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Increased CD40 Ligation and Reduced BCR Signalling Leads to Higher IL-10 Production in B Cells From Tolerant Kidney Transplant Patients

Nova-Lamperti, Estefania PhD; Chana, Prabhjoat MS; Mobillo, Paula MD, MS; Runglall, Manohursingh MS; Kamra, Yogesh MS; McGregor, Reuben MS; Lord, Graham M. MD, PhD; Lechler, Robert I. MD, PhD; Lombardi, Giovanna PhD; Hernandez-Fuentes, Maria P. MD, PhDThe GAMBIT Study

doi: 10.1097/TP.0000000000001341
Original Basic Science—General

Background An increased percentage of peripheral transitional B cells producing IL-10 has been observed in patients tolerant to kidney allografts. In healthy volunteers, the balance between the CD40 and B-cell receptor (BCR) signalling modulated IL-10 production by B cells, with stimulation via the BCR decreasing CD40-mediated IL-10 production. In this study, we evaluate whether in tolerant kidney transplant patients, the increased IL-10 production by B cells was due to an altered CD40 and/or BCR signalling.

Methods B cells obtained from a new cohort of tolerant renal transplant recipients and those from age- and sex-matched healthy volunteers were activated via CD40 and BCR, either alone or in combination.

Results In tolerant patients, we observed higher percentages of B cells producing IL-10 after CD40 ligation and higher expression of CD40L on activated T cells compared with healthy controls. Furthermore, B cells from tolerant recipients had reduced extracellular signal-regulated kinase signalling after BCR-mediated activation compared with healthy controls. In keeping with this, combining BCR signalling with CD40 ligation did not reduce IL-10 secretion as was observed in healthy control transitional B cells.

Conclusions Altogether, our data suggest that the altered response of B cells in tolerant recipients may contribute to long-term stable graft acceptance.

Nova-Lamperti and colleagues report that compared to transitional B cells from healthy volunteers, transitional B cells from tolerant patients produce more IL-10 following CD40-ligation, exhibit reduced ERK-phosphorylation following BCR-engagement and are more resistant to BCR-mediated suppression of CD40-induced IL-10 production. Supplemental digital content is available in the text.

1 King's College London, MRC Centre for Transplantation, London, United Kingdom.

2 BRC Flow Cytometry Laboratory, Guy's Hospital, London, United Kingdom.

3 NIHR Comprehensive Biomedical Research Centre at Guy's and St Thomas' Hospital, London, United Kingdom.

4 King's Health Partners, London, United Kingdom.

Received 1 February 2016. Revision received 25 April 2016.

Accepted 15 May 2016.

EN-L was funded by a scholarship from CONICYT Bicentennial Becas-Chile, Chile. The authors acknowledge financial support from the Medical Research Council (MRC) (grants G0801537/ID: 88245 and MRC Centre for Transplantation, MRC grant no. MR/J006742/1) and Guy's and St Thomas' Charity (grants R080530 and R090782). The research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. GL, and MPH-F have received funding from the European Union, Seventh Framework Programme [FP7/2007-2013], under grant agreement no HEALTH-F5-2010-260687: The ONE Study and PM and MPHF from FP7-HEALTH-2012-INNOVATION-1 project number 305147: BIO-DrIM.

The authors declare no conflicts of interest.

E.N.-L. processed the samples used in this study, designed the experiments, performed the experiments, analyzed the data, and prepared the article. P.C. and R.M. carried out Luminex analysis. P.M., M.R., and Y.K. processed GAMBIT samples. E.N.-L., G.L., R.I.L., and M.H.-F. wrote the article. G.M.L., R.I.L., G.L., and M.H.-F. obtained funding. M.H.-F. directed the project. GAMBIT Consortium collaborators provided patient samples and detailed clinical information.

Correspondence: Maria P. Hernandez-Fuentes, MD, PhD, MRC Centre for Transplantation, 5th Floor Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom. (

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