Diminished Production of T Helper 1 Cytokines and Lack of Induction of IL-2R+T Cells Correlate with T-Cell Unresponsiveness in Rhesus Monkeys Chronically Infected withBrugia malayi

Giambartolomei, Guillermo H.; Lasater, Barbara L.; Villinger, François; Dennis, Vida A.

doi:10.1006/expr.1998.4312

Cited by 15 publications

(11 citation statements)

References 30 publications

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“…Infected animals commonly exhibit disruption of lymphatic flow, dependent edema, and grossly enlarged lymph nodes (66)(67)(68). Microscopically, there is evidence of hyperplasia and eosinophilic lymphadenitis (67).…”

Section: Brugia Malayimentioning

confidence: 99%

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A Comprehensive, Model-Based Review of Vaccine and Repeat Infection Trials for Filariasis

et al. 2013

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SUMMARY Filarial worms cause highly morbid diseases such as elephantiasis and river blindness. Since the 1940s, researchers have conducted vaccine trials in 27 different animal models of filariasis. Although no vaccine trial in a permissive model of filariasis has provided sterilizing immunity, great strides have been made toward developing vaccines that could block transmission, decrease pathological sequelae, or decrease susceptibility to infection. In this review, we have organized, to the best of our ability, all published filaria vaccine trials and reviewed them in the context of the animal models used. Additionally, we provide information on the life cycle, disease phenotype, concomitant immunity, and natural immunity during primary and secondary infections for 24 different filaria models.

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Section: Brugia Malayimentioning

confidence: 99%

“…Microscopically, there is evidence of hyperplasia and eosinophilic lymphadenitis (67). Similar to humans, rhesus monkeys that develop lymphedema tend to be amicrofilaremic and exhibit strong immune responses to filarial antigens (68).…”

Section: Brugia Malayimentioning

confidence: 99%

A Comprehensive, Model-Based Review of Vaccine and Repeat Infection Trials for Filariasis

et al. 2013

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“…Also to understand the mechanisms of protective immune responses induced by vaccines, it is critical to use an animal model in which the immune system closely mimics that of human. Monkeys infected with B. malayi exhibited immunological changes in the lymphatic system similar to human lymphatic filariasis [10] . Therefore before testing the vaccine in human there is a need to evaluate its safety and immunogenicity in a non-human primate (NHP) model.…”

Section: Introductionmentioning

confidence: 96%

“…The infected macaques also develop fever, lymph node enlargement (around 5 weeks), lymphatic pathology (around 10–12 weeks) and chronic symptoms of elephantiasis very similar to that in the human lymphatic filariasis [15] , [16] . Therefore, rhesus macaques are extremely valuable and an ideal animal model to evaluate the safety and efficacy of a vaccine against lymphatic filariasis [10] , [17] . In fact, rhesus macaques have been used previously to test the vaccine potential of gamma-irradiation attenuated third stage B. malayi L3.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a Multivalent Vaccine against Lymphatic Filariasis in Rhesus macaque Model

et al. 2014

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Lymphatic filariasis affects 120 million people worldwide and another 1.2 billion people are at risk of acquiring the infection. Chemotherapy with mass drug administration is substantially reducing the incidence of the infection. Nevertheless, an effective vaccine is needed to prevent the infection and eradicate the disease. Previously we reported that a multivalent fusion protein vaccine (rBmHAT) composed of small heat shock proteins 12.6 (HSP12.6), abundant larval transcript-2 (ALT-2) and large extracellular domain of tetraspanin (TSP LEL) could confer >95% protection against the challenge infection with Brugia malayi infective larvae (L3) in mouse and gerbil models. In this study we evaluated the immunogenicity and efficacy of rBmHAT fusion protein vaccine in a rhesus macaque model. Our results show that rBmHAT is highly immunogenic in rhesus macaques. All the vaccinated monkeys developed significant titers of antigen-specific IgG antibodies against each of the component antigens (16,000 for rBmHSP12.6), (24,000 for rBmALT-2) and (16,000 for rBmTSP-LEL). An in vitro antibody dependent cellular cytotoxicity (ADCC) assay performed using the sera samples from vaccinated monkeys showed that the anti-rBmHAT antibodies are functional with 35% killing of B. malayi L3s. Vaccinated monkeys also had antigen responding cells in the peripheral blood. Vaccine-induced protection was determined after challenging the monkeys with 500 B. malayi L3. Following challenge infection, 3 out of 5 vaccinated macaques failed to develop the infection. These three protected macaques had high titers of IgG1 antibodies and their PBMC secreted significantly high levels of IFN-γ in response to the vaccine antigens. The two vaccinated macaques that picked the infection had slightly low titers of antibodies and their PBMC secreted high levels of IL-10. Based on these findings we conclude that the rBmHAT vaccine is highly immunogenic and safe and can confer significant protection against challenge infections in rhesus macaques.

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“…The role of the Th1/Th2 cytokine balance in the T cell response and the relative role of the innate and adaptive immune responses are major issues of debate (7)(8)(9)(10)(11)(12)(13)(14), particularly because T cell cytokines (15)(16)(17) as well as certain innate immune mechanisms (14, 18 -20) have been suggested to be trophic for filarial development as opposed to protection. Animal model-based studies of antifilarial immunity have been compromised by the fact that fully susceptible animal models such as gerbils, jirds, multimammate rats, or larger animal species (21) are not yet easily amenable to detailed immunological analyses.…”

Section: Macrophage Effector Functions Controlled By Bruton's Tyrosinmentioning

confidence: 99%

Macrophage Effector Functions Controlled by Bruton’s Tyrosine Kinase Are More Crucial Than the Cytokine Balance of T Cell Responses for Microfilarial Clearance

Mukhopadhyay

Mohanty

Mangla

et al. 2002

The Journal of Immunology

100

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Macrophages from X-linked immunodeficient (xid) mice lacking functional Bruton’s tyrosine kinase (Btk) show poor NO induction and enhanced IL-12 induction, and contribute to delayed clearance of injected microfilaria (mf) in vivo. We now show that Btk is involved in other macrophage effector functions, such as bactericidal activity and secretion of proinflammatory cytokines (TNF-α, IL-1β), but not the T cell-directed cytokine IL-12. Induction of some transcriptional regulators of the NF-κB family, crucial for the expression of proinflammatory cytokines, is also poor in Btk-deficient macrophages. Thus, Btk appears to be involved in signaling for inducible effector functions, but not APC functions, in macrophages. Furthermore, adoptive transfer of T cells from mf-infected xid or wild-type mice did not alter the course of mf clearance in recipients, mf clearance was unaltered in IFN-γ-deficient mice, and improved mf clearance was seen only if greater inducibility of IL-12 was accompanied by greater NO secretion from macrophages, as seen in Ityr C.D2 mice as compared with congenic Itys BALB/c mice. Thus, delayed mf clearance in xid mice was correlated not with the high IL-12/Th1 phenotype but with low NO induction levels. Also, xid macrophages showed poor toxicity to mf in vitro as compared with wild-type macrophages. Inhibition of NO production blocked this mf cytotoxicity, and an NF-κB inhibitor blocked both NO induction and mf cytotoxicity. Thus, Btk is involved in inducing many macrophage effector functions, and delayed mf clearance seen in Btk-deficient xid mice is due to poor NO induction in macrophages, resulting in compromised microfilarial toxicity.

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Diminished Production of T Helper 1 Cytokines and Lack of Induction of IL-2R+T Cells Correlate with T-Cell Unresponsiveness in Rhesus Monkeys Chronically Infected withBrugia malayi

Cited by 15 publications

References 30 publications

A Comprehensive, Model-Based Review of Vaccine and Repeat Infection Trials for Filariasis

A Comprehensive, Model-Based Review of Vaccine and Repeat Infection Trials for Filariasis

Evaluation of a Multivalent Vaccine against Lymphatic Filariasis in Rhesus macaque Model

Macrophage Effector Functions Controlled by Bruton’s Tyrosine Kinase Are More Crucial Than the Cytokine Balance of T Cell Responses for Microfilarial Clearance

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