Achievement of Tolerance Induction to Prevent Acute Graft-vs.-Host Disease

Thangavelu, Govindarajan; Blazar, Bruce R.

doi:10.3389/fimmu.2019.00309

Cited by 31 publications

(27 citation statements)

References 248 publications

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“…Thus, having few IFN-γ-producing alloreactive T cells in the host hematolymphoid compartment may be sufficient to mediate a potent GVL effect (47,48,65). Altogether, our findings significantly further our understanding of the role donor pDCs play in clinical allo-HSCT.…”

Section: Discussionsupporting

confidence: 52%

“…IFN-γ plays paradoxical roles in regulating GVH reactivity against lymphohematopoietic cells versus non-hematopoietic tissues (59)(60)(61)(62)(63). IFN-γ is known to prevent severe GVHD early after allo-HSCT in mice and repressed damage to the colon, skin and lung (47,(59)(60)(61)64). For example, donor T cell-derived IFN-γ upregulated the expression of IDO and PD-L1 in the local tissues, which in turn diminished T cell proliferation and inflammation (47,63).…”

Section: Discussionmentioning

confidence: 99%

“…However, the transfer of donor-type pDCs did not markedly decrease the frequency of IFNγ-producing alloreactive CD4 + T cells in the liver, spleen and BM ( Figure S8A-B). A substantial proportion of donor alloreactive T cells retained their ability to produce IFN-γ ( Figure 7C), a key cytokine that mediates GVL effects (47)(48)(49).…”

Section: Transfer Of Donor-type Pdcs Preserves Graft-versus-leukemia mentioning

confidence: 99%

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Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction

Tian¹,

Meng²,

Wang³

et al. 2021

Journal of Clinical Investigation

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Graft-versus-host disease (GVHD) causes failed reconstitution of donor plasmacytoid dendritic cells (pDCs) that are critical for immune protection and tolerance. We used both murine and human systems to uncover the mechanisms whereby GVHD induces donor pDC defects. GVHD depleted Flt3-expressing donor multipotent progenitors (MPPs) that sustained pDCs, leading to impaired generation of pDCs. MPP loss was associated with decreased amounts of MPP-producing hematopoietic stem cells (HSCs) and oxidative stress-induced death of proliferating MPPs. Additionally, alloreactive T cells produced GM-CSF to inhibit MPP expression of Tcf4, the transcription factor essential for pDC development, subverting MPP production of pDCs. GM-CSF did not affect the maturation of pDC precursors. Notably, enhanced recovery of donor pDCs upon adoptive transfer early after allogeneic HSC transplantation repressed GVHD and restored the de novo generation of donor pDCs in recipient mice. pDCs suppressed the proliferation and expansion of activated autologous T cells via a type-I IFN signaling-dependent mechanism. They also produced PD-L1 and LILRB4 to inhibit T cell production of IFN-γ. We thus demonstrate that GVHD impairs the reconstitution of tolerogenic donor pDCs by depleting DC progenitors rather than by preventing pDC maturation. MPPs are an important target to effectively bolster pDC reconstitution for controlling GVHD. Figure 2. GVHD causes loss of DC progenitors. (A-B) B6 TCD-BM (5 × 10 6) was transplanted with or without CD4 + T cells (5 × 10), into lethally irradiated BALB/C mice to induce GVHD. (A) Percentages and number of MPPs and CDPs in the BM from normal, TCD-BM and T cell recipients, each group contained 4 to 10 mice pooled from at least independent three experiments. (B) MPPs and CDPs were FACS-sorted from normal and GVHD mice (CD45.2 +) and cultured with feeder cells (BM from B6/SJL mice, CD45.1 +) in the presence of Flt3L+SCF. MPPs and CDPs were cultured for 9 days and 3 days, respectively. Percentages and numbers of pDCs were measured. (C-D) BM cells were obtained from HD and allo-HSCT patients. (C) Plots show pDC and cDC gating strategy. Plots show phenotypes of human CD34 + HSPCs from HD (n=12), grades 0-I GVHD patients (n=7) and grades II-IV GVHD patients (n=8), (D) Graphs show the percentages of human MPPs and CDPs from healthy donors (HD) (n=12), grades 0-I GVHD patients (n=8) and grades II-IV GVHD patients (n=9). Multiple comparisons by One-way ANOVA with Boferroni's multiple comparisons test (A), two group comparisons by unpaired t test (two-tailed) (B), and multiple comparisons by Kruskal-Wallis test with Dunne's multiple comparison test (D). Data shown are mean ± SD. Results shown in A and B are representative of three independent experiments.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Transfer Of Donor-type Pdcs Preserves Graft-versus-leukemia mentioning

confidence: 99%

See 1 more Smart Citation

Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction

Tian¹,

Meng²,

Wang³

et al. 2021

Journal of Clinical Investigation

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“…6,7 The complex and multifactorial nature of aGVHD, together with limited access to biological specimens, makes the study of the mechanisms involved in the development of human aGVHD particularly challenging. Although donor T cells are critical to the pathophysiology of acute and chronic GVHD, 3,[8][9][10] the precise mechanisms underlying their functions and the immune evasion leading to alloreactivity that occurs in allo-HCT recipients, despite immunosuppressive prophylaxis, are unclear.…”

Section: Introductionmentioning

confidence: 99%

Cellular and molecular profiling of T-cell subsets at the onset of human acute GVHD

et al. 2020

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The cellular and molecular processes involved in acute graft-versus-host disease (aGVHD) development early after allogeneic hematopoietic cell transplantation (HCT) in humans remain largely unknown. We have performed multiparameter immunophenotyping and molecular profiling of CD4+ and CD8+ T cells in 2 independent cohorts of patients undergoing HCT, as well as in their HLA-identical sibling donors. Cellular profiling using spectral flow cytometry showed an incomplete reconstitution of the T-cell compartment in recipients without aGVHD early after transplantation, as well as a shift toward an effector memory phenotype, paralleled by depletion of the naive T-cell pool. Molecular profiling of T-cell populations in donors vs recipients without aGVHD revealed increased pathway activity of >40 gene modules in recipients. These pathways were associated in particular with T-cell activation, adhesion, migration, and effector functions. Cellular profiles from recipients developing aGVHD displayed an enrichment of cells with a T memory stem cell–like phenotype compared with recipients without aGVHD. Comparison of gene profiles from these recipients revealed that transforming growth factor-β (TGF-β) signaling was most significantly downregulated, whereas the pathway activity of NF-κB–associated transcription factors and signaling pathways were increased, at aGVHD onset. This study suggests that the integration of cellular and molecular profiles provides new insights into the development of aGVHD in humans.

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“…The standard prophylactic treatments with cyclosporine, tacrolimus (FK506), and sirolimus globally target immune cells and impair their normal immune functions, which in turn results in suppressed GvHD. However, these treatments also increase the risk of leukemia relapse due to the impaired donor T cell activity [11][12][13]. Therefore, alternative and more selective therapeutic strategies are needed to suppress GvHD without affecting GvL.…”

Section: Introductionmentioning

confidence: 99%

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

Kim

Santhanam²,

Lim

et al. 2020

IJMS

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic strategy for patients with both malignant and nonmalignant disorders. The therapeutic benefits of allo-HSCT in malignant disorders are primarily derived from the graft-versus-leukemia (GvL) effect, in which T cells in the donor graft recognize and eradicate residual malignant cells. However, the same donor T cells can also recognize normal host tissues as foreign, leading to the development of graft-versus-host disease (GvHD), which is difficult to separate from GvL and is the most frequent and serious complication following allo-HSCT. Inhibition of donor T cell toxicity helps in reducing GvHD but also restricts GvL activity. Therefore, developing a novel therapeutic strategy that selectively suppresses GvHD without affecting GvL is essential. Recent studies have shown that inhibition of histone deacetylases (HDACs) not only inhibits the growth of tumor cells but also regulates the cytotoxic activity of T cells. Here, we compile the known therapeutic potential of HDAC inhibitors in preventing several stages of GvHD pathogenesis. Furthermore, we will also review the current clinical features of HDAC inhibitors in preventing and treating GvHD as well as maintaining GvL.

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Achievement of Tolerance Induction to Prevent Acute Graft-vs.-Host Disease

Cited by 31 publications

References 248 publications

Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction

Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction

Cellular and molecular profiling of T-cell subsets at the onset of human acute GVHD

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

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