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ABSTRACT: Stimulation of naive mouse CD4(+)Foxp3(-) T cells in the presence of TGF-β results in the induction of Foxp3 expression and T suppressor function. However, Foxp3 expression in these induced regulatory T cells (iTreg) is unstable, raising the possibility that iTreg would not be useful for treatment of autoimmune diseases. To analyze the factors that control the stability of Foxp3 expression in iTreg, we generated OVA-specific iTreg from OT-II Foxp3-GFP knockin mice. Following transfer to normal C57BL/6 mice, OT-II GFP(+) cells maintained high levels of Foxp3 expression for 8 d. However, they rapidly lost Foxp3 expression upon stimulation with OVA in IFA in vivo. This unstable phenotype was associated with a strong methylation of the Treg-specific demethylated region within the Foxp3 locus. Administration of IL-2/anti-IL-2 complexes expanded the numbers of transferred Foxp3(+) iTreg in the absence of Ag challenge. Notably, when the iTreg were stimulated with Ag, treatment with IL-2/anti-IL-2 complexes stabilized Foxp3 expression and resulted in enhanced demethylation of the Treg-specific demethylated region. Conversely, neutralization of IL-2 or disruption of its signaling by deletion of Stat5 diminished the level of Foxp3 expression resulting in decreased suppressor function of the iTreg in vivo. Our data suggest that stimulation with TGF-β in vitro is not sufficient for imprinting T cells with stable expression of Foxp3. Administration of IL-2 in vivo results in stabilization of Foxp3 expression and may prove to be a valuable adjunct for the use of iTreg for the treatment of autoimmune diseases.
The Journal of Immunology 06/2011; 186(11):6329-37. · 5.79 Impact Factor
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ABSTRACT: Regulatory T cells (Treg) play critical roles in the modulation of immune responses to infectious agents. Further understanding of the factors that control Treg activation and expansion in response to pathogens is needed to manipulate Treg function in acute and chronic infections. Here we show that chronic, but not acute, infection of mice with lymphocytic choriomeningitis virus results in a marked expansion of Foxp3(+) Treg that is dependent on retroviral superantigen (sag) genes encoded in the mouse genome. Sag-dependent Treg expansion was MHC class II dependent, CD4 independent, and required dendritic cells. Thus, one unique mechanism by which certain infectious agents evade host immune responses may be mediated by endogenous Sag-dependent activation and expansion of Treg.
Proceedings of the National Academy of Sciences 02/2011; 108(9):3677-82. · 9.68 Impact Factor
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ABSTRACT: Scurfy mice have a deletion in the forkhead domain of the forkhead transcription factor p3 (Foxp3), fail to develop thymic-derived, naturally occurring Foxp3+ regulatory T cells (nTreg), and develop a fatal lymphoproliferative syndrome with multi-organ inflammation. Transfer of thymic-derived Foxp3+ nTreg into neonatal Scurfy mice prevents the development of disease. Stimulation of conventional CD4+Foxp3(-) via the TCR in the presence of TGF-beta and IL-2 induces the expression of Foxp3 and an anergic/suppressive phenotype. To determine whether the TGF-beta-induced Treg (iTreg) were capable of suppressing disease in the Scurfy mouse, we reconstituted newborn Scurfy mice with polyclonal iTreg. Scurfy mice treated with iTreg do not show any signs of disease and have drastically reduced cell numbers in peripheral lymph nodes and spleen in comparison to untreated Scurfy controls. The iTreg retained their expression of Foxp3 in vivo for 21 days, migrated into the skin, and prevented the development of inflammation in skin, liver and lung. Thus, TGF-beta-differentiated Foxp3+ Treg appear to possess all of the functional properties of thymic-derived nTreg and represent a potent population for the cellular immunotherapy of autoimmune and inflammatory diseases.
European Journal of Immunology 08/2008; 38(7):1814-21. · 5.10 Impact Factor
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Kim A Lindblade,
Byron Arana,
Guillermo Zea-Flores,
Nidia Rizzo,
Charles H Porter,
Alfredo Dominguez,
Nancy Cruz-Ortiz,
Thomas R Unnasch, George A Punkosdy,
Jane Richards,
Mauricio Sauerbrey,
Julio Castro,
Eduard Catú,
Orlando Oliva,
Frank O Richards
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ABSTRACT: To eliminate transmission of Onchocerca volvulus, semiannual mass treatment with ivermectin (Mectizan; donated by Merck & Co) has been underway in Guatemala since 2000. We applied the 2001 World Health Organization (WHO) elimination criteria in the Santa Rosa focus of onchocerciasis transmission in Guatemala (10,923 persons at risk). No evidence of parasite DNA was found in 2,221 Simulium ochraceum vectors (one-sided 95% confidence interval [CI], 0-0.086%), and no IgG4 antibody positives to recombinant antigen OV16 were found in a sample of 3,232 school children (95% CI, 0-0.009%). We also found no evidence of microfilariae in the anterior segment of the eye in 363 area residents (95% CI, 0-0.08%). Our interpretation of these data, together with historical information, suggest that transmission of O. volvulus is permanently interrupted in Santa Rosa and that ivermectin treatments there can be halted.
The American journal of tropical medicine and hygiene 09/2007; 77(2):334-41. · 2.59 Impact Factor
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Amy E Gruszynski,
Frederick J van Deursen,
Maria C Albareda,
Alexander Best,
Kshitiz Chaudhary,
Laura J Cliffe,
Laura del Rio,
Joe Dan Dunn,
Louise Ellis,
Krystal J Evans, [......],
Nicholas A Malmquist,
Yusuf Omosun,
Jennifer B Palenchar,
Sara Prickett, George A Punkosdy,
Giel van Dooren,
Qian Wang,
Anant K Menon,
Keith R Matthews,
James D Bangs
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ABSTRACT: African trypanosomes (Trypanosoma brucei) have a digenetic lifecycle that alternates between the mammalian bloodstream and the tsetse fly vector. In the bloodstream, replicating long slender parasites transform into non-dividing short stumpy forms. Upon transmission into the fly midgut, short stumpy cells differentiate into actively dividing procyclics. A hallmark of this process is the replacement of the bloodstream-stage surface coat composed of variant surface glycoprotein (VSG) with a new coat composed of procyclin. Pre-existing VSG is shed by a zinc metalloprotease activity (MSP-B) and glycosylphosphatidylinositol-specific phospholipase C (GPI-PLC). We now provide a detailed analysis of the coordinate and inverse regulation of these activities during synchronous differentiation. MSP-B mRNA and protein levels are upregulated during differentiation at the same time as proteolysis whereas GPI-PLC levels decrease. When transcription or translation is inhibited, VSG release is incomplete and a substantial amount of protein stays cell-associated. Both modes of release are still evident under these conditions, but GPI hydrolysis plays a quantitatively minor role during normal differentiation. Nevertheless, GPI biosynthesis shifts early in differentiation from a GPI-PLC sensitive structure to a resistant procyclic-type anchor. Translation inhibition also results in a marked increase in the mRNA levels of both MSP-B and GPI-PLC, consistent with negative regulation by labile protein factors. The relegation of short stumpy surface GPI-PLC to a secondary role in differentiation suggests that it may play a more important role as a virulence factor within the mammalian host.
Molecular and Biochemical Parasitology 07/2006; 147(2):211-23. · 2.55 Impact Factor
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ABSTRACT: Baylisascaris procyonis, the raccoon roundworm responsible for fatal larva migrans in humans, has long been thought to be absent from many regions in the southeastern United States. During spring 2002, 11 (22%) of 50 raccoons trapped in DeKalb County, Georgia, had B. procyonis infection. The increasing number of cases highlight this emerging zoonotic infection.
Emerging infectious diseases 01/2004; 9(12):1636-7. · 6.17 Impact Factor
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ABSTRACT: Approximately 30 years ago, researchers reported intracellular bacteria in filarial nematodes. These bacteria are relatives of the arthropod symbiont Wolbachia and occur in many filarial nematodes, including Brugia pahangi and Brugia malayi. Wolbachia bacteria have been implicated in a variety of roles, including filaria development and fecundity and the pathogenesis of lymphatic lesions associated with filarial infections. However, the role of the bacteria in worm biology or filarial disease is still not clear. The present experiments support previous data showing that tetracycline eliminates or reduces Wolbachia bacteria in B. pahangi in vivo. The elimination of Wolbachia was closely linked to a reduction in female fecundity and the viability of both sexes, suggesting that the killing of Wolbachia is detrimental to B. pahangi. The gerbils treated with tetracycline showed reduced levels of interleukin-4 (IL-4) and IL-5 mRNA in renal lymph nodes and spleens compared with the levels in B. pahangi-infected gerbils not treated with tetracycline. However, similar findings were noted in B. pahangi-infected gerbils treated with ivermectin, suggesting that the loss of circulating microfilariae, not the reduction of Wolbachia bacteria, was associated with the altered cytokine profile. Despite the change in T-cell cytokines, there was no difference in the sizes of renal lymph nodes isolated from gerbils in each treatment group. Furthermore, the numbers, sizes, or cellular compositions of granulomas examined in the lymphatics or renal lymph nodes did not differ with treatment. These data suggest that Wolbachia may not play a primary role in the formation of lymphatic lesions in gerbils chronically infected with B. pahangi.
Infection and Immunity 01/2004; 71(12):6986-94. · 4.16 Impact Factor
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ABSTRACT: Symbiotic Wolbachia organisms of filarial nematodes have received much attention as possible chemotherapy targets and disease-causing organisms. In order to further investigate the association between anti-Wolbachia immune responses and chronic filarial disease in humans, antibody responses to Wolbachia surface protein (WSP) were assayed in serum samples collected from 232 individuals living in Leogane, Haiti, an area where Wuchereria bancrofti infection is endemic, and from 67 North Americans with no history of lymphatic filariasis. As opposed to antifilarial antibody responses, which were largely influenced by the patient's infection status, the prevalence and levels of anti-WSP immunoglobulin G (IgG) antibodies among individuals with lymphedema or hydrocele were significantly greater than those in gender- and infection-matched individuals without disease. In at least one case, the anti-WSP IgG response was coincident with the onset of lymphedema development, and among anti-WSP-positive women with lymphedema, anti-WSP IgG levels were negatively correlated with the duration of lymphedema. The presence of anti-WSP IgG was also associated with the severity of inguinal adenopathy among men with hydrocele. In addition to the presence of anti-WSP antibodies among Haitians, 15 of 67 (22%) serum samples collected from individuals from North America, where filariasis is not endemic, were also positive for anti-WSP antibodies. In comparison to those from Haitians, anti-WSP antibodies from North Americans primarily recognized a distinct region of WSP located within the highly conserved second transmembrane domain. The results of this study demonstrate that anti-WSP antibody responses are associated with the presence of chronic filarial morbidity and not filarial infection status in humans and suggest that WSP should be further studied as a potential trigger for the development of filarial disease.
Infection and Immunity 10/2003; 71(9):5104-14. · 4.16 Impact Factor
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ABSTRACT: Our understanding of the pathogenesis of filarial lymphedema, although evolving, is still limited. Recurrent bacterial infections play a major role in the progression of lymphedema to elephantiasis, but the host and parasite factors that trigger disease development are not known. Field studies in Haiti show that lymphedema and host responses to parasite antigens cluster in families, consistent with the hypothesis that host genes influence lymphedema susceptibility. The recent recognition that filarial parasites harbor the endosymbiotic bacteria, Wolbachia, also raises questions about the potential contribution of the inflammatory response to Wolbachia antigens to lymphedema development. In this review, we discuss potential risk factors for lymphedema and try to integrate these in a model of pathogenesis.
Annals of the New York Academy of Sciences 01/2003; 979:131-42; discussion 188-96. · 3.15 Impact Factor
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ABSTRACT: Our understanding of the pathogenesis of filarial lymphedema, although evolving, is still limited. Recurrent bacterial infections play a major role in the progression of lymphedema to elephantiasis, but the host and parasite factors that trigger disease development are not known. Field studies in Haiti show that lymphedema and host responses to parasite antigens cluster in families, consistent with the hypothesis that host genes influence lymphedema susceptibility. The recent recognition that filarial parasites harbor the endosymbiotic bacteria, Wolbachia, also raises questions about the potential contribution of the inflammatory response to Wolbachia antigens to lymphedema development. In this review, we discuss potential risk factors for lymphedema and try to integrate these in a model of pathogenesis.
Annals of the New York Academy of Sciences 11/2002; 979(1):131 - 142. · 3.15 Impact Factor
