Jeffery S Miller

Indiana Blood and Marrow Transplantation, Indianapolis, Indiana, United States

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Publications (4)22.7 Total impact

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    ABSTRACT: 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] is the biologically active form of vitamin D and is immunoregulatory. 1,25(OH)2D3 binds the vitamin D receptor complex present in many immune populations and can illicit transcriptional responses that vary among different immune subsets. The effects of 1,25(OH)2D3 on mature and developing human NK cells are not well characterized. In the present study, we examined the influence of 1,25(OH)2D3 using an established NK cell differentiation system. Briefly, umbilical cord blood CD34(+) cells were isolated and cultured in conditions optimal for NK cell differentiation, and varying concentrations of 1,25(OH)2D3 were administered. At physiological concentrations (10 nM), 1,25(OH)2D3 impaired NK cell development. Moreover, the NK cells that did develop under the influence of 1,25(OH)2D3 showed a significant reduction in function (cytotoxicity and cytokine production). Conversely, 1,25(OH)2D3 strongly induced hematopoietic stem cells to differentiate along a myeloid pathway, giving rise to CD14(+) cells. Mechanistically, 1,25(OH)2D3 drives hematopoietic progenitor cells to rapidly upregulate monocyte genes (i.e., C/EBP-α and CD14). There were no effects of 1,25(OH)2D3 on mature NK cytotoxicity or cytokine production. Collectively, these studies provide novel data showing the negative regulatory effect of 1,25(OH)2D3 on NK cell development.
    Journal of immunology (Baltimore, Md. : 1950). 08/2014;
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    ABSTRACT: Early after umbilical cord blood transplantation, patients show marked differences in bone marrow (BM) hematogone percentages. Little is known about whether these differences are clinically relevant. We hypothesized that early recovery of hematogones may be associated with improved transplantation outcomes. BM aspirates were assessed from 88 patients with acute myeloid leukemia by two independent reviewers at day 21 and 100 after umbilical cord blood transplantation. Interobserver variability for BM hematogone percentages at these time points showed correlation coefficients of 0.83 and 0.98, respectively (P ≤ .01 for both). A high percentage of hematogones at day 21 was associated with less acute graft-versus-host disease grade 3 to 4 (P = .01). At day 100, a high percentage of BM hematogones was associated with improved overall survival (P = .02) and lower treatment-related mortality (P ≤ .01). This study shows that BM hematogone percentages may be useful prognostic indicators in patients with acute myeloid leukemia after umbilical cord blood transplantation and should be routinely reported in BM differential counts.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2011; 18(6):930-6. · 3.15 Impact Factor
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    ABSTRACT: Human secondary lymphoid tissues (SLTs) contain interleukin-22 (IL-22)-producing cells with an immature NK phenotype. Given their location, these cells are difficult to study. We have generated large numbers of NK22 cells from hematopoietic stem cells. HSC-derived NK22 cells show a CD56(+)CD117(high)CD94(-) phenotype, consistent with stage III NK progenitors. Like freshly isolated SLT stage III cells, HSC-derived NK22 cells express NKp44, CD161, CCR6, IL1 receptor, AHR, and ROR-γτ. IL-1β and IL-23 stimulation results in significant IL-22 but not interferon-γ production. Supernatant from these cells increases CD54 expression on mesenchymal stem cells. Thus, IL-22-producing NK cells can be generated in the absence of SLT. HSC-derived NK22 cells will be valuable in understanding this rare NK subset and create the opportunity for human translational clinical trials.
    Blood 02/2011; 117(15):4052-5. · 9.78 Impact Factor
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    ABSTRACT: Natural killer (NK) cells can alter the outcome of hematopoietic cell transplantation (HCT) if donor alloreactivity targets the recipient. Since most NK cells express inhibitory killer-immunoglobulin receptors (KIRs), we hypothesized that the susceptibility of recipient cells to donor NK cell-mediated lysis is genetically predetermined by the absence of known KIR ligands. We analyzed data from 2062 patients undergoing unrelated donor HCT for acute myeloid leukemia (AML; n = 556), chronic myeloid leukemia (CML; n = 1224), and myelodysplastic syndrome (MDS; n = 282). Missing 1 or more KIR ligands versus the presence of all ligands protected against relapse in patients with early myeloid leukemia (relative risk [RR] = 0.54; n = 536, 95% confidence interval [CI] 0.30-0.95, P = .03). In the subset of CML patients that received a transplant beyond 1 year from diagnosis (n = 479), missing a KIR ligand independently predicted a greater risk of developing grade 3-4 acute graft-versus-host disease (GVHD; RR = 1.58, 95% CI 1.13-2.22; P = .008). These data support a genetically determined role for NK cells following unrelated HCT in myeloid leukemia.
    Blood 07/2007; 109(11):5058-61. · 9.78 Impact Factor

Publication Stats

138 Citations
22.70 Total Impact Points

Institutions

  • 2014
    • Indiana Blood and Marrow Transplantation
      Indianapolis, Indiana, United States
  • 2011
    • University of Minnesota Duluth
      • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States
  • 2007–2011
    • University of Minnesota Twin Cities
      • • Department of Pediatrics
      • • Division of Hematology, Oncology and Transplantation
      Minneapolis, MN, United States