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Hubbard L.L.N.,Graduate Program in Immunology
American Journal of Respiratory Cell and Molecular Biology | Year: 2011

Hematopoietic stem cell transplant patients are susceptible to infection despite cellular reconstitution. In a murine model of syngeneic bone marrow transplantation (BMT), we previously reported that BMT mice have impaired host defense against Pseudomonas aeruginosa pneumonia due to overproduction of (PG)E 2 in lung. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is an effector in the PGE 2 signaling pathway that negatively regulates alveolar macrophage (AM) phagocytosis and bacterial killing. Therefore, examined whether overproduction of PGE 2 after BMT inhibits AM host defense by up-regulating PTEN phosphatase activity. We found that PTEN activity is elevated in BMT AMs in response to increased PGE 2 signaling and that pharmacological inhibition of PTEN activity in BMT AMs fully restores phagocytosis of serum-opsonized P. aeruginosa but only partially restores phagocytosis of nonopsonized P. aeruginosa. In wild-type mice transplanted with myeloid-specific conditional PTEN knockout (PTEN CKO) bone marrow, bacterial clearance is improved after challenge with P. aeruginosa pneumonia. Furthermore, PTEN CKO BMT AMs display improved TNF-a production and enhanced phagocytosis and killing of serum-opsonized P. aeruginosa despite overproduction of PGE2. However, AM phagocytosis of nonopsonized P. aeruginosa is only partially restored in the absence of PTEN after BMT. This may be related to elevated AM expression of IL-1 receptor-associated kinase (IRAK)-M, a molecule previously identified in the PGE 2 signaling pathway to inhibit AM phagocytosis of nonopsonized bacteria. These data suggest that PGE 2 signaling up-regulates IRAK-M independently of PTEN and that these molecules differentially inhibit opsonized and nonopsonized phagocytosis of P. aeruginosa.


Poluektov Y.O.,Graduate Program in Immunology | Hartman I.Z.,Graduate Program in Immunology | Hartman I.Z.,University of Texas Southwestern Medical Center | Sadegh-Nasseri S.,Graduate Program in Immunology
PLoS ONE | Year: 2013

Processing of antigens for presentation to helper T cells by MHC class II involves HLA-DM (DM) and HLA-DO (DO) accessory molecules. A mechanistic understanding of DO in this process has been missing. The leading model on its function proposes that DO inhibits the effects of DM. To directly study DO functions, we designed a recombinant soluble DO and expressed it in insect cells. The kinetics of binding and dissociation of several peptides to HLA-DR1 (DR1) molecules in the presence of DM and DO were measured. We found that DO reduced binding of DR1 to some peptides, and enhanced the binding of some other peptides to DR1. Interestingly, these enhancing and reducing effects were observed in the presence, or absence, of DM. We found that peptides that were negatively affected by DO were DM-sensitive, whereas peptides that were enhanced by DO were DM-resistant. The positive and negative effects of DO could only be measured on binding kinetics as peptide dissociation kinetics were not affected by DO. Using Surface Plasmon Resonance, we demonstrate direct binding of DO to a peptide-receptive, but not a closed conformation of DR1. We propose that DO imposes another layer of control on epitope selection during antigen processing. © 2013 Poluektov et al.


Paczosa M.K.,Graduate Program in Immunology | Mecsas J.,Tufts University
Microbiology and Molecular Biology Reviews | Year: 2016

Klebsiella pneumoniae causes a wide range of infections, including pneumonias, urinary tract infections, bacteremias, and liver abscesses. Historically, K. pneumoniae has caused serious infection primarily in immunocompromised individuals, but the recent emergence and spread of hypervirulent strains have broadened the number of people susceptible to infections to include those who are healthy and immunosufficient. Furthermore, K. pneumoniae strains have become increasingly resistant to antibiotics, rendering infection by these strains very challenging to treat. The emergence of hypervirulent and antibioticresistant strains has driven a number of recent studies. Work has described the worldwide spread of one drug-resistant strain and a host defense axis, interleukin-17 (IL-17), that is important for controlling infection. Four factors, capsule, lipopolysaccharide, fimbriae, and siderophores, have been well studied and are important for virulence in at least one infection model. Several other factors have been less well characterized but are also important in at least one infection model. However, there is a significant amount of heterogeneity in K. pneumoniae strains, and not every factor plays the same critical role in all virulent Klebsiella strains. Recent studies have identified additional K. pneumoniae virulence factors and led to more insights about factors important for the growth of this pathogen at a variety of tissue sites. Many of these genes encode proteins that function in metabolism and the regulation of transcription. However, much work is left to be done in characterizing these newly discovered factors, understanding how infections differ between healthy and immunocompromised patients, and identifying attractive bacterial or host targets for treating these infections. Copyright © 2016, American Society for Microbiology. All Rights Reserved.


Keenan B.P.,Graduate Program in Immunology | Keenan B.P.,Sidney Kimmel Cancer Center at Johns Hopkins | Jaffee E.M.,Sidney Kimmel Cancer Center at Johns Hopkins
Seminars in Oncology | Year: 2012

Cancer vaccines have shown success in curing tumors in preclinical models. Accumulating evidence also supports their ability to induce immune responses in patients. In many cases, these responses correlate with improved clinical outcomes. However, cancer vaccines have not yet demonstrated their true potential in clinical trials. This is likely due to the difficulty in mounting a significant anti-tumor response in patients with advanced disease because of pre-existing tolerance mechanisms that are actively turning off immune recognition in cancer patients. This review will examine the recent progress being made in the design and implementation of whole cell cancer vaccines, one vaccine approach that simultaneously targets multiple tumor antigens to activate the immune response. These vaccines have been shown to induce antigen-specific T-cell responses. Preclinical studies evaluating these vaccines given in sequence with other agents and cancer treatment modalities support the use of immunomodulating doses of chemotherapy and radiation, as well as immune-modulating pathway-targeted monoclonal antibodies, to enhance the efficacy of cancer vaccines. Based on emerging preclinical data, clinical trials are currently exploring the use of combinatorial immune-based therapies for the treatment of cancer. © 2012 Elsevier Inc. © 2012 Elsevier Inc. All rights reserved.


PubMed | Graduate Program in Immunology
Type: Journal Article | Journal: Seminars in oncology | Year: 2012

Cancer vaccines have shown success in curing tumors in preclinical models. Accumulating evidence also supports their ability to induce immune responses in patients. In many cases, these responses correlate with improved clinical outcomes. However, cancer vaccines have not yet demonstrated their true potential in clinical trials. This is likely due to the difficulty in mounting a significant anti-tumor response in patients with advanced disease because of pre-existing tolerance mechanisms that are actively turning off immune recognition in cancer patients. This review will examine the recent progress being made in the design and implementation of whole cell cancer vaccines, one vaccine approach that simultaneously targets multiple tumor antigens to activate the immune response. These vaccines have been shown to induce antigen-specific T-cell responses. Preclinical studies evaluating these vaccines given in sequence with other agents and cancer treatment modalities support the use of immunomodulating doses of chemotherapy and radiation, as well as immune-modulating pathway-targeted monoclonal antibodies, to enhance the efficacy of cancer vaccines. Based on emerging preclinical data, clinical trials are currently exploring the use of combinatorial immune-based therapies for the treatment of cancer.

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