Deciphering the HVEM/BTLA pathway’s role in immune-mediated kidney diseases
Final Report Abstract
Inflammatory diseases of the glomerulus (glomerulonephritis, GN), the kidney filtering apparatus, are among the leading causes of end-stage renal disease and comprise a rather heterogeneous group of disorders. While different mechanisms cause the development of the disease all forms of glomerulonephritis result in the destruction of the glomerulus which ultimately results in the loss of renal function and ultimately the need for dialysis treatment. Therefore, glomerulonephritis causes loss of quality of life and significant mortality for patients, along with high costs for the health system. Thus, the identification of new therapeutic targets is crucial for the development of new treatment strategies for our patients. T-cells play a central role in the development of the disease. BTLA (B and T lymphocyte attenuator) is checkpoint protein and a central regulator of the magnitude of the T-cell based immune response making it an interesting new structure for the treatment of GN. The aim of this project was to define the role of BTLA in the development of GN and to evaluate its role as a therapeutic target. We used an established mouse-model of immune-complex mediated glomerulonephritis (nephrotoxic nephritis, NTN) in Btla-deficient (BtlaKO) mice and littermate controls. BtlaKO mice developed aggravated NTN, driven by an increase of infiltrating renal Th1 cells, a subset of proinflammatory T-cells. A comprehensive single-cell gene-expression analysis (single cell RNA sequencing) revealed an increase in T-cell activation and positive regulation of the immune response. Anti-inflammatory T-regulatory cells (Tregs) exhibited a preserved suppressive function in vitro and in vivo. However, BtlaKO T effector cells could escape Treg-mediated suppression. To demonstrate that BTLA is a potential therapeutic target, we stimulated BTLA by injecting an agonistic antibody during glomerulonephritis. The treated mice showed a robust amelioration of the disease with reduced loss of protein into the urine and improved kidney function. Anti-BTLA treatment was able to suppress infiltration of T effector cells and increased T-regulatory cell numbers. In conclusion, BTLA signaling effectively restrains glomerulonephritis by inhibiting harmful Th1 cells and promoting anti-inflammatory regulatory T cells in our disease model. We plan future studies to better pinpoint the mechanisms involved in this and to investigate the relevance of this mechanism for other kidney diseases.
Publications
-
The Atypical Cyclin-Dependent Kinase 5 (Cdk5) Guards Podocytes from Apoptosis in Glomerular Disease While Being Dispensable for Podocyte Development. Cells, 10(9), 2464.
Mangold, Nicole; Pippin, Jeffrey; Unnersjoe-Jess, David; Koehler, Sybille; Shankland, Stuart; Brähler, Sebastian; Schermer, Bernhard; Benzing, Thomas; Brinkkoetter, Paul T. & Hagmann, Henning
-
Super-Resolution Imaging of the Filtration Barrier Suggests a Role for Podocin R229Q in Genetic Predisposition to Glomerular Disease. Journal of the American Society of Nephrology, 33(1), 138-154.
Butt, Linus; Unnersjö-Jess, David; Höhne, Martin; Hahnfeldt, Robert; Reilly, Dervla; Rinschen, Markus M.; Plagmann, Ingo; Diefenhardt, Paul; Brähler, Sebastian; Brinkkötter, Paul T.; Brismar, Hjalmar; Blom, Hans; Schermer, Bernhard & Benzing, Thomas
-
Stimulation of Immune Checkpoint Molecule B and T-Lymphocyte Attenuator Alleviates Experimental Crescentic Glomerulonephritis. Journal of the American Society of Nephrology, 34(8), 1366-1380.
Diefenhardt, Paul; Braumann, Marie; Schömig, Thomas; Trinsch, Bastian; Sierra, Gonzalez Claudio; Becker-Gotot, Janine; Völker, Linus A.; Ester, Lioba; Mandel, Amrei M.; Hawiger, Daniel; Abdallah, Ali T.; Schermer, Bernhard; Göbel, Heike; Brinkkötter, Paul; Kurts, Christian; Benzing, Thomas & Brähler, Sebastian
