Brugia malayi: Acquired Resistance to Microfilariae in BALB/C Mice Correlates with Local Th2 Responses

Pearlman, Eric; Kroeze, W.K.; Hazlett, Fred E.; Chen, Swe-Shen Alex; Mawhorter, Steven D.; Boom, W. Henry; Kazura, J. W.

doi:10.1006/expr.1993.1023

Cited by 41 publications

(35 citation statements)

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“…Development of pulmonary inflammation induced by filarial parasites appears to result from an early inductive phase, in which parasite Ags stimulate a predominantly Th2-associated response (elevated IL-4 and IL-5 production and decreased IFN-␥ production), and a secondary effector stage, in which Mf trapped in lung capillaries stimulate a local inflammatory response. With regard to the inductive phase, earlier studies from this laboratory showed that inoculation of mice with B. malayi Mf or immunization with soluble Ags selectively induced a Th2-like response associated with elevated serum IgE and eosinophil production (26)(27)(28)34). The present study showed that IL-4 and IFN-␥ modulation of pulmonary inflammation did not occur at the inductive phase of parasite-specific IL-5 and eosinophil production, as these responses were not significantly altered in knockout mice.…”

Section: Discussionmentioning

confidence: 99%

“…injection of live Mf (8). Previous studies from this laboratory demonstrated that sensitization of mice to B. malayi microfilarial antigens induces a selective T helper type 2 (Th2)-associated response (increased interleukin 4 and IL-5 production and decreased gamma interferon [IFN-␥] production) with eosinophilia and elevated levels of immunoglobulin E (IgE) in the serum (26)(27)(28). On subsequent i.v.…”

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confidence: 99%

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Reciprocal Immunomodulatory Effects of Gamma Interferon and Interleukin-4 on Filaria-Induced Airway Hyperresponsiveness

Mehlotra¹,

Hall²,

Haxhiu

et al. 2001

Infect Immun

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Tropical pulmonary eosinophilia (TPE) is a severe asthmatic syndrome of lymphatic filariasis, in which an allergic response is induced to microfilariae (Mf) in the lungs. Previously, in a murine model for TPE, we have demonstrated that recombinant interleukin-12 (IL-12) suppresses pulmonary eosinophilia and airway hyperresponsiveness (AHR) by modulating the T helper (Th) response in the lungs from Th2- to Th1-like, with elevated gamma-interferon (IFN-γ) production and decreased IL-4 and IL-5 production. The present study examined the immunomodulatory roles of IL-4 and IFN-γ in filaria-induced AHR and pulmonary inflammation using mice genetically deficient in these cytokines. C57BL/6, IL-4 gene knockout (IL-4−/−), and IFN-γ−/− mice were first immunized with soluble Brugia malayi antigens and then inoculated intravenously with 200,000 live Mf. Compared with C57BL/6 mice, IL-4−/− mice exhibited significantly reduced AHR, whereas IFN-γ−/− mice had increased AHR. Histopathologically, each mouse strain showed increased cellular infiltration into the lung parenchyma and bronchoalveolar space compared with naïve animals. However, consistent with changes in AHR, IL-4−/− mice had less inflammation than C57BL/6 mice, whereas IFN-γ−/− mice had exacerbated pulmonary inflammation with the loss of pulmonary architecture. Systemically, IL-4−/− mice produced significantly higher IFN-γ levels compared with C57BL/6 mice, whereas IFN-γ−/− mice produced significantly higher IL-4 levels. These data indicate that IL-4 is required for the induction of filaria-induced AHR, whereas IFN-γ suppresses AHR

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Reciprocal Immunomodulatory Effects of Gamma Interferon and Interleukin-4 on Filaria-Induced Airway Hyperresponsiveness

Mehlotra¹,

Hall²,

Haxhiu

et al. 2001

Infect Immun

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“…In contrast to work done with other filaria models, almost every reported vaccine trial using B. malayi in mice has demonstrated efficacy. Irradiated larvae (46,114,129,131), dead larvae (117), the soluble fraction of larvae (117), live MF (117,132), killed MF (46), MF antigen (46,133), and SDS extracts of adults (134) were all protective against L3 infection, even though many of these antigen preparations contained no adjuvant. Specific antigens that have been tried in this model include abundant larval transcript (135,136), thioredoxin peroxidase (135), transglutaminase (137), Bm97 (138), HSP12.6␣c (139), and paramyosin (138), all of which have been shown to be at least partially protective.…”

Section: Morris Et Almentioning

confidence: 99%

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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“…The T cell responses of asymptomatic humans with microfilaraemia show a prominence of Th2 cytokines such as IL-4, while T cells from symptomatic patients of elephantiasis show a relative dominance of the Th1 cytokine IFN-␥, as do some putatively immune "endemic normal" individuals (2,12). However, Th2 responses appear to be protective in some experimental animal models (10,(25)(26)(27).…”

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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Brugia malayi: Acquired Resistance to Microfilariae in BALB/C Mice Correlates with Local Th2 Responses

Cited by 41 publications

References 0 publications

Reciprocal Immunomodulatory Effects of Gamma Interferon and Interleukin-4 on Filaria-Induced Airway Hyperresponsiveness

Reciprocal Immunomodulatory Effects of Gamma Interferon and Interleukin-4 on Filaria-Induced Airway Hyperresponsiveness

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

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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