Animal models for the study of immunity in human filariasis

Lok, James B.; Abraham, David

doi:10.1016/0169-4758(92)90014-s

Cited by 38 publications

(23 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

“…Immunological studies performed in immunocompromised mice have been very useful in dissecting the nature of immunity in experimental filariasis, notwithstanding the fact that even such mice are not always fully susceptible to development of filarial parasites (21,22). However, in immunocompetent mice, i.p.…”

Section: Macrophage Effector Functions Controlled By Bruton's Tyrosinmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Macrophage Effector Functions Controlled By Bruton's Tyrosinmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Because of the difficulty in obtaining O. volvulus L3, previous studies have been limited to adult or microfilarial extracts, and data on responses specific to the infective stages are lacking. Antigens from L3 and subsequent developmental stages of molting L3 (mL3) have been shown to be promising sources for protective antigens and targets for the control of filarial infections (8,13,30). It was previously shown that PI individuals express enhanced Th2 and Th1 responses to larval antigens (46); however, the mechanisms that may allow INF individuals to limit new infections are not known.…”

mentioning

confidence: 99%

Differential Cytokine and Antibody Responses to Adult and Larval Stages ofOnchocerca volvulusConsistent with the Development of Concomitant Immunity

et al. 2002

View full text Add to dashboard Cite

The possibility of concomitant immunity and its potential mechanisms in Onchocerca volvulus infection were examined by analyzing cytokine and antibody responses to infective larval (third-stage larvae [L3] and molting L3 [mL3]), adult female worm (F-OvAg), and skin microfilaria (Smf) antigens in infected individuals in a region of hyperendemicity in Cameroon as a function of age. Peripheral blood mononuclear cell interleukin 5 (IL-5) responses to F-OvAg and Smf declined significantly with age (equivalent to years of exposure to O. volvulus). In contrast, IL-5 secretion in response to L3 and mL3 remained elevated with increasing age. Gamma interferon responses to L3, mL3, and F-OvAg were low or suppressed and unrelated to age, except for responses to Smf in older subjects. IL-10 levels were uniformly elevated, regardless of age, in response to L3, mL3, and F-OvAg but not to Smf, for which levels declined with age. A total of 49 to 60% of subjects had granulocytemacrophage colony-stimulating factor responses to all O. volvulus antigens unrelated to age. Analysis of levels of stage-specific immunoglobulin G3 (IgG3) and IgE revealed a striking, age-dependent dissociation between antibody responses to larval antigens (L3 and a recombinant L3-specific protein, O. volvulus ALT-1) which were significantly increased or maintained with age and antibody responses to F-OvAg, which decreased. Levels of IgG1 to L3 and F-OvAg were elevated regardless of age, and levels of IgG4 increased significantly with age, although not to O. volvulus ALT-1, which may have unique L3-specific epitopes. Immunofluorescence staining of whole larvae showed that total anti-L3 immunoglobulin levels also increased with the age of the serum donor. The separate and distinct cytokine and antibody responses to adult and infective larval stages of O. volvulus which are age related are consistent with the acquisition of concomitant immunity in infected individuals.The filarial parasite Onchocerca volvulus infects about 18 million people, and a further 100 million live in areas in which O. volvulus is endemic in Africa and Latin America. The resulting disease, onchocerciasis, is characterized by severe dermatitis and blindness (21). There is epidemiological evidence that acquired immunity against O. volvulus infection occurs in humans. For example, in regions of high endemicity, despite constant exposure to infected Simulium flies, 1 to 5% of the population exhibits no clinical manifestations of disease. These individuals are considered to be immune to infection and are referred to as putatively immune (PI) (15,17,46,47). Furthermore, in chronically infected (INF) individuals, the number of skin microfilariae (mf) tends to level off between the ages of 20 and 40 years, suggesting that these individuals have developed a means of limiting acquired infections (11). It has been suggested that the means of limiting acquired infections is through concomitant immunity (36), whereby newly introduced infective-stage larvae (third-stage larvae [L3]) are eliminated ...

show abstract

“…Only the silvered leaf monkey (Presbytis cristatus) is permissive to Wuchereria bancrofti for life cycle progression. Jirds (Meriones unguiculatus) and ferrets (Mustela putorius) are fully permissive for Brugia species and develop lymphatic pathology to an extent, but reagents for working with these animals are limited (Lok 1992). Only chimpanzees and mangabey monkeys are fully susceptible to Onchocerca volvulus.…”

Section: Challenges In Filarial Vaccine Developmentmentioning

confidence: 99%

“…Wuchereria bancrofti and Onchocerca volvulus cannot be maintained indefinitely in the laboratory (Lok 1992). Therefore, parasite material is often drawn from the more readily available Brugia species or from related filarial species obtained from their natural animal hosts (e.g Onchocerca spp in ungulates, Brugia spp in cats, Dirofilaria in dogs).…”

Section: Challenges In Filarial Vaccine Developmentmentioning

confidence: 99%

Vaccines for Filarial Infections

Keiser

Nutman

World Class Parasites

View full text Add to dashboard Cite

The development of an effective vaccine against lymphatic filariasis and onchocerciasis would improve efforts to eradicate these infections. Despite the limited availability of parasites and animal models, a number of strategies have emerged to identify targets for protective and transmission-blocking immune responses. This chapter reviews these strategies and discusses some of the vaccine candidates that are currently being evaluated.

show abstract

Animal models for the study of immunity in human filariasis

Cited by 38 publications

References 26 publications

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

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

Differential Cytokine and Antibody Responses to Adult and Larval Stages ofOnchocerca volvulusConsistent with the Development of Concomitant Immunity

Vaccines for Filarial Infections

Contact Info

Product

Resources

About