Elevated Cellular Immune Responses and Interferon-  Release after Long-Term Diethylcarbamazine Treatment of Patients with Human Lymphatic Filariasis

Sartono, Erliyani; Kruize, Yvonne C. M.; Kurniawan, Agnes; Meide, P. H. Van Der; Partònò, F; Maizels, Rick M.; Yazdanbakhsh, Maria

doi:10.1093/infdis/171.6.1683

Cited by 78 publications

(73 citation statements)

References 14 publications

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“…Similar results were obtained in Brugiainfected gerbils, where Mf þ gerbils are unable to produce IL-2 [31]. Moreover, ivermectin leads to a partial restoration of the suppressed Th1 responses in humans [13,32]. Several mechanisms may explain the induction of unresponsiveness by Mf.…”

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T helper responsiveness in human Loa loa infection; defective specific proliferation and cytokine production by CD4+ T cells from microfilaraemic subjects compared with amicrofilaraemics

Baize

Wahl

Soboslay

et al. 1997

Clinical and Experimental Immunology

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SUMMARYThe proliferation and cytokine profiles of peripheral blood mononuclear cells (PBMC) from microfilaraemic (Mf þ ) subjects infected by Loa loa in response to antigens of several parasitic stages were compared with those from amicrofilaraemic (Mf ¹ ) individuals. While a strong lymphoproliferative response and consistent levels of both Th1 (IL-2, interferon-gamma (IFN-g)) and Th2 (IL-4, IL-5) type cytokines were observed in response to adult worm (AW) and microfilariae (Mf) antigen in Mf ¹ individuals, Mf þ subjects were characterized by a T cell unresponsiveness, including proliferation, cytokine production and IL-2 mRNA expression. Conversely, T cell responsiveness to mitogens and non-specific antigen were similar in the two endemic populations. Depletion of lymphocyte subpopulations indicated that T CD4 þ were mainly involved in the specific cellular response. In contrast to other cytokines, IL-10 was produced in response to all parasitic stages, in both Mf þ and Mf ¹ patients. Neutralization of IL-10 did not restore cytokine production in Mf þ patients, while B7 mRNA expression was similar between Mf þ and Mf ¹ subjects in response to Mf antigen, suggesting that IL-10 was not the only factor responsible for T cell unresponsiveness. Mf þ patients have lower Mf antigen-specific IgG levels compared with Mf ¹ , and there is a significant correlation between Mf antigen-specific antibodies and IL-5 responses. These findings suggest that Mf ¹ status is correlated with T helper responsiveness, including proliferation and production of both Th1-and Th2-type cytokines, whereas Mf þ status is characterized by unresponsiveness of the same cell population, induced and/or maintained by microfilariae.

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T helper responsiveness in human Loa loa infection; defective specific proliferation and cytokine production by CD4+ T cells from microfilaraemic subjects compared with amicrofilaraemics

Baize

Wahl

Soboslay

et al. 1997

Clinical and Experimental Immunology

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“…The fact that only live parasites can induce Foxp3 within the CD4 ϩ population is consistent with both field and laboratory data linking active infection to immune regulation. For example, in human studies, T cell responsiveness is regained after drug-induced parasite killing (11). Moreover, live L3 larvae have been shown to directly inhibit in vitro responses of human Langerhans cells (69) and peripheral blood lymphocytes (13).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, the asymptomatic subjects, who carry high levels of circulating transmissionstage microfilariae, display a muted immunological response (5)(6)(7)(8), failing to mount parasite-specific T cell proliferative and cytokine responses. The degree of suppression is accentuated with higher parasite loads (9), and can be reversed by anti-filarial chemotherapy (10,11). Peripheral T cell populations in infected individuals show elevated expression of CTLA-4 and Foxp3, suggesting an increase in effector T cell anergy and regulatory T cell (Treg) 3 activity (12,13).…”

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confidence: 99%

Expansion of Foxp3+ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi

McSorley

Harcus

Murray

et al. 2008

The Journal of Immunology

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Many helminths, including Brugia malayi, are able to establish long-lived infections in immunocompetent hosts. Growing evidence suggests that the immune system’s failure to eliminate parasites is at least partially due to the effects of regulatory T cells (Tregs). To test whether parasites may directly stimulate host regulatory activity, we infected mice with two key stages of B. malayi. Both mosquito-borne infective larvae and mature adults i.p. introduced were found to preferentially expand the proportion of CD25+Foxp3+ cells within the CD4+ T cell population. The induction of Foxp3 was accompanied by raised CD25, CD103, and CTLA-4 expression, and was shown to be an active process, which accompanied the introduction of live, but not dead parasites. CTLA-4 expression was also markedly higher on Foxp3− cells, suggesting anergized effector populations. Peritoneal lavage CD4+CD25+ cells from infected mice showed similar suppressive activity in vitro to normal splenic “natural” Tregs. Both B. malayi larvae and adults were also able to induce Foxp3 expression in adoptively transferred DO11.10 T cells, demonstrating that filarial infection can influence the development of T cells specific to a third party Ag. In addition, we showed that induction was intact in IL-4R-deficient animals, in the absence of a Th2 or alternatively activated macrophage response. We conclude that filarial infections significantly skew the balance of the host immune system toward Treg expansion and activation, in a manner dependent on live parasites but independent of a concomitant Th2 response.

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“…Studies of Bancroftian filariasis in Haiti 11,12 and Malayan filariasis in Indonesia 13 have demonstrated increased T cell proliferation to parasite antigen at a variety of timepoints (3.9-12 months) following treatment with diethylcarbamazine (DEC) administered at a dose of 6 mg/kg/day or /week for 12 doses 11 or with ivermectin. 12 Of interest, PBMCs from a population in the Cook Islands infected with W. bancrofti displayed not only impaired cellular proliferation to Brugia malayi worm extract at baseline, but ongoing suppression of proliferation for up to two weeks following treatment with DEC. 14 Sartono and others 15 have shown that in addition to T cell proliferative responses, production of IFN-␥ in response to B. malayi crude adult antigen increased significantly one year after treatment in a study population in Indonesia, an area endemic for Brugian filariasis; however, patients in this study were treated with DEC every week for the entire year prior to reassessment of their cellular responsiveness. Diethylcarbamazine, in addition to its antifilarial activity, has measurable antifungal and antibacterial properties 16 and has been shown to exert an effect on the response to mf in vitro independent of the effector cell population.…”

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confidence: 64%

Long-term persistence of cellular hyporesponsiveness to filarial antigens after clearance of microfilaremia.

Gopinath¹,

Hanna²,

Kumaraswami³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. The persistence of parasite-specific cellular hyporesponsiveness after clearance of blood microfilariae (mf) was studied in 18 individuals who had been treated with a single dose of ivermectin, diethylcarbamazine, or a combination 2-3 years previously and who had initially cleared their parasitemia. At recruitment into the present study, 50% were again mfϩ and 50% remained mfϪ. There were no significant differences between the mfϩ and mfϪ groups in the amount of interferon-␥ (IFN-␥) produced by peripheral blood mononuclear cells in response to adult or microfilarial antigens, although IFN-␥ production in response to purified protein derivative was greater in the mfϩ group (geometric mean [gm] ϭ 3,791 pg/ml; P ϭ 0.02) than in the mfϪ group (gm ϭ 600 pg/ml). These data suggest that although microfilaremic individuals may temporarily regain the ability to produce IFN-␥ to parasite antigens post-treatment, they subsequently revert to a state of hyporesponsiveness to mfϪcontaining antigens that appears to be independent of the recurrence of microfilaremia and the response to nonparasite antigens.The clinically asymptomatic microfilariae (mf)-positive group of Wuchereria bancrofti-infected individuals has been of particular immunologic interest because of the relatively sparse inflammatory response seen despite the high intravascular parasite burden. Peripheral blood mononuclear cells (PBMCs) from the majority of individuals with subclinical microfilaremia display an inability to proliferate or produce interferon-␥ (IFN-␥) to filarial adult, mf, or larval antigens.

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Elevated Cellular Immune Responses and Interferon- Release after Long-Term Diethylcarbamazine Treatment of Patients with Human Lymphatic Filariasis

Cited by 78 publications

References 14 publications

T helper responsiveness in human Loa loa infection; defective specific proliferation and cytokine production by CD4+ T cells from microfilaraemic subjects compared with amicrofilaraemics

T helper responsiveness in human Loa loa infection; defective specific proliferation and cytokine production by CD4+ T cells from microfilaraemic subjects compared with amicrofilaraemics

Expansion of Foxp3+ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi

Long-term persistence of cellular hyporesponsiveness to filarial antigens after clearance of microfilaremia.

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