Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial

Banham, Gemma D.; Flint, Shaun; Torpey, Nicholas; Lyons, Paul; Shanahan, Don N; Gibson, Adele; Watson, Christopher J.; O'Sullivan, Ann-Marie; Chadwick, Joseph A; Foster, Katie; Jones, Rachel; Devey, Luke; Richards, Anna; Erwig, Lars-Peter; Savage, Caroline O.S.; Smith, Kenneth G. C.; Henderson, Robert B.; Clatworthy, Menna R.

doi:10.1016/s0140-6736(18)30984-x

Cited by 79 publications

(51 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A high serum concentration of the B‐cell survival factor, BAFF, in kidney transplant recipients is associated with the development of de novo and increased preformed DSA levels, and increased ABMR rates [80,81]. Administration of belimumab, an anti‐BAFF mAb, to kidney transplant recipients, led to an increase in the B‐cell IL‐10 to IL‐6 ratio for the first 3 months post‐transplant [82]. Despite a decrease in the frequency of transitional B cells, the belimumab group demonstrated a skewing of the IL‐10 to IL‐6 ratio in transitional and memory B‐cell subsets, towards a more regulatory profile compared with controls.…”

Section: Introductionmentioning

confidence: 99%

Regulatory B cells in transplantation: roadmaps to clinic

et al. 2020

View full text Add to dashboard Cite

Over the last two decades, an additional and important role for B cells has been established in immune regulation. Preclinical studies demonstrate that regulatory B cells (Breg) can prolong allograft survival in animal models and induce regulatory T cells. Operationally tolerant human kidney transplant recipients demonstrate B-cell-associated gene signatures of immune tolerance, and novel therapeutic agents can induce Bregs in phase I clinical trials in transplantation. Our rapidly expanding appreciation of this novel B-cell subtype has made the road to clinical application a reality. Here, we outline several translational pathways by which Bregs could soon be introduced to the transplant clinic.

show abstract

Section: Introductionmentioning

confidence: 99%

Regulatory B cells in transplantation: roadmaps to clinic

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Further clinical trials with anti-BAFF-Ab are ongoing in various autoimmune disease. 38,39 In conclusion, the current study revealed that serum BAFF level is associated with disease activity in DM patients with anti-MDA5-Ab. Furthermore, serum BAFF could be considered a potential target for DM patients with anti-MDA5-Ab.…”

Section: Serum Baff Levels (Ng/ml)mentioning

confidence: 53%

“…Serum BAFF level has shown to be associated with high disease activity, including anti‐dsDNA‐Ab and low complement, rather than specific organ damage in SLE patients, although serum BAFF level is associated with ILD with DM patients in the current study. Further clinical trials with anti‐BAFF‐Ab are ongoing in various autoimmune disease …”

Section: Discussionmentioning

confidence: 99%

Elevated serum B‐cell activating factor levels in patients with dermatomyositis: Association with interstitial lung disease

Matsushita

Kobayashi

Kano

et al. 2019

The Journal of Dermatology

View full text Add to dashboard Cite

Patients with dermatomyositis (DM) frequently have myositis‐specific autoantibodies (MSA), which are closely associated with different clinical features. Patients with anti‐aminoacyl‐tRNA synthetase antibody (ARS‐Ab) and anti‐melanoma differentiation‐associated gene 5 (MDA5)‐Ab often have interstitial lung disease (ILD). Recently, anti‐MDA5‐Ab levels have been shown to correlate with disease activity in DM patients. Thus, B cells that are stimulated by excess B‐cell activating factor (BAFF) play an important role in the pathogenesis of DM through auto‐Ab production. In this study, we investigated the role of BAFF in DM patients. We measured the serum BAFF levels in 56 adult DM patients (14 with anti‐ARS‐Ab, 18 with anti‐MDA5‐Ab, seven with anti‐Mi‐2‐Ab and 17 with anti‐transcriptional intermediary factor‐1γ‐Ab) . For a longitudinal study, 130 serum specimens from 10 DM patients with anti‐MDA5‐Ab were analyzed. Serum BAFF levels were significantly higher in DM patients than in healthy controls. DM patients with elevated serum BAFF levels more frequently had ILD. In subgroup analysis, DM patients with anti‐ARS‐Ab and DM patients with anti‐MDA5‐Ab exhibited increased BAFF levels compared with controls, while DM patients with other MSA showed BAFF levels comparable with controls. In the longitudinal study, serum BAFF levels in DM patients with anti‐MDA5‐Ab were decreased after immunosuppressive therapy along with serum levels of anti‐MDA5‐Ab and ferritin, which are biomarkers of disease activity. These results suggest that BAFF plays an important role in the pathogenesis of ILD in DM patients with anti‐ARS and anti‐MDA5‐Ab. Furthermore, serum BAFF level is associated with disease activity in DM patients with anti‐MDA5‐Ab.

show abstract

“…This population was associated before and after transplant with anti-HLA DSA development within the first year after transplant (23,24). In addition, belimumab, an anti-B lymphocyte stimulator (BLyS) antibody, associated at the time of transplant with standard transplant immunosuppression, decreased significantly naïve B-cells 24 weeks after transplant and de-novo IgG antibody formation (25). High dose IVIG could via the decrease of naïve B-cells (Bm2) limits de-novo IgG DSA formation.…”

Section: Discussionmentioning

confidence: 99%

“…Lower proportion of memory B cell before transplant, has been associated with high immunization levels (24) while higher proportion of memory B cell after transplant, has been described in operationally tolerant patients (no DSA and no immunosuppressive treatment) (26). In addition, in patients treated with belimumab proportion of memory B cell increased throughout the treatment with lower de-novo DSA (25). Whether increasing memory B-cell could decrease anti-HLA DSA production in our patients with immunomodulatory effects should be analyzed further.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and Transcriptomic Lymphocytes Changes in Allograft Recipients After Intravenous Immunoglobulin Therapy in Kidney Transplant Recipients

et al. 2020

View full text Add to dashboard Cite

High dose intravenous immunoglobulin (IVIG) are widely used after kidney transplantation and its biological effect on T and B cell phenotype in the context of maintenance immunosuppression was not documented yet. We designed a monocentric prospective cohort study of kidney allograft recipients with anti-HLA donor specific antibodies (DSA) without acute rejection on screening biopsies treated with prophylactic high-dose IVIG (2 g/kg) monthly for 2 months. Any previous treatment with Rituximab was an exclusion criterion. We performed an extensive analysis of phenotypic and transcriptomic T and B lymphocytes changes and serum cytokines after treatment (day 60). Twelve kidney transplant recipients who completed at least two courses of high-dose IVIG (2 g/kg) were included in a median time of 45 (12-132) months after transplant. Anti-HLA DSA characteristics were similar before and after treatment. At D60, PBMC population distribution was similar to the day before the first infusion. CD8 + CD45RA + T cells and naïve B-cells (Bm2 +) decreased (P = 0.03 and P = 0.012, respectively) whereas Bm1 (mature B-cells) increased (P = 0.004). RORγt serum mRNA transcription factor and CD3 serum mRNA increased 60 days after IVIG (P = 0.02 for both). Among the 25 cytokines tested, only IL-18 serum concentration significantly decreased at D60 (P = 0.03). In conclusion, high dose IVIG induced limited B cell and T cell phenotype modifications that could lead to anti-HLA DSA decrease. However, no clinical effect has been isolated and the real benefit of prophylactic use of IVIG after kidney transplantation merits to be questioned.

show abstract

Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial

Abstract: GlaxoSmithKline.

Cited by 79 publications

References 43 publications

Regulatory B cells in transplantation: roadmaps to clinic

Regulatory B cells in transplantation: roadmaps to clinic

Elevated serum B‐cell activating factor levels in patients with dermatomyositis: Association with interstitial lung disease

Phenotypic and Transcriptomic Lymphocytes Changes in Allograft Recipients After Intravenous Immunoglobulin Therapy in Kidney Transplant Recipients

Contact Info

Product

Resources

About