Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3⁺ regulatory T cells

Abstract

Summary We sought to determine whether Litomosoides sigmodontis, a filarial infection of rodents, protects against type 1 diabetes in non‐obese diabetic (NOD) mice. Six‐week‐old NOD mice were sham‐infected or infected with either L3 larvae, adult male worms, or adult female worms. Whereas 82% of uninfected NOD mice developed diabetes by 25 weeks of age, no L. sigmodontis‐infected mice developed disease. Although all mice had evidence of ongoing islet cell inflammation by histology, L. sigmodontis‐infected mice had greater numbers of total islets and non‐infiltrated islets than control mice. Protection against diabetes was associated with a T helper type 2 (Th2) shift, as interleukin‐4 (IL‐4) and IL‐5 release from α‐CD3/α‐CD28‐stimulated splenocytes was greater in L. sigmodontis‐infected mice than in uninfected mice. Increased circulating levels of insulin‐specific immunoglobulin G1, showed that this Th2 shift occurs in response to one of the main autoantigens in diabetes. Multicolour flow cytometry studies demonstrated that protection against diabetes in L. sigmodontis‐infected NOD mice was associated with significantly increased numbers of splenic CD4+ CD25+ FoxP3+ regulatory T cells. Interestingly, injection of crude worm antigen into NOD mice also resulted in protection against type 1 diabetes, though to a lesser degree than infection with live L. sigmodontis worms. In conclusion, these studies demonstrate that filarial worms can protect against the onset of type 1 diabetes in NOD mice. This protection is associated with a Th2 shift, as demonstrated by cytokine and antibody production, and with an increase in CD4+ CD25+ FoxP3+ regulatory T cells.

Decreased Prevalence of Lymphatic Filariasis Among Subjects with Type-1 Diabetes

“…In addition, clinical trials in humans examining effects of helminth products on disease severity in autoimmune diseases have shown promising results, as well as showing the safety of these helminth-derived immunomodulators for use as therapeutic agents. Although there is evidence to show that helminth infection can prevent T1DM in mice, 11,13,[23][24][25] there are no reports to support this hypothesis in humans. Epidemiologic studies carried out in southern India have shown reduced prevalence of LF after mass drug administration.…”

“…Our findings thus support the animal experiments that have shown that infection with the filarial parasite was enough to confer protection against T1DM. 23 It is unlikely that the decreased prevalence of LF among persons with diabetes was caused by LF-mediated mortality because LF is a chronic, nonlethal disease. More studies are clearly needed on the prevalence of diabetes (T1DM and T2DM) and other infectious diseases to have a better understanding of the interplay of infection/ inflammation and diabetes.…”

Helminth Products Protect against Autoimmunity via Innate Type 2 Cytokines IL-5 and IL-33, Which Promote Eosinophilia

“…It has been reported that SEA enhanced the expression of Foxp3 in naive NOD-specific T cells in a TGF-b-dependent manner (34). Similarly, infection with Litomosoides sigmodontis-protected mice from diabetes in a Treg-and TGF-bdependent manner (5,35). Furthermore, we have previously shown that infection with live F. hepatica attenuated EAE in a TGF-bdependent manner and this was associated with an expansion of Tregs (7).…”

Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

“…Surgical implantation of L. sigmodontis adults into BALB/c mice reduced induced allergic airway inflammation and hyperreactivity in a model for OVA-induced asthma (30). Also, onset of type 1 diabetes was prevented by injection of L3 and implantation of adults (31), and LPS-induced sepsis was slightly mitigated by adult implantation (22). Finally, it was shown that a preexisting natural L. sigmodontis infection prevented the development of cerebral malaria in C57BL/6 mice coinfected with Plasmodium berghei ANKA (32).…”