Flt3L Treatment of Bone Marrow Donors Increases Graft Plasmacytoid Dendritic Cell Content and Improves Allogeneic Transplantation Outcomes

Hassan, Mojibade; Antonova, Alina Ulezko; Li, Jian Ming; Hosoba, Sakura; Rupji, Manali; Kowalski, Jeanne; Perricone, Adam; Jaye, David L.; Marsh, Henry C.; Yellin, Michael; Devine, Steven M.; Waller, Edmund K.

doi:10.1016/j.bbmt.2018.11.029

Cited by 10 publications

(17 citation statements)

References 53 publications

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“…Our studies together with others (28,30,53) suggest that Flt3L improves the ability of pDCs to prevent and treat GVHD. Clinically relevant approaches to produce adequate amounts of pDCs remain a bottleneck that limits pDC therapy feasibility for GVHD prevention and treatment.…”

Section: Discussionsupporting

confidence: 70%

“…All these results indicate that donor pDC therapy can largely preserve donor T cells' anti-leukemia activity. This is further supported by others' observations that pDC treatment does not compromise GVL effects in other mouse models of human allo-HSCT (28,53).…”

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

confidence: 77%

“…Elegant studies by Waller's group suggest that in vivo administration of Flt3L represents a promising strategy to increase the number of pDCs (53). Donor mice receiving two doses of Flt3L treatment had a 5-fold increase in pDC content without significant impact on HSCs.…”

Section: Discussionmentioning

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: 70%

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

confidence: 77%

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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“…Unrelated BM allograft with a higher content of pDCs led to improved survival in GVHD patients as compared with grafts with lower pDCs 137 . Relatively, in a MHC‐mismatched murine transplant model, recipients of Flt3L‐treated BM (containing a higher proportion of inactivated pDCs) had increased survival and decreased GVHD scores with fewer Th1 and Th17 polarised T cells post‐transplant as compared with recipients of unmanipulated BM 138 . Interestingly, in a murine model of MHC‐mismatched transplantation, the 120G8 mAb‐mediated pDC depletion from BM grafts resulted in an acceleration of GVHD mortality while the pDC depletion from G‐CSF‐mobilised splenic grafts had no effect 139 .…”

Section: Pdcs In Alloreactivitymentioning

confidence: 96%

Plasmacytoid dendritic cell biology and its role in immune‐mediated diseases

Gaugler

Mohty

et al. 2020

Clin & Trans Imm

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Plasmacytoid dendritic cells (pDCs) are a unique subset of dendritic cells specialised in secreting high levels of type I interferons. pDCs play a crucial role in antiviral immunity and have been implicated in the initiation and development of many autoimmune and inflammatory diseases. This review summarises the latest advances in recent years in several aspects of pDC biology, with special focus on pDC heterogeneity, pDC development via the lymphoid pathway, and newly identified proteins/pathways involved in pDC trafficking, nucleic acid sensing and interferon production. Finally, we also highlight the current understanding of pDC involvement in autoimmunity and alloreactivity, and opportunities for pDCtargeting therapies in these diseases. These new insights have contributed to answers to several fundamental questions remaining in pDC biology and may pave the way to successful pDC-targeting therapy in the future.

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“…In human recipients of unrelated donor BM grafts, but not granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood grafts, a higher number of donor pDCs is associated with increased survival and reduced GVHD (145). Data from experimental studies indicate that transfer of pDC-enriched BM grafts preserved GVL effects without aggravating GVHD in mice (56, 146). pDCs produce high levels of IFN-α and IL-12 (147, 148), cytokines important to promote differentiation and expansion of antigen-specific effector cells (149).…”

Section: Modulation Of Alloimmunitymentioning

confidence: 99%

Dendritic Cell Regulation of Graft-Vs.-Host Disease: Immunostimulation and Tolerance

Tian

Wang

et al. 2019

Front. Immunol.

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Graft-vs.-host disease (GVHD) remains a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Significant progresses have been made in defining the dichotomous role of dendritic cells (DCs) in the development of GVHD. Host-derived DCs are important to elicit allogeneic T cell responses, whereas certain donor-types of DCs derived from newly engrafted hematopoietic stem/progenitor cells (HSPCs) can amply this graft-vs.-host reaction. In contrast, some DCs also play non-redundant roles in mediating immune tolerance. They induce apoptotic deletion of host-reactive donor T cells while promoting expansion and function of regulatory T cells (Treg). Unfortunately, this tolerogenic effect of DCs is impaired during GVHD. Severe GVHD in patients subject to allo-HSCT is associated with significantly decreased number of circulating peripheral blood DCs during engraftment. Existing studies reveal that GVHD causes delayed reconstitution of donor DCs from engrafted HSPCs, impairs the antigen presentation function of newly generated DCs and reduces the capacity of DCs to regulate Treg. The present review will discuss the importance of DCs in alloimmunity and the mechanism underlying DC reconstitution after allo-HSCT.

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Flt3L Treatment of Bone Marrow Donors Increases Graft Plasmacytoid Dendritic Cell Content and Improves Allogeneic Transplantation Outcomes

Cited by 10 publications

References 53 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

Plasmacytoid dendritic cell biology and its role in immune‐mediated diseases

Dendritic Cell Regulation of Graft-Vs.-Host Disease: Immunostimulation and Tolerance

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