About this item:

619 Views | 400 Downloads

Author Notes:

Corresponding author: Edmund K. Waller, M.D., Ph.D., 1365C Clifton Road NE, Room C4002, Winship Cancer Institute, Emory University Medical School, Atlanta, GA30322, ewaller@emory.edu., Phone: 404-727-4995, Fax: 404-778-5530

Acknowledgments: We thank Drs. James C. Zimring and Robert Mittler for their careful reading of the manuscript and helpful comments.

Disclosures: E.K.W. has nonlicensed patents in China and Australia that describe the potential clinical utility of manipulating the DC content of hemopoietic progenitor cell allografts.

The other authors declare no competing financial interests.

Subject:

Research Funding:

This work was supported by National Institute of Health Grants R01 CA-74364-03 (to E.K.W.) and NHLBI P01Hl086773 (to C.D.H. and E.K.W.) and an Amy Strelzer Manasevit fellowship sponsored by the National Marrow Donor Program and the SuperGen Corporation and a research fund from When Everyone Survives Foundation, Inc. (J.-M.L.).

Keywords:

  • Antigen presenting cells
  • Dendritic Cells
  • T-cells
  • Graft versus Host Disease
  • Cell Activity
  • Tumor Immunity

Activation, Immune Polarization, and Graft-versus-Leukemia Activity of Donor T-cells are Regulated by Specific Subsets of Donor Bone Marrow Antigen-Presenting Cells in Allogeneic Hematopoietic Stem Cell Transplantation

Tools:

Journal Title:

Journal of Immunological Methods

Volume:

Volume 183, Number 12

Publisher:

, Pages 7799-7809

Type of Work:

Article | Post-print: After Peer Review

Abstract:

We investigated the roles of specific subsets of donor APCs purified from bone marrow in donor T cell activation and graft-vs-leukemia (GvL) activity in murine models of hemopoietic stem cell transplantation. Lineage−CD11c+ APC precursors were separated from donor bone marrow based on expression of CD11b. Transplanting lineage−CD11c+CD11b− APC (CD11b− APC) in combination with c-kit+Sca-1+lineage− hemopoietic stem cells (HSC) and congenic donor T cells led to increased donor CD4+ and CD8+ T cell proliferation and higher donor T cell chimerism than with transplanting grafts containing HSC, T cells, and lineage−CD11c+CD11b+ APCs (CD11b+ APC), or grafts containing only HSC and T cells. Transplanting CD11b− APCs induced Th1/type 1 cytotoxic T lymphocyte donor T cell immune polarization and enhanced GvL activity of donor T cells without increased graft-vs-host disease in both MHC- and minor histocompatibility Ag-mismatched murine hemopoietic stem cell transplantation models, whereas CD11b+ APCs led to Th2/type 2 cytotoxic T lymphocyte donor T cell immune polarization. Donor CD11b− APCs were plasmacytoid dendritic cell progenitors (>90% CD317; PDCA-1+) and up-regulated CD80, CD86, and IL-12 during alloantigen presentation, whereas CD11b+ APCs expressed Gr-1 and up-regulated expression of programmed death ligands-1 and 2 after activation. These results are the first to show that manipulation of the content of donor APCs in allogeneic HSC grafts can regulate donor T cell immunity and enhance GvL without increasing graft-vs-host disease activity.

Copyright information:

© 2009 by The American Association of Immunologists, Inc.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Creative Commons License

Export to EndNote