Dean T. Nardelli

Inhibition of Interleukin-17 Prevents the Development of Arthritis in Vaccinated Mice Challenged with Borrelia burgdorferi

ABSTRACT We showed that Borrelia burgdorferi-vaccinated interferon gamma-deficient (IFN-γ0) mice challenged with the Lyme spirochete developed a prominent chronic severe destructive osteoarthropathy. The immune response underlying the development of the severe destructive arthritis involves interleukin-17 (IL-17). Treatment of vaccinated IFN-γ0 mice challenged with B. burgdorferi with anti-IL-17 antibody delayed the onset of swelling of the hind paws but, more importantly, inhibited the development of arthritis. Histopathologic examination confirmed that treatment with anti-IL-17 antibody prevented the destructive arthropathy seen in vaccinated and challenged IFN-γ0 mice. Similar preventive results were obtained when vaccinated and challenged IFN-γ0 mice were treated with anti-IL-17 receptor antibody or sequentially with anti-IL-17 antibody followed by anti-IL-17 receptor antibody. By contrast, treatment of vaccinated and challenged IFN-γ0 mice with recombinant IL-17 (rIL-17) did not alter the development and progression of arthritis found in vaccinated and challenged IFN-γ0 mice without treatment with rIL-17. Therapeutic intervention may be a realistic approach to prevent arthritis, especially if IL-17 is involved in the perpetuation of chronic or intermittent arthritis.

Lyme arthritis: current concepts and a change in paradigm.

Lyme disease is the most common arthropod-borne infection in the United States, affecting approximately 23,000 individuals bitten by Borrelia burgdorferi -infected Ixodes ticks in 2005 ([30][1]). Infection with B. burgdorferi results in a multisystem disorder, manifesting as early as a week

Interleukin-35 enhances Lyme arthritis in Borrelia-vaccinated and -infected mice.

ABSTRACT Interleukin-35 (IL-35) has been reported to inhibit the production of interleukin-17 (IL-17) as a means of preventing arthritis and other inflammatory diseases. We previously showed that treatment of Borrelia-vaccinated and -infected mice with anti-IL-17 antibody at the time of infection prevented the development of arthritis. The anti-IL-17 antibody-treated mice lacked the extensive tissue damage, such as bone and cartilage erosion, that occurred in the tibiotarsal joints of untreated Borrelia-vaccinated and -infected control mice. We hypothesized that IL-35 would reduce the severity of arthritis by suppressing the production of IL-17 in Borrelia-vaccinated and -infected mice. Here, we show that administration of recombinant IL-35 (rIL-35) to Borrelia-vaccinated and -infected mice augments the development of severe arthritis compared to the results seen with untreated control mice. Borrelia-vaccinated and -infected mice treated with rIL-35 had significantly (P < 0.05) greater hind paw swelling and histopathological changes from day 4 through day 10 than non-rIL-35-treated Borrelia-vaccinated and -infected mice. In addition, the treatment with IL-35 only slightly decreased the production of IL-17 in Borrelia-primed immune cells and did not prevent the development of borreliacidal antibody. Our data do not support a role for IL-35 as a potential therapeutic agent to reduce inflammation in Lyme arthritis.

Anti-Interleukin-15 Prevents Arthritis in Borrelia-Vaccinated and -Infected Mice

ABSTRACT We showed previously that interleukin-17 (IL-17) plays a significant role in the induction of arthritis associated with Borrelia vaccination and challenge. Little information, however, is available about the chain of immunologic events that leads to the release of IL-17. The production of IL-17 has been linked to stimulation of memory cells by IL-15. Therefore, we hypothesized that IL-15 is involved in the induction of arthritis associated with Borrelia vaccination and infection of mice. Here we present evidence that treatment of Borrelia-vaccinated and -infected mice with anti-IL-15 antibody prevents swelling of the hind paws. More importantly, both anti-IL-15 antibody- and recombinant IL-15 receptor alpha-treated Borrelia-vaccinated and -infected mice were free of major histopathologic indications of arthritis, including hyperplasia, hypertrophy, and vilus formation of the synovium. Similarly, the synovial space and perisynovium were free of inflammatory cells. By contrast, the synovium of nontreated Borrelia-vaccinated and -infected mice had overt hyperplasia, hypertrophy, and vilus formation. Moreover, the synovial space and perisynovium were infiltrated with neutrophils, macrophages, and lymphocytes. Finally, we show that recombinant IL-15 stimulates the release of IL-17 from lymph node cells obtained near the arthritic site. These results suggest that IL-15 plays a major role in orchestrating IL-17 induction of arthritis associated with Borrelia-vaccinated and -infected mice.

Anti-CD25 Antibody Treatment of Mice Vaccinated and Challenged with Borrelia spp. Does Not Exacerbate Arthritis but Inhibits Borreliacidal Antibody Production

ABSTRACT CD4+ CD25+ T cells are a population of regulatory T cells responsible for the modulation of the immune response in several autoimmune and infectious disease models. We previously showed that adoptive transfer of enriched CD4+ CD25+ T cells also plays a major role in the prevention of arthritis in Borrelia-vaccinated (Borrelia burgdorferi isolate 297) and -challenged (B. bissettii) mice. Here, we present evidence that administration of anti-CD25 antibody at the time of challenge or at later intervals fails to enhance the development of severe destructive osteoarthropathy in Borrelia-vaccinated C57BL mice. However, Borrelia-vaccinated and -challenged mice receiving anti-CD25 antibody developed decreased borreliacidal antibody titers compared to vaccinated and challenged controls. These findings suggest that additional mechanisms besides CD4+ CD25+ T cells are involved in the regulation of the immune response to Borrelia infection following vaccination.

Significant differences between the Borrelia-infection and Borrelia-vaccination and -infection models of Lyme arthritis in C3H/HeN mice

The immunological events leading to the development of Lyme arthritis in humans are partially understood. Much of this information has been gained by studying the course of infection of naïve or vaccinated mice with Borrelia burgdorferi. However, the Borrelia-vaccination and -infection model has not been described using the organismal parameters commonly used in the widely accepted Borrelia-infection model. This is the first comparison between the Borrelia-infection and the Borrelia-vaccination and -infection models of arthritis. Borrelia-vaccinated and -infected C3H/HeN mice develop acute inflammation comparable to that of nonvaccinated, Borrelia-infected C3H/HeN mice. The duration and severity of arthritis in Borrelia-vaccinated and -infected mice was slightly increased compared with Borrelia-infected mice. Significantly, Borrelia-vaccinated and -infected C3H/HeN mice produce interleukin-17 (IL-17), while Borrelia-infected mice that had not been previously vaccinated do not. Neutralization of IL-17 in Borrelia-vaccinated and -infected C3H/HeN mice decreased the severity of arthritis, although not to the degree we observed previously in C57BL/6 mice. Collectively, these findings show that the Borrelia-vaccination and -infection model of Lyme arthritis incorporates elements of adaptive immunity that likely have relevance to human disease, but may not be observed in Borrelia-infected C3H/HeN mice.

Interleukin-10 (IL-10) Inhibits Borrelia burgdorferi-Induced IL-17 Production and Attenuates IL-17-Mediated Lyme Arthritis

ABSTRACT Previous studies have shown that cells and cytokines associated with interleukin-17 (IL-17)-driven inflammation are involved in the arthritic response to Borrelia burgdorferi infection. Here, we report that IL-17 is a contributing factor in the development of Lyme arthritis and show that its production and histopathological effects are regulated by interleukin-10 (IL-10). Spleen cells obtained from B. burgdorferi-infected, “arthritis-resistant” wild-type C57BL/6 mice produced low levels of IL-17 following stimulation with the spirochete. In contrast, spleen cells obtained from infected, IL-10-deficient C57BL/6 mice produced a significant amount of IL-17 following stimulation with B. burgdorferi. These mice developed significant arthritis, including erosion of the bones in the ankle joints. We further show that treatment with antibody to IL-17 partially inhibited the significant hind paw swelling and histopathological changes observed in B. burgdorferi-infected, IL-10-deficient mice. Taken together, these findings provide additional evidence of a role for IL-17 in Lyme arthritis and reveal an additional regulatory target of IL-10 following borrelial infection.

Neutralization of Gamma Interferon Augments Borreliacidal Antibody Production and Severe Destructive Lyme Arthritis in C3H/HeJ Mice

ABSTRACT Development of a high level of sustained borreliacidal antibody is paramount for maintaining protection against infection with Borrelia burgdorferi. We show that production of borreliacidal antibody can be enhanced by preventing the effects of gamma interferon (IFN-γ). When lymph node cells capable of producing borreliacidal antibody were cultured with anti-murine IFN-γ, an eightfold increase in borreliacidal antibody production was obtained. However, anti-IFN-γ treatment of these cells also enhanced their ability to adaptively induce arthritis. When anti-IFN-γ-treated lymph node cells producing borreliacidal antibody were infused into C3H/HeJ mice and the mice were then challenged with B. burgdorferi, the mice developed severe destructive Lyme arthritis. Additional studies are needed to delineate the immune response responsible for the induction of arthritis and production of borreliacidal antibody. These studies are needed to ensure an effective and safe vaccine against infection with B. burgdorferi.

Hamster and Murine Models of Severe Destructive Lyme Arthritis

Arthritis is a frequent complication of infection in humans with Borrelia burgdorferi. Weeks to months following the onset of Lyme borreliosis, a histopathological reaction characteristic of synovitis including bone, joint, muscle, or tendon pain may occur. A subpopulation of patients may progress to a chronic, debilitating arthritis months to years after infection which has been classified as severe destructive Lyme arthritis. This arthritis involves focal bone erosion and destruction of articular cartilage. Hamsters and mice are animal models that have been utilized to study articular manifestations of Lyme borreliosis. Infection of immunocompetent LSH hamsters or C3H mice results in a transient synovitis. However, severe destructive Lyme arthritis can be induced by infecting irradiated hamsters or mice and immunocompetent Borrelia-vaccinated hamsters, mice, and interferon-gamma- (IFN-γ-) deficient mice with viable B. burgdorferi. The hamster model of severe destructive Lyme arthritis facilitates easy assessment of Lyme borreliosis vaccine preparations for deleterious effects while murine models of severe destructive Lyme arthritis allow for investigation of mechanisms of immunopathology.

Interleukin-6 Promotes Anti-OspA Borreliacidal Antibody Production In Vitro

ABSTRACT Determination of the immunological mediators responsible for promoting the production of borreliacidal antibody may facilitate the development of an improved borreliosis vaccine for human and veterinary use. Previously, we developed an in vitro assay to determine if borreliacidal antibody production could be augmented by treatment with different cytokines. In this study, in vitro treatment of lymph node cells producing borreliacidal antibody with recombinant interleukin-6 (rIL-6) resulted in a fourfold enhancement of anti-OspA borreliacidal antibody. Moreover, rIL-6 enhanced Western immunoblot titers and increased the number of B lymphocytes. In contrast, treatment of anti-OspA borreliacidal antibody-producing cells with anti-IL-6 resulted in a fourfold reduction in borreliacidal activity. Treatment with anti-IL-6 also inhibited enhanced borreliacidal antibody production induced by anti-gamma interferon. These data suggest that IL-6 plays a significant role in the production of anti-OspA borreliacidal antibodies.