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1.
Adv Radiat Oncol ; 6(5): 100677, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646962

RESUMO

PURPOSE: Ionizing radiation causes acute damage to hematopoietic and immune cells, but the long-term immunologic consequences of irradiation are poorly understood. We therefore performed a prospective study of the delayed immune effects of radiation using a rhesus macaque model. METHODS AND MATERIALS: Ten macaques received 4 Gy high-energy x-ray total body irradiation (TBI) and 6 control animals received sham irradiation. TBI caused transient lymphopenia that resolved over several weeks. Once white blood cell counts recovered, flow cytometry was used to immunophenotype the circulating adaptive immune cell populations 4, 9, and 21 months after TBI. Data were fit using a mixed-effects model to determine age-dependent, radiation-dependent, and interacting effects. T cell receptor (TCR) sequencing and quantification of TCR Excision Circles were used to determine relative contributions of thymopoiesis and peripheral expansion to T cell repopulation. Two years after TBI, the cohort was vaccinated with a 23-valent pneumococcal polysaccharide vaccine and a tetravalent influenza hemagglutinin vaccine. RESULTS: Aging, but not TBI, led to significant changes in the frequencies of dendritic cells, CD4 and CD8 T cells, and B cells. However, irradiated animals exhibited increased frequencies of central memory T cells and decreased frequencies of naïve T cells. These consequences of irradiation were time-dependent and more prolonged in the CD8 T cell population. Irradiation led to transient increases in CD8+ T cell TCR Excision Circles and had no significant effect on TCR sequence entropy, indicating T cell recovery was partially mediated by thymopoiesis. Animals that were irradiated and then vaccinated showed normal immunoglobulin G binding and influenza neutralization titers in response to the 4 protein antigens but weaker immunoglobulin G binding titers to 10 of the 23 polysaccharide antigens. CONCLUSIONS: These findings indicate that TBI causes subtle but long-lasting immune defects that are evident years after recovery from lymphopenia.

4.
Vaccine ; 34(9): 1193-200, 2016 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-26812077

RESUMO

The Ducreyi serum resistance A (DsrA) protein of Haemophilus ducreyi belongs to a large family of multifunctional outer membrane proteins termed trimeric autotransporter adhesins responsible for resistance to the bactericidal activity of human complement (serum resistance), agglutination and adhesion. The ability of DsrA to confer serum resistance and bind extracellular matrix proteins lies in its N-terminal passenger domain. We have previously reported that immunization with a recombinant form of the passenger domain of DsrA, rNT-DsrA, in complete/incomplete Freund's adjuvant, protects against a homologous challenge in swine. We present herein the results of an immunogenicity study in mice aimed at investigating the persistence, type of immune response, and the effect of immunization route and adjuvants on surrogates of protection. Our results indicate that a 20 µg dose of rNT-DsrA administered with alum elicited antisera with comparable bacterial surface reactivity to that obtained with complete/incomplete Freund's adjuvant. At that dose, high titers and bacterial surface reactivity persisted for 211 days after the first immunization. Administration of rNT-DsrA with CpG or imiquimod as adjuvants elicited a humoral response with similar quantity and quality of antibodies (Abs) as seen with Freund's adjuvant. Furthermore, intramuscular administration of rNT-DsrA elicited high-titer Abs with significantly higher reactivity to the bacterial surface than those obtained with subcutaneous immunization. All rNT-DsrA/adjuvant combinations tested, save CpG, elicited a Th2-type response. Taken together, these findings show that a 20 µg dose of rNT-DsrA administered with the adjuvants alum, CpG or imiquimod elicits high-quality Abs with reactivity to the bacterial surface that could protect against an H. ducreyi infection.


Assuntos
Adesinas Bacterianas/imunologia , Adjuvantes Imunológicos/administração & dosagem , Vacinas Bacterianas/química , Haemophilus ducreyi , Imunidade Humoral , Sistemas de Secreção Tipo V/imunologia , Compostos de Alúmen/administração & dosagem , Aminoquinolinas/administração & dosagem , Animais , Anticorpos Antibacterianos/sangue , Ilhas de CpG , Feminino , Adjuvante de Freund/administração & dosagem , Imiquimode , Soros Imunes/imunologia , Switching de Imunoglobulina , Camundongos , Camundongos Endogâmicos BALB C
5.
Infect Immun ; 82(6): 2504-10, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24686053

RESUMO

The adaptive immune response to Francisella tularensis is dependent on the route of inoculation. Intradermal inoculation with the F. tularensis live vaccine strain (LVS) results in a robust Th1 response in the lungs, whereas intranasal inoculation produces fewer Th1 cells and instead many Th17 cells. Interestingly, bacterial loads in the lungs are similar early after inoculation by these two routes. We hypothesize that the adaptive immune response is influenced by local events in the lungs, such as the type of cells that are first infected with Francisella. Using fluorescence-activated cell sorting, we identified alveolar macrophages as the first cell type infected in the lungs of mice intranasally inoculated with F. novicida U112, LVS, or F. tularensis Schu S4. Following bacterial dissemination from the skin to the lung, interstitial macrophages or neutrophils are infected. Overall, we identified the early interactions between Francisella and the host following two different routes of inoculation.


Assuntos
Francisella tularensis/imunologia , Interações Hospedeiro-Patógeno/imunologia , Pulmão/microbiologia , Tularemia/imunologia , Imunidade Adaptativa , Administração Intranasal , Animais , Carga Bacteriana , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Pulmão/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/microbiologia , Alvéolos Pulmonares/microbiologia , Tularemia/microbiologia
6.
J Clin Invest ; 121(3): 941-55, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21285515

RESUMO

Allergic asthma is characterized by airway hyperresponsiveness, inflammation, and a cellular infiltrate dominated by eosinophils. Numerous epidemiological studies have related the exacerbation of allergic asthma with an increase in ambient inhalable particulate matter from air pollutants. This is because inhalable particles efficiently deliver airborne allergens deep into the airways, where they can aggravate allergic asthma symptoms. However, the cellular mechanisms by which inhalable particulate allergens (pAgs) potentiate asthmatic symptoms remain unknown, in part because most in vivo and in vitro studies exploring the pathogenesis of allergic asthma use soluble allergens (sAgs). Using a mouse model of allergic asthma, we found that, compared with their sAg counterparts, pAgs triggered markedly heightened airway hyperresponsiveness and pulmonary eosinophilia in allergen-sensitized mice. Mast cells (MCs) were implicated in this divergent response, as the differences in airway inflammatory responses provoked by the physical nature of the allergens were attenuated in MC-deficient mice. The pAgs were found to mediate MC-dependent responses by enhancing retention of pAg/IgE/FcεRI complexes within lipid raft­enriched, CD63(+) endocytic compartments, which prolonged IgE/FcεRI-initiated signaling and resulted in heightened cytokine responses. These results reveal how the physical attributes of allergens can co-opt MC endocytic circuitry and signaling responses to aggravate pathological responses of allergic asthma in mice.


Assuntos
Alérgenos/química , Asma/metabolismo , Hiper-Reatividade Brônquica/imunologia , Regulação da Expressão Gênica , Hipersensibilidade/metabolismo , Imunoglobulina E/metabolismo , Mastócitos/citologia , Poluentes Atmosféricos , Animais , Antígenos CD/biossíntese , Modelos Animais de Doenças , Endocitose , Inflamação , Lipídeos/química , Masculino , Microdomínios da Membrana , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteínas da Membrana de Plaquetas/biossíntese , Tetraspanina 30
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