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Immunomodulatory effects of MSCs to Aid Transplantation?

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Alterations in the Cellular Immune Compartment of Patients Treated with Third-Party Mesenchymal Stromal Cells Following Allogeneic Hematopoietic Stem Cell Transplantation

From Stem Cells

Allogeneic hematopoietic stem cell transplantation is often complicated by graft-versus-host disease (GVHD) mediated by the donors immune cells (Ferrara et al) and novel intervention strategies are highly sought after.   Mesenchymal stem cells (MSCs) are known to have immunoregulatory properties and have been applied in clinical trials (Le Blanc et al), although few reports have shed light on the effects of MSCs on the patient's immune system (Dander et al).   Now, in a study published in Stem Cells, researchers from the laboratory of Katarina Le Blanc at the Karolinska University Hospital, Stockholm, Sweden have investigated the alterations in the immune system caused by third-party (i.e. from an unrelated source) MSC treatment to aid in the design of future clinical studies and to establish novel monitoring procedures (Jitschin and Mougiakakos et al).

Patients with GVHD who received a single infusion of third-party MSCs were compared to placebo-treated GVHD patients by assessing early humoral alterations (at 7 and 30 days after MSC infusion) and cellular parameters at later stages (30, 90 and 180 days after MSC infusion).   This wide-ranging “immunome”-analysis found MSC treatment to have a response which was generally associated with a reduction in GVHD.   The authors found a significant decline in the cleaved and uncleaved forms of K18 (indicators of epithelial cell death and validated biomarkers for acute GVHD [Luft et al.) in the MSC-treated group, but not the placebo group, possibly reflecting the biological activity of the MSCs.   T-cells, the main mediators of GVH immune reactions, were then analysed which revealed a lower proportion of HLA-DR+ CD4+ and CD8+ T-cells upon MSC treatment, representing a decrease in the late T-cell response. Levels of IFN-γ and IL-4, assessed as prototypic T-Helper 1 (TH1) and T-Helper 2 (TH2) cytokines, found a greater TH2-mediated response to MSCs and, as GVHD is considered to be a TH1-driven disease (Ferrara et al), this finding suggests that MSCs may be useful for its treatment.   MSC patients also had a significantly higher CD4+/CD8+ T-cell ratio, although this declined to placebo levels by Day 180, while there was a trend toward a reduced thymic output of CD4+ T-cells in MSC-treated patients.

IL-7 and IL-15, which modulate T-cell homeostasis, are elevated in GVHD but did not correlate with observed T-cell frequency, which indicates that they were not the primary promoters of homeostatic T-cell proliferation. These cytokines may lead to the accumulation of T effector memory RA (TEMRA) CD8+ cells observed at day 180 which have been associated with the development of chronic GVHD after allo-haematopoietic stem cell transplantation (D'Asaro et al).   One obviously altered cytokine was IL-2, which mediates Regulatory T cell (Treg cell) homeostasis.   After MSC treatment, IL-2 increased at each time points assayed and was correlated to an increase in CD4+CD25med-hiCD127lo Treg-cells, which is associated with a reduction in GVHD (Koreth et al) and an increase in Tr1-cell, which control GVHD by promoting long-term tolerance (Andolfi et al).   Pro-inflammatory TH17-cells were decreased upon MSC treatment, and promoted their reprogramming to Treg-cells, as preciously observed (Le Blanc et al).   Myelopoiesis analysis after MSC treatment found that both myeloid dendritic cells and plasmacytoid dendritic cells tended to be elevated in MSC-treated patients, with low numbers being associated with increased risk of disease relapse and acute GVHD (Reddy et al) while monocyte number did not change. Lastly, natural killer (NK) cells are positively involved in the control of GVHD (Leveson-Gower et al), but MSC treated patients had a tendency for lower levels of NK cells and activated CD56bright NK-cells, while no differences in B-cell responses were observed.

The authors note that while some of these differences are in line with previous analysis from other groups and show a beneficial role for third-party MSCs, the data presented must be interpreted with caution because of the small cohorts included in the trial.   However, its strengths; being a randomized, placebo-controlled single-centre study with all patients treated similarly regarding supportive care and basic immunosuppression (Ringden et al), do make this an attractive study.   Overall, the induction of Treg-cells reduced TH17-cell numbers and a shift toward TH2-cell responses in response to MSC treatment confirms MSCs tolerogenic function, while the further examination of the role of IL-2 could uncover further details behind the response.

 

References

  • Andolfi G et al. Enforced IL-10 expression confers type 1 regulatory T cell (Tr1) phenotype and function to human CD4(+) T Cells. Mol Ther 2012; 20: 1778–1790
  • Dander E et al. Mesenchymal stromal cells for the treatment of graft-versus-host disease: understanding the in vivo biological effect through patient immune monitoring. Leukemia 2012; 26: 1681–1684
  • D'Asaro M et al. Increase of CCR7-CD45RA+ CD8 T cells (T(EMRA)) in chronic graft-versus-host disease. Leukemia 2006; 20: 545–547
  • Ferrara JL et al. Graft-versus-host disease. Lancet 2009; 373: 1550–1561
  • Koreth J et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 2011; 365: 2055–2066
  • Le Blanc K et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371: 1579–1586
  • Leveson-Gower DB et al. Low doses of natural killer T cells provide protection from acute graft-versus-host disease via an IL-4-dependent mechanism. Blood 2011; 117: 3220–3229
  • Luft T et al. Steroid-refractory GVHD: T-cell attack within a vulnerable endothelial system. Blood 2011; 118: 1685–1692
  • Reddy Vet al. Low dendritic cell count after allogeneic hematopoietic stem cell transplantation predicts relapse, death, and acute graft-versus-host disease. Blood 2004; 103: 4330–4335
  • Ringden O et al. Similar incidence of graft-versus-host disease using HLA-A, -B and -DR identical unrelated bone marrow donors as with HLA-identical siblings. Bone Marrow Transplant 1995; 15: 619–625

From Stem Cells.

Stem Cell Correspondent Stuart P Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.