Yixuan Zhou

Administering human adipose-derived mesenchymal stem cells to prevent and treat experimental arthritis.

Rheumatoid arthritis is a chronic autoimmune disease and affecting approximately 1% of the population. Human adipose-derived mesenchymal stem cells (hASCs) were recently found to suppress effector T cell and inflammatory responses and, thus, to have beneficial effects in various autoimmune diseases. In this study, we examined whether hASCs could play a protective and/or therapeutic role in collagen-induced arthritis (CIA). We showed that hASCs both prevented and treated CIA by significantly reducing the incidence and severity of experimental arthritis. We further demonstrated that treatment with hASCs inhibited the production of various inflammatory mediators, decreased antigen-specific Th1/Th17 cell expansion, and induced the production of anti-inflammatory cytokine interleukin-10. Moreover, hASCs could induce the generation of antigen-specific Treg cells with the capacity to suppress collagen-specific T cell responses.

The therapeutic efficacy of human adipose tissue‐derived mesenchymal stem cells on experimental autoimmune hearing loss in mice

Autoimmune inner ear disease is characterized by progressive, bilateral although asymmetric, sensorineural hearing loss. Patients with autoimmune inner ear disease had higher frequencies of interferon‐γ‐producing T cells than did control subjects tested. Human adipose‐derived mesenchymal stem cells (hASCs) were recently found to suppress effector T cells and inflammatory responses and therefore have beneficial effects in various autoimmune diseases. The aim of this study was to examine the immunosuppressive activity of hASCs on autoreactive T cells from the experimental autoimmune hearing loss (EAHL) murine model. Female BALB/c mice underwent β‐tubulin immunization to develop EAHL; mice with EAHL were given hASCs or PBS intraperitoneally once a week for 6 consecutive weeks. Auditory brainstem responses were examined over time. The T helper type 1 (Th1)/Th17‐mediated autoreactive responses were examined by determining the proliferative response and cytokine profile of splenocytes stimulated with β‐tubulin. The frequency of regulatory T (Treg) cells and their suppressive capacity on autoreactive T cells were also determined. Systemic infusion of hASCs significantly improved hearing function and protected hair cells in established EAHL. The hASCs decreased the proliferation of antigen‐specific Th1/Th17 cells and induced the production of anti‐inflammatory cytokine interleukin‐10 in splenocytes. They also induced the generation of antigen‐specific CD4+ CD25+ Foxp3+  Treg cells with the capacity to suppress autoantigen‐specific T‐cell responses. The experiment demonstrated that hASCs are one of the important regulators of immune tolerance with the capacity to suppress effector T cells and to induce the generation of antigen‐specific Treg cells.

Experimental autoimmune hearing loss is exacerbated in IL-10-deficient mice and reversed by IL-10 gene transfer.

Interleukin-10 (IL-10) has an important role in the homeostatic regulation of autoreactive T-cell repertoire. We hypothesized that endogenous IL-10 would regulate the severity of β-tubulin-induced experimental autoimmune hearing loss (EAHL) and that exogenous IL-10 would abrogate it. BALB/c wild-type (WT) and homozygous IL-10-deficient mice (IL-10−/−) underwent β-tubulin immunization to develop EAHL; some IL-10 mice with EAHL were administered IL-10 DNA at the peak of EAHL. Auditory brainstem responses were examined over time. EAHL developed progressively in both WT and IL-10−/− mice. However, the severity of hearing loss in the IL-10−/− mice was significantly greater than that in WT animals. Moreover, disease severity was associated with a significantly enhanced interferon-γ level and loss of hair cells in IL-10−/− mice. IL-10 administered to EAHL IL-10−/− mice promoted IL-10 expression. Consequently, hearing significantly improved by protecting hair cells in established EAHL. Importantly, IL-10 treatment suppressed proliferation of antigen-specific T-helper type 1 (Th1) cells, and the suppression can be attributed to inducing IL-10-secreting regulatory T cells that suppressed autoreactive T cells. We demonstrated that the lack of IL-10 exacerbated hearing loss, and the exogenous administration of IL-10 improved hearing. Mechanistically, our results indicate that IL-10 is capable of controlling autoimmune reaction severity by suppressing Th1-type proinflammatory responses and inducing IL-10-secreting regulatory T cells.

Murine autoimmune hearing loss mediated by CD4+ T cells specific for β-tubulin

Autoimmune inner ear disease is described as progressive, bilateral although asymmetric, sensorineural hearing loss and can be improved by immunosuppressive therapy. We showed that the inner ear autoantigen β-tubulin is capable of inducing experimental autoimmune hearing loss (EAHL) in mice. Immunization of BALB/c mice with β-tubulin resulted in hair cell loss and hearing loss, effects that were not seen in animals immunized with control peptide. Moreover, the EAHL model showed that β-tubulin responsiveness involved CD4(+) T cells producing IFN-γ, and T cell mediation of EAHL was determined by significantly increased auditory brainstem response after adoptive transfer of β-tubulin-activated CD4(+) T cells into naive BALB/c recipients. The potential mechanisms responsible for the observed pathology of EAHL can be attributed to decreased frequency and impaired suppressive function of regulatory T cells. Our study suggests that EAHL may be a T cell-mediated organ-specific autoimmune disorder of the inner ear.

Prevention and treatment of DNA vaccine encoding cockroach allergen Bla g 1 in a mouse model of allergic airway inflammation

To cite this article: Zhou B, Ensell M, Zhou Y, Nair U, Glickstein J, Kermany MH, Cai Q, Cai C, Liu W, Deng Y‐P, Kakigi A, Barbieri M, Mora M, Kanangat S, Yoo TJ. Prevention and treatment of DNA vaccine encoding cockroach allergen Bla g 1 in a mouse model of allergic airway inflammation. Allergy 2012; 67: 166–174.

The attenuation of cockroach allergy by DNA vaccine encoding cockroach allergen Bla g 2.

Bla g 2 is one of the most potent cockroach allergens. No effective treatment or vaccination strategies are yet available. We evaluated the prophylactic efficacy of Bla g 2 DNA vaccination in a mouse model of allergic airway inflammation. C57/BL6 mice were given Bla g 2 DNA vaccine prior to sensitization with recombinant Bla g 2 (rBla g 2) antigens, followed by nebulized rBla g 2 challenge. Bla g 2 vaccine could express at both transcriptional and translational levels in mammalian cells. Moreover, Bla g 2 vaccine significantly reduced the total inflammatory cell infiltrate and eosinophilia in bronchoalveolar lavage fluid, and markedly decreased allergen-induced inflammatory infiltrates in the lungs and Bla g 2-specific IgE in serum upon challenge with rBla g 2. Importantly, Bla g 2 vaccine could induce the production of antigen-specific IFN-γ and downregulated Th2 pro-inflammatory cytokines IL-4, IL-5, and IL-13. Thus, DNA vaccination showed protective efficacy against a clinically relevant allergen, Bla g 2.