REFRACT – Refractory lupus nephritis: a tissue-based pathophysiological approach

Concept

Lupus nephritis (LN) remains a severe complication of SLE, impacting long-term survival and quality of life.

In REFRACT, we use kidney biopsies from LN patients in order to study molecular and cellular mechanisms underlying LN refractory disease.

One of the hypotheses to explain resistance to therapy is that the kidney itself is not only a target for autoantibodies but also acts as a true lymphoid organ that hosts immunologically relevant processes resulting in further local adaptive immune cell activation and differentiation.

Facts and figures

Project lead
B Lauwerys
Cliniques Universitaires Saint-Luc
Bernard.Lauwerys@uclouvain.be
FOREUM research grant: € 298.860
2016 - 2019

Meet the team

B Lauwerys
Cliniques Universitaires Saint-Luc
M Mahévas
Université Paris-Descartes
R van Vollenhoven
Karolinska Institutet
D Jayne
University of Cambridge
R Cervera
Fundacio Clinic per a la Recerca Biomedica Barcelona
P Remy
Université Paris-Est
D Mazzoni
Lupus Europe

Patient voice

We have involved Lupus Europe in the process as a patient partner organisation.

Interim results

Our initial results, obtained in two independent sets of LN kidney biopsies, confirmed our hypothesis that intrarenal activation of adaptive immune effectors is associated with tubular damage and decreased renal function in LN (1).

Single cell gene expression profiling of (CD3-CD14-CD16-CD27+ CD38high) plasma cells (PC) was performed using kidney biopsies and blood from patients with a flare of class III/IV LN treated or not with mycophenolate mofetil (MMF). We obtained single kidney plasma cells that we compared with long-lived plasma cells from the bone marrow of heathy donors. In untreated patients, most PC were plasmablasts expressing multiple genes involved in cell division. By contrast, PC from the kidney of MMF-treated patients were over-expressing multiple plasmacell specific genes while not harboring a proliferative profile.

Similarly, single cell RNASeq and clonal expansion of CD8 T cells from kidney, urine and blood from patients with a severe flare of class III/IV LN showed the presence of clonally expanded CD8 T cells with an activated phenotype. One of these clones displayed cytotoxic properties against cultured renal tubular cells that were abrogated after targeted deletion of the T Cell Receptor.

Conclusions

These very encouraging results showed the presence in the lupus kidney of adaptive immune cells with a differentiated and effector phenotype, associated with more severe and refractory disease.

Publications

Pamfil C, Makowska Z, De Groof A, et al. Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis. Annals of the Rheumatic Diseases Published Online First: 31 July 2018. doi: 10.1136/annrheumdis-2018-213485
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