SFB 1192

Project B5

Purinergic receptors and nanobody-based treatment strategies in glomerulonephritis

The P2X7 purinergic receptor is emerging as a key regulator of inflammation. Genetic and pharmacological blockade of this ATP-gated ion channel have shown clinical benefit in rodent models of nephrotoxic nephritis. However, the precise role of P2X7 on inflammatory cells and on resident kidney cells during glomerulonephritis remain largely unknown. Our group has generated functional nanobodies (single domain antibodies) against P2X7. In the mouse model of anti-podocyte nephritis, we found that P2X7-blocking nanobodies ameliorate disease whereas P2X7-agonistic nanobodies potentiate disease. A central goal of the proposed project is to elucidate the role of P2X7 on infiltrating inflammatory cells and on resident kidney cells in nephrotoxic and anti-podocyte nephritis and to evaluate the therapeutic potential of P2X7-antagonizing nanobodies in these diseases. Antibodies directed against the podocyte membrane protein THSD7A have recently been shown to play a pathogenic role in membranous nephropathy in humans and mice. A further goal of the project is to develop therapeutic nanobodies that block the binding of pathogenic autoantibodies to THSD7A.

We expect that the results of our project will shed new light on the role of P2X7 on infiltrating inflammatory and on resident kidney cells. Moreover, the results will help pave the way for new, nanobody-based therapeutics of glomerulonephritis.

Linden, Koch-Nolte, Dahl. 2019. Purine Release, Metabolism and Signaling in the Inflammatory Response. Ann. Rev. Immunol. 13:17.

Publications

  • Purine Release, Metabolism, and Signaling in the Inflammatory Response.

    Linden J, Koch-Nolte F, Dahl G.Annu Rev Immunol. 2019 Jan

  • T RM maintenance is regulated by tissue damage via P2RX7.

    Stark R, Wesselink TH, Behr FM, Kragten NAM, Arens R, Koch-Nolte F, van Gisbergen KPJM, van Lier RAW.Sci Immunol. 2018 Dec

  • CD38-Specific Biparatopic Heavy Chain Antibodies Display Potent Complement-Dependent Cytotoxicity Against Multiple Myeloma Cells.

    Schütze K, Petry K, Hambach J, Schuster N, Fumey W, Schriewer L, Röckendorf J, Menzel S, Albrecht B, Haag F, Stortelers C, Bannas P, Koch-Nolte F.Front Immunol. 2018 Nov

  • Monitoring the Sensitivity of T Cell Populations Towards NAD+ Released During Cell Preparation.

    Rissiek B, Lukowiak M, Haag F, Magnus T, Koch-Nolte F.Methods Mol Biol. 2018 Aug

  • Modulating ion channel function with antibodies and nanobodies.

    Stortelers C, Pinto-Espinoza C, Van Hoorick D, Koch-Nolte F.Curr Opin Immunol. 2018 Jun

  • The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy.

    Seifert L, Hoxha E, Eichhoff AM, Zahner G, Dehde S, Reinhard L, Koch-Nolte F, Stahl RAK, Tomas NMJ Am Soc Nephrol. 2018 May

  • Nanobody-Based Biologics for Modulating Purinergic Signaling in Inflammation and Immunity.

    Menzel S, Schwarz N, Haag F, Koch-Nolte F.Front Pharmacol. 2018 Mar

  • A Heterologous Model of Thrombospondin Type 1 Domain-Containing 7A-Associated Membranous Nephropathy

    Tomas N, Meyer-Schwesinger C, von Spiegel H, Kotb A, Zahner G, Hoxha E, Helmchen U, Endlich N, Koch-Nolte F, Stahl R J Am Soc Nephrol. 2017 Nov

  • Nanobodies that block gating of the P2X7 ion channel ameliorate inflammation. 

    Danquah W, Meyer-Schwesinger C, Rissiek B, Pinto C, Serracant-Prat A, Amadi M, Iacenda D, Knop JH, Hammel A, Bergmann P, Schwarz N, Assunção J, Rotthier W, Haag F, Tolosa E, Bannas P, Boué-Grabot E, Magnus T, Laeremans T, Stortelers C, Koch-Nolte FSci Transl Med. 2016 Nov

  • Autoantibodies against thrombospondin type 1 domain-containing 7A induce membranous nephropathy. 

    Tomas NM, Hoxha E, Reinicke AT, Fester L, Helmchen U, Gerth J, Bachmann F, Budde K, Koch-Nolte F, Zahner G, Rune G, Lambeau G, Meyer-Schwesinger C, Stahl RA.J Clin Invest. 2016 Jul

III. Medizinische Klinik und Poliklinik
Universitätsklinikum Hamburg-Eppendorf

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