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Biomedical subjects

Heather L Van Epps

Publications and source records attributed to Heather L Van Epps.

18 recordsLinked to original sources
PubMed2006

Innate immune activation and CD4+ T cell priming during respiratory fungal infection.

Aspergillus fumigatus is a mold that causes a spectrum of diseases, including lethal lung infections in immunocompromised humans and allergic asthma in atopic individuals. T helper 1 (Th1) CD4(+) T cells protect against invasive A. fumigatus infections whereas Th2 CD4(+) T cells exacerbate asthma upon inhalation of A. fumigatus spores. Herein, we demonstrate that A. fumigatus-specific T cells were rapidly primed in lymph nodes draining the lung and fully differentiated into interferon-gamma (IFN-gamma)-producing Th1 CD4(+) T cells upon arrival in the airways. T-bet induction in A. fumigatus-specific CD4(+) T cells was enhanced by MyD88-mediated signals in draining lymph nodes, but T cell proliferation, trafficking, and Th1 differentiation in the airways were Toll-like receptor (TLR) and MyD88 independent. Our studies demonstrate that CD4(+) T cell differentiation during respiratory fungal infection occurs incrementally, with TLR-mediated signals in the lymph node enhancing the potential for IFN-gamma production whereas MyD88-independent signals promote Th1 differentiation in the lung.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Bringing order to early B cell chaos.

In the early 1990s, Richard (Randy) Hardy and colleagues divided B cell precursors into subpopulations--the Hardy fractions--based on the cells' expression of various cell surface proteins. This classification helped lay the groundwork for our present-day understanding of the molecular events that control early B cell development.

B-Lymphocytes↗
PubMed2006

Singapore's multibillion dollar gamble.

Figure 1Biopolis, Singapore's futuristic research hub.How does a country one-fourth the size of Rhode Island with little history in biomedical science become one of the world's biomedical research giants? The answer: with a pile of money and a large dose of chutzpah. Since 2000, Singapore has dumped more than US$2 billion into developing a biomedical research industry-from scratch. Is the gamble paying off?

Biomedical Research↗
PubMed2006

Ignoring endotoxin.

In 1947, Paul Beeson showed that rabbits repeatedly injected with certain bacteria eventually become resistant to the bacteria's fever-provoking effects-a phenomenon known as endotoxin tolerance.

Animals↗
PubMed2006

Influenza: exposing the true killer.

In the early 1930s, Richard Shope isolated influenza virus from infected pigs. Shope's finding was quickly followed by the isolation of the influenza virus from humans, proving that a virus-not a bacterium, as was widely believed-caused influenza.

Animals↗
PubMed2006

René Dubos: unearthing antibiotics.

In 1939, René Dubos discovered gramicidin-the first clinically tested antibiotic agent. This discovery helped revive the stalled interest in penicillin and launched the era of antibiotics.

Anti-Bacterial Agents↗
PubMed2006

Michael Heidelberger and the demystification of antibodies.

Having defined the protein nature of antibodies under the tutelage of Oswald Avery, Michael Heidelberger was the first to apply mathematics to the reaction of antibodies and their antigens (the "precipitin reaction"). Heidelberger's calculations launched decades of research that helped reveal the specificity, function, and origin of antibodies.

Antibodies↗
PubMed2005

How Heidelberger and Avery sweetened immunology.

In 1923, a young chemist-turned-microbiologist and his mentor made the startling discovery that bacterial sugars could be targeted by the immune system--a groundbreaking finding that helped launch the field of immunochemistry.

Allergy and Immunology↗
PubMed2005

Aspergillus fumigatus triggers inflammatory responses by stage-specific beta-glucan display.

Inhalation of fungal spores (conidia) occurs commonly and, in specific circumstances, can result in invasive disease. We investigated the murine inflammatory response to conidia of Aspergillus fumigatus, the most common invasive mold in immunocompromised hosts. In contrast to dormant spores, germinating conidia induce neutrophil recruitment to the airways and TNF-alpha/MIP-2 secretion by alveolar macrophages. Fungal beta-glucans act as a trigger for the induction of these inflammatory responses through their time-dependent exposure on the surface of germinating conidia. Dectin-1, an innate immune receptor that recognizes fungal beta-glucans, is recruited in vivo to alveolar macrophage phagosomes that have internalized conidia with exposed beta-glucans. Antibody-mediated blockade of Dectin-1 partially inhibits TNF-alpha/MIP-2 induction by metabolically active conidia. TLR-2- and MyD88-mediated signals provide an additive contribution to macrophage activation by germinating conidia. Selective responsiveness to germinating conidia provides the innate immune system with a mechanism to restrict inflammatory responses to metabolically active, potentially invasive fungal spores.

Animals↗
PubMed2005

T cell traffic signals.

In 1990, Charles Mackay and colleagues combined classical physiology with modern molecular biology to provide the first concrete evidence that naive and memory T cells follow distinct migratory routes out of the bloodstream--a discovery that helped invigorate the field of lymphocyte homing.

Animals↗
PubMed2005

Harry Goldblatt and the discovery of renin.

In 1934, pathologist Harry Goldblatt established the first animal model of hypertension. This model provided researchers with the tools to delineate the renin-angiotensin system of blood pressure control and, eventually, to design enzyme inhibitors for the treatment of chronic hypertension.

History, 20th Century↗
PubMed2005

Broadening the horizons for yellow fever: new uses for an old vaccine.

The vaccine against yellow fever is one of the safest and most effective ever developed. With an outstanding record in humans, has this live attenuated vaccine been overlooked as a promising vector for the development of vaccines against pathogens outside its own genus? Recent studies, including a report by Tao et al. on page 201 of this issue, have sparked renewed interest.

Flavivirus Infections↗
PubMed2005

Discovering lymphocyte subsets.

At a scientific meeting in 1968, Jacques Miller was accused of complicating immunology. He and others suggested that there was not one but two kinds of lymphocytes--one from the thymus and one from the bone marrow. In a pair of groundbreaking articles published in the Journal of Experimental Medicine in 1968, Miller and his student Graham Mitchell proved that two subsets of lymphocytes did exist and identified which subset mediated antibody responses.

Allergy and Immunology↗
PubMed2005

Distinct CD4+-T-cell responses to live and heat-inactivated Aspergillus fumigatus conidia.

Aspergillus fumigatus is an important fungal pathogen that causes invasive pulmonary disease in immunocompromised hosts. Respiratory exposure to A. fumigatus spores also causes allergic bronchopulmonary aspergillosis, a Th2 CD4+-T-cell-mediated disease that accompanies asthma. The microbial factors that influence the differentiation of A. fumigatus-specific CD4+ T lymphocytes into Th1 versus Th2 cells remain incompletely defined. We therefore examined CD4+-T-cell responses of immunologically intact mice to intratracheal challenge with live or heat-inactivated A. fumigatus spores. Live but not heat-inactivated fungal spores resulted in recruitment of gamma interferon (IFN-gamma)-producing, fungus-specific CD4+ T cells to lung airways, achieving A. fumigatus-specific frequencies exceeding 5% of total CD4+ T cells. While heat-inactivated spores did not induce detectable levels of IFN-gamma-producing, A. fumigatus-specific CD4+ T cells in the airways, they did prime CD4+ T-cell responses in draining lymph nodes that produced greater amounts of interleukin 4 (IL-4) and IL-13 than T cells responding to live conidia. While immunization with live fungal spores induced antibody responses, we found a marked decrease in isotype-switched, A. fumigatus-specific antibodies in sera of mice following immunization with heat-inactivated spores. Our studies demonstrate that robust Th1 T-cell and humoral responses are restricted to challenge with fungal spores that have the potential to germinate and cause invasive infection. How the adaptive immune system distinguishes between metabolically active and inactive fungal spores remains an important question.

Animals↗
PubMed2003

Voriconazole inhibits fungal growth without impairing antigen presentation or T-cell activation.

Invasive aspergillosis (IA) is the most common life-threatening invasive mold infection worldwide. The principal therapy for IA is amphotericin B, despite its known toxicity and immunosuppressive side effects. Studies in animal models of IA suggest a role for T lymphocytes in the pathology of the disease, although the precise role for Aspergillus-specific T cells remains undefined. The isolation and characterization of T lymphocytes in animal models of IA are hampered by the rapid outgrowth of the fungus in cultures derived from infected organs. In the present study, we tested the abilities of the antifungal drugs caspofungin acetate and voriconazole to inhibit fungal growth in vitro as a means of maintaining cultures of T cells from Aspergillus-infected mice. We demonstrate that while both antifungal drugs are inhibitory, only voriconazole completely inhibited fungal growth, allowing long-term maintenance of T-cell cultures. In addition, voriconazole had no inhibitory effect on the activation and maturation of dendritic cells or the proliferation of T lymphocytes. Thus, voriconazole appears to be a promising agent for use in in vitro studies of Aspergillus-specific T lymphocytes in animal models of IA.

Animals↗
PubMed2002

Long-lived memory T lymphocyte responses after hantavirus infection.

Puumala virus (PUUV) is a hantavirus that causes hemorrhagic fever with renal syndrome (HFRS), which is an important public health problem in large parts of Europe. We examined the memory cytolytic T lymphocyte (CTL) responses in 13 Finnish individuals who had HFRS between 1984 and 1995. In seven of these donors, we detected virus-specific CTL responses against the PUUV nucleocapsid (N) protein after in vitro stimulation with PUUV. Six novel CD8(+) CTL epitopes were defined on the N protein and were found to be restricted by various HLA alleles including A2, A28, B7, and B8. This is the first demonstration of PUUV-specific CTL responses in humans, and the first identification of CTL epitopes on PUUV. In addition, this study provides one of the few characterizations of a human antiviral memory T cell response, without the complicating issues of virus persistence or reinfection. Interferon (IFN)-gamma ELISPOT analysis showed that memory CTL specific for these epitopes were present at high frequency in PUUV-immune individuals many years after acute infection in the absence of detectable viral RNA. The frequencies of PUUV-specific CTL were comparable to or exceeded those found in other viral systems including influenza, EBV and HIV, in which CTL responses may be boosted by periodic reinfection or virus persistence.

Amino Acid Sequence↗
PubMed2002

Generation of recombinant vaccinia viruses expressing Puumala virus proteins and use in isolating cytotoxic T cells specific for Puumala virus.

Puumala (PUU) virus causes a form of hemorrhagic fever with renal syndrome (HFRS), called nephropathia epidemica (NE), in Europe. HFRS is characterized by an increased capillary permeability, which we hypothesize is caused by hyperactivation of the host immune system, especially cellular immune responses. To identify cytotoxic T lymphocytes (CTLs) specific for the PUU virus from NE patients, we have made recombinant vaccinia viruses expressing PUU virus proteins, the nucleocapsid (N) and two surface glycoproteins, G1 and G2. Recombinant vaccinia viruses carrying the N or the first half of the G2 cDNA under the control of a strong synthetic promoter were made. To express G1 and the second half of the G2 proteins, however, we needed to use a T7 expression system, where the T7 RNA polymerase is produced from another recombinant vaccinia virus co-infecting the same cells. These recombinant vaccinia viruses were used to detect and clone PUU virus-specific CTLs from the peripheral blood mononuclear cells of NE patients. An HLA-A24-restricted CTL line recognizing the G2 protein was isolated and its 9-mer epitope was determined.

Animals↗