cells may be critical regulators of T-cell functions previously shown to play important roles in IR. We demonstrate that B cells from T2D (but not non-T2D) subjects support proinflammatory T-cell function in obesity/T2D through contact-dependent mechanisms. In contrast, human monocytes increase proinflammatory T-cell cytokines in both T2D and non-T2D analyses. These data support the conclusion that B cells are critical regulators of inflammation in T2D due to their direct ability to promote proinflammatory T-cell function and secrete a proinflammatory cytokine profile. Thus, B cells are potential therapeutic targets for T2D.immunometabolism | lymphocytes M ultiple studies support the concept that inflammation strongly associates with insulin resistance (IR), which, in addition to loss of islet function, defines type 2 diabetes (T2D) (1). Work implicating B cells in IR/T2D is limited. We showed B cells from T2D subjects secrete a proinflammatory cytokine profile, including an extraordinary inability to secrete the potent anti-inflammatory cytokine IL-10 and an elevated production of proinflammatory IL-8 compared with B cells from non-T2D subjects (2). Given the importance of B-cell IL-10 in preventing numerous inflammatory diseases (3, 4) and the links between IL-8 and T2D (5, 6), these data suggest that altered B-cell cytokine production plays an important role in initiating or promoting IR/T2D. Published analyses further support a role for B cells in IR and include studies of B cell-null New Zealand Obese (NZO) mice, which, in contrast to B cell-sufficient NZOs, fail to develop IR in response to obesity (7). These findings have been recently reproduced in studies showing obese B cell-null or B cell-depleted mice have less inflammation and IR than obese WT mice (8). Interestingly, T-cell cytokine production is decreased in obese B cell-null mouse adipose tissue (AT) (8), which raises the possibility that, in addition to production of a proinflammatory cytokine profile, B cells may function in IR by regulating the T cell-mediated inflammation known to drive disease pathogenesis (9, 10). We identified a proinflammatory T-cell ratio [defined by increased Th17 cells plus decreased regulatory T cells (Tregs)] in T2D patients that mirror...

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Section: Discussionsupporting

confidence: 91%

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

DeFuria

Belkina

Jagannathan-Bogdan

et al. 2013

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

449

442

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“…Second, rituximab affects regulatory elements of B cells positive for CD20 that are implicated in innate immunity and affects Th17 cells. [28][29][30][31] Finally, preliminary observations suggest that rituximab reduces expression of soluble urokinase-type plasminogen activator receptor by monocytes (Ghiggeri, personal observation). This is of particular importance because this receptor has recently been identified as a circulating factor that plays a direct pathogenetic role in FSGS by interacting with b3 integrin.…”

Section: Discussionmentioning

confidence: 99%

Rituximab in Children with Resistant Idiopathic Nephrotic Syndrome

Magnasco

Ravani

Edefonti

et al. 2012

Journal of the American Society of Nephrology

148

112

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Idiopathic nephrotic syndrome resistant to standard treatments remains a therapeutic dilemma in pediatric nephrology. To test whether the anti-CD20 monoclonal antibody rituximab may benefit these patients, we conducted an open-label, randomized, controlled trial in 31 children with idiopathic nephrotic syndrome unresponsive to the combination of calcineurin inhibitors and prednisone. All children continued prednisone and calcineurin inhibitors at the doses prescribed before enrollment, and one treatment group received two doses of rituximab (375 mg/m 2 intravenously) as add-on therapy. The mean age was 8 years (range, 2-16 years). Rituximab did not reduce proteinuria at 3 months (change, 212% [95% confidence interval, 273% to 110%]; P=0.77 in analysis of covariance model adjusted for baseline proteinuria). Additional adjustment for previous remission and interaction terms (treatment by baseline proteinuria and treatment by previous remission) did not change the results. In conclusion, these data do not support the addition of rituximab to prednisone and calcineurin inhibitors in children with resistant idiopathic nephrotic syndrome.

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“…It is also of interest that both SMPDL-3b and ASM are expressed on Th17 (44), a cell lineage whose activation is considered a key element in the pathogenesis of nephrotic syndrome (6). Other studies also demonstrated that rituximab reduces Th17 cell response in rheumatoid arthritis (45), thus making a logical connection among rituximab, Th17, and nephrotic syndrome.…”

Section: Implications For Researchmentioning

confidence: 99%

Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children

Ravani

Bonanni²,

Rossi³

et al. 2016

Clinical Journal of the American Society of Nephrology

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Rituximab, a chimeric anti-CD20 monoclonal antibody originally licensed for lymphoma, is emerging as a novel steroid-sparing agent for idiopathic nephrotic syndrome in children. The potential use of anti-CD20 monoclonal antibodies in idiopathic nephrotic syndrome has contributed to shifting the view of podocytopathies from T cellmediated to more complex immunomediated disorders that can benefit from targeting B cells and other mediators of the early immune response. Clinical data on the use of rituximab also have implications on disease management and classification. In this review, we present results of clinical studies that support rituximab as an effective steroid-sparing agent in steroid-dependent idiopathic nephrotic syndrome. Recent randomized controlled trials suggest that potential benefits of rituximab therapy in steroid-dependent forms of idiopathic nephrotic syndrome vary depending on whether children are dependent on steroids alone or on both steroids and calcineurin inhibitors, with greater probabilities to achieve drug-free remission in the former group. Multiple-drug dependence may identify a different disease state with different prognosis and treatment options. Insufficient data are available on optimal use of rituximab as a maintenance steroid-sparing agent in these steroid-sensitive forms of the disease, including how often and for how long rituximab infusions should be repeated to maximize expected benefits and minimize potential harms. Finally, one randomized controlled trial in children with steroid-resistant idiopathic nephrotic syndrome yielded negative results. New anti-CD20 antibodies are under study in this patient population.

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The anti-CD20 antibody rituximab reduces the Th17 cell response

Cited by 162 publications

References 34 publications

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

Rituximab in Children with Resistant Idiopathic Nephrotic Syndrome

Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children

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