Chronic kidney disease (CKD) leads to significant morbidity and mortality worldwide. Glomerulonephritis (GN) is the second leading cause of CKD resulting in end stage renal failure. The most severe and rapidly progressive type of GN is characterized by glomerular crescent formation and can cause a rapid loss of kidney function resulting in the need for dialysis.
The current therapies for crescentic GN consist of broad immunosuppressive drugs which might cause serious side effects, highlighting the need for targeted therapies. The modulation of T-lymphocytes such a therapeutic option for glomerulonephritis (GN) because these cells mediate damage in various experimental and human GN types.
Since the immune checkpoint molecule B and T-lymphocyte attenuator (BTLA) has shown its potential to restrain inflammation in other T-cell–mediated disease models, an interdisciplinary research group led by Sebastian Brähler (Clinic II of Internal Medicine and the Center for Molecular Medicine Cologne at the University of Cologne/University Hospital) report now that that BTLA is important for the control of inflammation of the kidney filtering units in a mouse model system. The data are published in the prestigious Journal of the American Society of Nephrology with following title: Stimulation of Immune Checkpoint Molecule B and T-Lymphocyte Attenuator Alleviates Experimental Crescentic Glomerulonephritis - DOI: 10.1681/ASN.0000000000000159
To investigate a differential expression of BTLA on renal immune cells during GN nephrotoxic nephritis (NTN) was induced in BTLA-deficient (BtlaKO) mice and wild-type littermates as a mouse model of crescentic GN. Disease severity was assessed by functional and histological parameters, by immunological changes assessed by flow cytometry, RNA sequencing, and in vitro assays for dendritic cell and T cell function. In addition, the potential of an agonistic anti-BTLA antibody for the treatment of NTN was investigated in vivo.
The study showed in the murine of crescentic GN, BTLA signaling effectively restrained nephritogenic Th1 cells and promoted regulatory T cells. The BtlaKO mice developed aggravated NTN, driven by an increase of infiltrating renal Th1 cells. Single-cell RNA sequencing showed increased renal T-cell activation and positive regulation of the immune response. Although BTLA-deficient regulatory T cells (Tregs) exhibited preserved suppressive function in vitro and in vivo, BtlaKO T effector cells evaded Treg suppression. Administration of an agonistic anti-BTLA antibody robustly attenuated NTN by suppressing nephritogenic T effector cells and promoting Treg expansion. Thus, BTLA signaling effectively dampens harmful Th1 cells and promotes protective regulatory T cells and the modulation of BTLA by a monoclonal antibody was found to attenuate the course of the disease.
“In this study, we demonstrate a differential expression of BTLA on renal immune cells during GN. Our findings show that the immune checkpoint molecule B and T-lymphocyte attenuator (BTLA) has great potential to restrain T-cell mediated kidney inflammation. The suppression of T-cell–mediated inflammation by BTLA stimulation may prove relevant for a broad range of conditions involving acute GN”, Sebastian Brähler - senior author of the publication.
Because of their fundamental role during T-cell activation, modulation of checkpoint proteins emerges as a promising tool to treat a variety of immune-mediated diseases.
This study was supported by Career Advancement Program of the Center for Molecular Medicine Cologne (CMMC)
Stimulation of Immune Checkpoint Molecule B and T-Lymphocyte Attenuator Alleviates Experimental Crescentic Glomerulonephritis
Paul Diefenhardt, Marie Braumann, Thomas Schömig, Bastian Trinsch, Claudio Sierra Gonzalez, Janine Becker-Gotot, Linus A Völker, Lioba Ester, Amrei M Mandel, Daniel Hawiger, Ali T Abdallah, Bernhard Schermer, Heike Göbel, Paul Brinkkötter, Christian Kurts, Thomas Benzing, Sebastian Brähler J Am Soc Nephrol 2023 Jun 27. doi: 10.1681/ASN.0000000000000159. Online ahead of print.
PD. Dr. med. Sebastian Brähler
Clinic II for Internal Medicine and Center for Molecular Medicine Cologne