-
[show abstract]
[hide abstract]
ABSTRACT: We previously established a systemic lupus erythematosus (SLE) animal model in non-susceptible BALB/c mice by immunizing with activated syngeneic lymphocyte-derived DNA (ALD-DNA), manifested by high level of anti-double-stranded DNA (dsDNA) antibodies (Abs), proteinuria, glomerular deposition of immune complex and glomerulonephritis. The production of anti-dsDNA Abs is closely related with the renal inflammation and damage in this model. However, recognition of ALD-DNA and its signaling pathway within antigen-presenting cells (APC) remains not fully clarified. Herein, in this study, Toll-like receptor 9 (TLR9), a well-known pattern-recognition receptor for dsDNA with CpG motif, was found to be dynamically up-regulated in B cells during the process of the SLE disease. Knockdown of TLR9 by short interfering RNA (siRNA) in B cells in vitro and in vivo reduced the production of anti-dsDNA antibody and consequently ameliorated the SLE syndrome in mice while the affinity and isotype of the antibody remained the same. Our results implied that TLR9 signaling of B cells might play an important role in the production of anti-dsDNA Abs triggered by auto dsDNA, which would extend our understanding of TLR9 immune recognition in the pathogenesis of SLE disease.
Molecular Immunology 07/2011; 48(12-13):1532-9. · 2.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Antibodies to CD25 (anti-CD25) were used clinically to achieve immunosuppression in autoimmune disease, while the possibility of anti-antibodies generation influenced its efficiency. Here we reported that DNA vaccine encoding the extracellular domain of murine CD25 gene (pCD25-ECD) elicited anti-CD25 antibody production in BALB/c mice and subsequently prevents the host against ConA-induced autoimmune hepatitis. We found that serum CD25-specific antibodies were generated after vaccination with pCD25-ECD. Moreover, high levels of IL-4, IL-10 and anti-CD25 antibody were produced by splenocytes of vaccinated mice after CD25 protein restimulation in vitro. Furthermore, we demonstrated that the vaccinated mice suffered less from liver injury induced by ConA, accompanied by the reduction of pathogenic CD4+ T cells. Finally, we showed that the immunized serum could cause cytolysis of activated CD4+ T cells in vitro, depending on complements activation. Our study showed pCD25-ECD induced self anti-CD25 antibodies which executed immunosuppression in autoimmune hepatitis via antibody-complement pathway.
Clinical Immunology 07/2009; 132(3):412-9. · 4.05 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Adoptive cell transfer (ACT) immunotherapy administered with prior host immunosuppression significantly improved the anti-tumor efficacy in a murine model. However, bulk transfer of lymphocytes containing suppressor lymphocyte subsets, including regulatory T cells to mice bearing late-stage tumors impaired this anti-tumor effect. In this study, we investigated the enhanced anti-tumor efficacy by adoptive transfer of Treg-depleted autologous tumor infiltrating lymphocytes in advanced murine breast cancer. We found that, compared to bulk cell transfer, Treg-depleted cell transfer enhanced the activation and proliferation of both CD4(+) and CD8(+) T cells. Most importantly, the immune response deviated towards the Th1 response reflected by increased IFNgamma and reduced IL-4 secretion in both CD4(+) and CD8(+) T cells and an enhanced granzyme B release of CTL. Furthermore, the elicited Th1 response subsequently resulted in delayed tumor growth and prolonged mice survival as well as reduced lung metastasis in tumor-bearing nude mice. These results strongly indicated that Treg-depleted autologous cell transfer greatly enhanced Th1 type immune response, consequently leading to delayed tumor growth and reduced tumor burden. Therefore, ACT immunotherapy based on ex vivo selection of tumor-reactive lymphocytes resulted in enhanced anti-tumor immunity and provides important implications for further human studies.
Cancer biology & therapy 02/2009; 8(1):66-72. · 2.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Alpha-dystroglycan has been proved to be involved in lymphocyte activation by participating in immunological synapse (IS) formation. Considering the existence of IS formation in thymic development, we questioned whether alpha-dystroglycan was expressed in thymus and influenced thymic development. In this study, we demonstrated that alpha-dystroglycan was expressed on fetal thymocytes, especially on double-positive (DP, CD4(+)CD8(+)) cells. Blocking alpha-dystroglycan by treatment of fetal thymus organ culture (FTOC) with anti-alpha-dystroglycan antibody IIH6C4 decreased the number of DP cells compared with nontreated or isotype antibody controls. Down-regulation of alpha-dystroglycan by retroviruses carrying antisense cDNA of dystroglycan in reaggregate thymus organ culture (RTOC) further confirmed these results. Enhanced apoptosis of DP cells was observed after blocking alpha-dystroglycan. Interestingly, we found that blocking alpha-dystroglycan reduced IS formation between DP cells and thymic epithelial cells. Furthermore, blocking alpha-dystroglycan up-regulated CD95/CD95L expression and reduced Bcl-2 expression on DP cells in the developing thymus. Finally, the increase in the apoptosis of DP cells was associated with a consequent decrease in the positive selection, as indicated by the reduction of both ERK phosphorylation in DP cells and single-positive (SP, CD4(+) or CD8(+)) cell outcome. Altogether, these results indicated that alpha-dystroglycan was involved in positive selection of thymocytes by participating in the IS formation.
The FASEB Journal 06/2008; 22(5):1426-39. · 5.71 Impact Factor
