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TLR agonists regulate alloresponses and uncover a critical role for donor APCs in allogeneic bone marrow rejection

Patricia A Taylor1, Michael J Ehrhardt, Christopher J Lees

  • 1Cancer Center and the Department of Pediatrics, Division of BMT, University of Minnesota, Minneapolis, USA.

Blood
|July 11, 2008
PubMed

Insights

Cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG ODNs) accelerate graft-versus-host disease (GVHD) by activating host Toll-like receptor 9 (TLR9). CpG ODNs also promote bone marrow graft rejection via donor TLR9, highlighting donor APCs

Area of Science:

  • Immunology
  • Transplantation immunology

Background:

  • Cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG ODNs) mimic microbial DNA and stimulate immune responses via Toll-like receptor 9 (TLR9).
  • CpG ODNs are investigated for their potential in immunotherapy and as vaccine adjuvants.
  • Graft-versus-host disease (GVHD) and bone marrow (BM) graft rejection are critical challenges in transplantation.

Purpose of the Study:

  • To elucidate the mechanisms by which CpG ODNs influence GVHD lethality and allogeneic BM rejection.
  • To investigate the differential roles of host and donor antigen-presenting cells (APCs) in CpG ODN-mediated immune responses.
  • To identify key molecular pathways and cellular players involved in CpG ODN-modulated alloresponses.

Main Methods:

  • In vivo studies using murine models of GVHD and BM transplantation.
  • Administration of CpG ODNs and assessment of lethality, immune cell infiltration, and graft rejection.
  • Utilizing knockout mouse models (TLR9-/-, B7-1/B7-2-/-) and specific cell lineage depletions.
  • Flow cytometry and imaging techniques to track immune cell populations and distribution.

Main Results:

  • CpG ODNs significantly accelerated GVHD lethality, dependent on host IFN-gamma but independent of IL-12, IL-6, or NK cells.
  • CpG ODNs promoted allogeneic BM rejection independently of host IFN-gamma, IL-12, or IL-6.
  • CpG ODNs induced BM rejection primarily through ligation of donor BM TLR9, not host TLR9.
  • Donor myeloid APCs, but not B-lineage cells, were critical for CpG ODN-mediated BM rejection, with B7-1/B7-2 expression on donor BM APCs enhancing rejection.

Conclusions:

  • CpG ODNs exacerbate GVHD by activating host TLR9 on APCs, with IFN-gamma being a key mediator.
  • CpG ODNs promote allogeneic BM rejection via donor TLR9 ligation, critically involving donor myeloid APCs.
  • Donor BM APCs play a pivotal role in modulating the host anti-donor immune response to CpG ODN treatment.
  • These findings reveal novel mechanisms of alloresponses and have implications for managing transplantation outcomes.

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