2. Academic Validation
  3. Generation of human ILC3 from allogeneic and autologous CD34+ hematopoietic progenitors toward adoptive transfer

Generation of human ILC3 from allogeneic and autologous CD34+ hematopoietic progenitors toward adoptive transfer

  • Cytotherapy. 2023 Dec 25:S1465-3249(23)01126-X. doi: 10.1016/j.jcyt.2023.11.011.
Jolien M R Van der Meer 1,  Ingrid Bulder 2,  Carlijn Kuijk 1,  Marion Kleijer 1,  Myrddin W Verheij 2,  Said Z Omar 3,  Nienke J E Haverkate 3,  Harry Dolstra 4,  Bianca Blom 3,  Mette D Hazenberg 5,  Carlijn Voermans 6
Affiliations

Affiliations

  • 1 Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands.
  • 2 Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands; Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands.
  • 3 Department of Experimental Immunology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, The Netherlands.
  • 4 Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 5 Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands; Department of Experimental Immunology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Hematology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
  • 6 Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands; Department of Hematology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Electronic address: c.voermans@sanquin.nl.
PMID: 38149947 DOI: 10.1016/j.jcyt.2023.11.011
Abstract

Type 3 innate lymphoid cells (ILC3) are important in tissue homeostasis. In the gut, ILC3 repair damaged epithelium and suppress inflammation. In allogeneic hematopoietic cell transplantation (HCT), ILC3 protect against graft-versus-host disease (GvHD), most likely by restoring tissue damage and preventing inflammation. We hypothesize that supplementing HCT grafts with interleukin-22 (IL-22)-producing ILC3 may prevent acute GvHD. We therefore explored ex vivo generation of human IL-22-producing ILC3 from hematopoietic stem and progenitor cells (HSPC) obtained from adult, neonatal and fetal sources. We established a stroma-free system culturing human cord blood-derived CD34+ HSPC with successive cytokine mixes for 5 weeks. We analyzed the presence of phenotypically defined ILC, their viability, proliferation and IL-22 production (after stimulation) by flow cytometry and enzyme-linked immunosorbent assay (ELISA). We found that the addition of recombinant human IL-15 and the enhancer of zeste homolog 1/2 inhibitor UNC1999 promoted ILC3 generation. Similar results were demonstrated when UNC1999 was added to CD34+ HSPC derived from healthy adult granulocyte colony-stimulating factor mobilized peripheral blood and bone marrow, but not fetal liver. UNC1999 did not negatively impact IL-22 production in any of the HSPC sources. Finally, we observed that autologous HSPC mobilized from the blood of adults with hematological malignancies also developed into ILC3, albeit with a significantly lower capacity. Together, we developed a stroma-free protocol to generate large quantities of IL-22-producing ILC3 from healthy adult human HSPC that can be applied for adoptive transfer to prevent GvHD after allogeneic HCT.

Keywords

adoptive transfer; hematopoietic stem and progenitor cells; human; interleukin-22; stroma-free; type 3 innate lymphoid cells.

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