Jörg Seebach
"Modulation of effector functions of NK cells by human purified and recombinant immunoglobulin G"
Lecture
Intravenous immunoglobulins G (IVIG) are a second-line treatment for autoimmune diseases. However, the high demand for IVIG is not met by the limited supply of human plasma. Alternatives include engineered recombinant molecules, e.g. hexamer (HEX) composed of Fc from IgG1 fused to IgM μ-tailpiece [1]. One of the anti-inflammatory mechanisms of IVIG is blocking Fc-gamma receptors (FcγRs), therefore antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by natural killer (NK) cells.
The goals of this study were first, to assess NK cell-mediated cytotoxicity after overnight incubation with IVIG or HEX-variants, having different affinities to FcγRs. Molecules used were recombinant IgG1 Fc-monomer (recFc), non-modified HEX (HEX), HEX with low affinity to FcγRII and FcγRIII (HEXlowR2, HEXlowR3), and IVIG. Direct cytotoxicity and ADCC were assessed by non-radioactive Delfia assays using K562 or Daudi plus anti-CD20 as target cells, respectively. The second goal was to detect cytokine release by NK cells after overnight incubation with IVIG or HEX-variants by cytometric bead array.
HEX was the most potent inhibitor of ADCC (87.1% inhibition), followed by IVIG (80.2%), HEXlowR2 (73.7%), HEXlowR3 (51.2%), and recFc (20.7%). Remarkably, direct cytotoxicity was also inhibited by the tested molecules, with an inhibition mediated by IVIG > HEXlowR3 > HEX > recFc > HEXlowR2 (44.9%, 31.5%, 29.5%, 27.7%, and 23.6%, respectively). All molecules but recFc triggered the release of TNF and IFNγ by NK cells.
In conclusion, HEX inhibit NK cell effector functions and may have the potential to substitute IVIG for the treatment of auto-antibody-mediated diseases.
Reference
[1] J Immunol. 2018;200(8):2542.
In collaboration with CSL Behring AG, CSL Biologics Research Center, Bern, Switzerland
Funding: SNSF; CSL Behring, and private foundation
Biography
Jörg Dieter Seebach did his undergraduate studies, Medical School, University of Zürich, Switzerland and obtained the Swiss Federal Exams and Diploma in Medicine in 1990. After clinical training in Internal Medicine, he moved to Boston in 1995 to complete a three year Postdoctoral Research fellowship at the Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, USA. Between 1999 and 2001 he did the Clinical Fellowship in Allergology, Department of Dermatology, University Hospital Zürich. Before moving to Geneva in 2007, he was the Head of the Laboratory for Transplantation Immunology, Department of Internal Medicine, University Hospital Zurich between 1998 and 2007 while being Consultant in Internal Medicine, Medizinische Klinik, University Hospital Zürich. Since October 2007, he is the Head, Division of Immunology and Allergology, Medicine, University Hospital Geneva, and the laboratory for Translational Immunology.
15 Aug 2023