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"Smith, Kent A"
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Antigen kinetics determines immune reactivity
A current paradigm in immunology is that the strength of T cell responses is governed by antigen dose, localization, and costimulatory signals. This study investigates the influence of antigen kinetics on CD8 T cell responses in mice. A fixed cumulative antigen dose was administered by different schedules to produce distinct dose-kinetics. Antigenic stimulation increasing exponentially over days was a stronger stimulus for CD8 T cells and antiviral immunity than a single dose or multiple dosing with daily equal doses. The same was observed for dendritic cell vaccination, with regard to T cell and anti-tumor responses, and for T cells stimulated in vitro. In conclusion, stimulation kinetics per se was shown to be a separate parameter of immunogenicity. These findings warrant a revision of current immunization models and have implications for vaccine development and immunotherapy.
Journal Article
Programmed cell death-1 (PD-1) at the heart of heterologous prime-boost vaccines and regulation of CD8+ T cell immunity
Developing new vaccination strategies and optimizing current vaccines through heterologous prime-boost carries the promise of integrating the benefits of different yet synergistic vectors. It has been widely thought that the increased immunity afforded by heterologous prime-boost vaccination is mainly due to the minimization of immune responses to the carrier vectors, which allows a progressive build up of immunity against defined epitopes and the subsequent induction of broader immune responses against pathogens. Focusing on CD8
+
T cells, we put forward a different yet complementary hypothesis based primarily on the systematic analysis of DNA vaccines as priming agents. This hypothesis relies on the finding that during the initiation of immune response, acquisition of co-inhibitory receptors such as programmed cell death-1 (PD-1) is determined by the pattern of antigen exposure in conjunction with Toll-like receptor (TLR)-dependent stimulation, critically affecting the magnitude and profile of secondary immunity. This hypothesis, based upon the acquisition and co-regulation of pivotal inhibitory receptors by CD8
+
T cells, offers a rationale for gene-based immunization as an effective priming strategy and, in addition, outlines a new dimension to immune homeostasis during immune reaction to pathogens. Finally, this model implies that new and optimized immunization approaches for cancer and certain viral infections must induce highly efficacious T cells, refractory to a broad range of immune-inhibiting mechanisms, rather than solely or primarily focusing on the generation of large pools of vaccine-specific lymphocytes.
Journal Article
Repositioning therapeutic cancer vaccines in the dawning era of potent immune interventions
Based on lessons learned with various immune interventions, this review aims to provide a constructive framework for repositioning therapeutic cancer vaccination. Intensive research throughout the past decade has identified key hurdles interfering with the efficacy of cancer vaccines. The vaccination concept still holds promise if positioned appropriately in minimal residual disease and select early disease stage cancer indications. However, in advanced cancer, it must be integrated with complementary immune interventions to ensure reconstruction of a functional immune repertoire and simultaneous blockade of immune inhibiting mechanisms. Vaccination could render complex and integrative immune interventions simpler, safer and more effective. The near future will witness an explosion of activities in the cancer immunotherapy arena, witnessing a rational repositioning of vaccines rather than their extinction.
Journal Article
Transduction of Human CD34$^+$ Cells That Mediate Long-Term Engraftment of NOD/SCID Mice by HIV Vectors
Efficient gene transfer into human hematopoietic stem cells (HSCs) is an important goal in the study of the hematopoietic system as well as for gene therapy of hematopoietic disorders. A lentiviral vector based on the human immunodeficiency virus (HIV) was able to transduce human CD34$^+$ cells capable of stable, long-term reconstitution of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. High-efficiency transduction occurred in the absence of cytokine stimulation and resulted in transgene expression in multiple lineages of human hematopoietic cells for up to 22 weeks after transplantation.
Journal Article
Enhancing DNA vaccination by sequential injection of lymph nodes with plasmid vectors and peptides
DNA vaccines or peptides are capable of inducing specific immunity; however, their translation to the clinic has generally been problematic, primarily due to the reduced magnitude of immune response and poor pharmacokinetics. Herein, we demonstrate that a novel immunization strategy, encompassing sequential exposure of the lymph node milieu to plasmid and peptide in a heterologous prime-boost fashion, results in considerable MHC class I-restricted immunity in mice. Plasmid-primed antigen expression was essential for the generation of a population of central memory T cells, expressing CD62L and low in PD-1, with substantial capability to expand and differentiate to peripheral memory and effector cells, following subsequent exposure to peptide. These vaccine-induced T cells dominated the T cell repertoire, were able to produce large amounts of chemokines and pro-inflammatory cytokines, and recognized tumor cells effectively. In addition to outlining a feasible and effective method to transform plasmid DNA vaccination into a potentially viable immunotherapeutic approach for cancer, this study sheds light on the mechanism of heterologous prime-boost and the considerable heterogeneity of MHC class I-restricted T cell responses.
Journal Article
Laws, leaders, and legends of the modern National Library of Medicine
The paper is an expanded version of the 2007 Joseph Leiter National Library of Medicine (NLM)/Medical Library Association Lecture presented at MLA '07, the Medical Library Association annual meeting in Philadelphia in May 2007. It presents an historical accounting of four major pieces of legislation, beginning with the NLM Act of 1956 up through the creation of the National Center for Biotechnology Information.
The transition from the United States Armed Forces Medical Library to the United States National Library of Medicine in 1956 was a major turning point in NLM's history, scope, and direction. The succeeding landmark legislative achievements--namely, the 1965 Medical Library Assistance Act, the 1968 Joint Resolution forming the Lister Hill National Center for Biomedical Communications, and the 1988 authorization for the National Center for Biotechnology Information--transformed the library into a major biomedical communications institution and a leader and supporter of an effective national network of libraries of medicine. The leaders of the library and its major advocates--including Dr. Michael DeBakey, Senator Lister Hill, and Senator Claude Pepper-together contributed to the creation of the modern NLM.
Journal Article
Martin M. Cummings, AHIP, FMLA, 1920–2011
Knowing the importance and prestige of a presidentially appointed advisory group, he quickly assembled a host of major players, including William Anlyan, head of the Duke University Medical Center; Bruno Augenstein, vice president of research at the Rand Corporation; William Baker, president of Bell Labs; Susan Crawford, AHIP, FMLA, the American Medical Association's director of libraries; Michael E. DeBakey, worldrenowned cardiac surgeon and chancellor, Baylor College of Medicine; Bernice Hetzner, Regional Medical Library (RML) director at the University of Nebraska; William Hubbard, dean of the University of Michigan Medical School and president of UpJohn; and Al Zipf, pioneer in electronic banking and executive vice president of the Bank of America, among others. When Marty Cummings retired from the National Library of Medicine, he could have taken a welldeserved rest, but the entire library community benefitted from his decision to join the Council on Library Resources as a senior advisor to work on broad, general problems, mostly related to the economics of libraries.
Journal Article
Support of human hematopoiesis in long-term bone marrow cultures by murine stromal cells selectively expressing the membrane-bound and secreted forms of the human homolog of the steel gene product, stem cell factor
The maintenance and differentiation of hematopoietic stem cells is influenced by cells making up the hematopoietic microenvironment (HM), including bone marrow-derived stromal cells. We and several other investigators have recently demonstrated the molecular basis of abnormal HM observed in the steel mutant mouse and cloned the normal cDNA products of this gene (termed SCF, KL, or MCF). In this report, we focus on the human counterpart of the mouse Steel (Sl) gene. Alternative splicing of the human SCF pre-mRNA transcript results in secreted and membrane-bound forms of the protein. To investigate the role of these two forms of human SCF, we targeted an immortalized stromal cell line derived from fetal murine homozygous (Sl/Sl) SCF-deficient embryos for gene transfer of various human cDNAs encoding SCF. We report that stable stromal cell transfectants can differentially process the two forms of human SCF protein product. We also demonstrate that both soluble SCF and membrane-bound SCF are active in increasing the number of human progenitor cells in the context of stromal cell cultures, although in a qualitatively different manner. Hence, the membrane-bound form of SCF may play an important role in the cell-cell interactions observed between stromal and hematopoietic cells both in vitro and in vivo.
Journal Article
Radioprotection of Mice by Recombinant Rat Stem Cell Factor
Treatment with recombinant rat stem cell factor (rSCF) protects mice from the lethal effects of irradiation. Mice treated with a single dose of rSCF prior to irradiation of up to 1150 rads [given as a split dose (1 rad = 0.01 Gy)] resulted in >80% long-term survival, whereas a single injection given after the last dose of irradiation was not radioprotective. The combination of pre- and posttreatment (-20 h, -2 h, and +4 h) with rSCF resulted in 100% survival of otherwise lethally irradiated mice. Using this optimum schedule of rSCF administration, a radioprotective factor of 1.3-1.35 was achieved. The major cause of death in the control animals was massive bacteremia consisting of enteric organisms. The rSCF-treated animals had a much lower frequency of septicemia, due primarily to a rapid hematopoietic recovery of bone marrow function not evident in control animals.
Journal Article