Resveratrol promotes activation-induced cell death of T lymphocytes and improves experimental autoimmune encephalomyelitis / 中国药理学通报

Aim To explore the characteristics and mechanism of resveratrol(Res)in promoting apoptosisof T lymphocytes and to investigate the therapeutic effect of Res on experimental autoimmune encephalomyelitis(EAE)in mice. Methods Annexin V/PI double staining was used to investigate the effect of Res on the apoptosis of mouse primary naïve T lymphocytes and anti-CD3/anti-CD28 activated T lymphocytes. Activation-induced cell death models were established on CD4+ T lymphocytes and Jurkat cells in vitro,and the effect of Res on activation-induced cell death was detected by PI single staining or Annexin V/PI double staining. The expression of apoptosis related proteins were detected by Western blot. EAE model in mice was induced by MOG35-55,and the therapeutic effect of Res administration was investigated. The apoptosis of CD4+ T lymphocytes from vehicle group and Res group was detected. Results Res did not affect the survival of naïve T cells,but promoted the apoptosis of activated T lymphocytes. With the increase of Res concentration,activation-induced cell death of CD4+ T cells and Jurkat cells significantly increased,and the cleavage of apoptosis related proteins PARP and Caspase-3 increased. In addition,Res delayed the onset of EAE,reduced the clinical score,and decreased the infiltration of inflammatory cells in spinal cord. The CD4+ T lymphocytes from the mice with Res administration were more sensitive to activation-induced cell death. Conclusion Res promotes activation-induced cell death of T lymphocytes and ameliorates EAE in mice.

rhPDCD5 suppresses pro-inflammatory cytokine secretion and proliferation and induces apoptosis of activated lymphocytes from rats with collagen-induced arthritis / 南方医科大学学报

OBJECTIVE@#To investigate the effect of recombinant human PDCD5 (rhPDCD5) treatment in a rat model of bovine II collagen (CII)-induced arthritis (CIA) on inflammatory cytokine secretion, proliferation and apoptosis of activated lymphocytes and explore the mechanisms of rhPDCD5-induced immunosuppression on activated lymphocytes.@*METHODS@#Female Wistar rats were randomly divided into normal control group, CIA+ ovalbumin (OVA) group, CIA+ rhTNFR: Fc group, and CIA+rhPDCD5 group. The rats in the latter 3 groups received intraperitoneal injections of OVA (14 mg/kg), rhTNFR: Fc (3.5 mg/kg) or rhPDCD5 (14 mg/kg) from day 2 to day 26 following CII injection. On day 28, the spleens of the rats were harvested for preparing single cell suspensions of splenocytes, which were activated by CII (20μg/mL) or anti-CD3 (1μg/mL)+ anti-CD28 (2μg/mL) for 48 h and 72 h. The production of interferon-γ(IFN-γ) and interleukin-17A (IL-17A) by the activated lymphocytes was determined by ELISA of the culture supernatants. The proliferation and apoptosis of the activated lymphocytes were assessed using [H]-thymidine incorporation assay and flow cytometry, respectively.@*RESULTS@#Compared with those in CIA + OVA group, IFN-γand IL-17A secretions by the activated lymphocytes from rhPDCD5-treated CIA rats significantly decreased. RhPDCD5 treatment of the CIA rats obviously suppressed the proliferation and promoted apoptosis of the lymphocytes activated by CII or by anti-CD3 + anti-CD28.@*CONCLUSIONS@#rhPDCD5 reduces pro-inflammatory cytokine secretion, inhibits the proliferation and promotes activation-induced cell death of activated CD4 lymphocytes to produce immunosuppression in rat models of CIA.

Investigation of the Effective Dose of Agonistic 4-1BB Monoclonal Antibody in a Murine Colon Cancer Metastasis Model

PURPOSE: The aim of this study was to find the dose of agonistic 4-1BB monoclonal antibody (mAb) that results in optimal T cell activation. METHODS: Cancer was induced in mice by an intrahepatic parenchymal injection of 1x10(5) cells of CT26 cells. Cancer-carrying mice (n=84) were divided into seven groups and treated with either rat IgG or agonistic 4-1BB monoclonal antibody (mAb) (5microgram, 10microgram, 20microgram, 100microgram, 200microgram, or 300microgram). All treatments were administered intraperitoneally on days 7, 9, and 11. Mice from each group were sacrificed on days 14, 28, and 42. Harvested livers were weighed and the numbers of T cells in the splenocytes were analyzed with a FACS Vantage flow cytometer. RESULTS: Liver weights increased when 5microgram of agonistic 4-1BB mAb was administered, but showed no additional weight increase for doses greater than 10microgram. The absolute numbers of CD4+ and CD8+ T cells increased in groups treated with low doses of agonistic 4-1BB mAb (5microgram, 10microgram, or 20microgram), but did not increase in the groups treated with high doses of mAb (100microgram, 200microgram, or 300microgram). The levels of CD4/annexin V and CD8/annexin V increased as the dose increased, and the absolute cell numbers of CD4/annexin V were greater than those of CD8/annexin V. CONCLUSION: Liver weight, including the cancer mass, failed to increase at agonistic 4-1BB mAb doses greater than 10microgram. A high dose (> or =100microgram) of agonistic 4-1BB mAb resulted in lower counts of absolute T cells. This study suggests that a low dose (20microgram) of agonistic 4-1BB mAb can be used for optimal T cell activation in combination with other anti-cancer treatments.

Crucial Role of Tissue-specific Apoptosis on the Development of Primary Sjögren's Syndrome / Oral Science International

Primary Sjögren's syndrome is an autoimmune disorder characterized by lymphocytic infiltrates and destruction of the salivary and lacrimal glands, and systemic production of autoantibodies to the ribonucleoprotein (RNP) particles SS-A/Ro and SS-B/La, leading to clinical symptoms of dryness of the mouth and eyes (sicca syndrome). Autoreactive T cells bearing the CD4 molecule may recognize an unknown self antigen, triggering autoimmunity in the salivary and lacrimal glands. Although several candidate autoantigens including α-fodrin have been reported in Sjögren's syndrome, the pathogenic roles of the autoantigens in initiation and progression of SS are still unclear. It is possible that individual T cells activated by an appropriate self antigen can proliferate and form a restricted clone. Recent evidence suggests that the apoptotic pathway plays a central role in making T cells tolerant to tissue-specific self antigen, and may drive the autoimmune phenomenon. We recently reported that tissue-specific apoptosis in estrogen-deficient mice may contribute to autoantigen cleavage, leading to the development of autoimmune exocrinopathy. The studies reviewed imply that tissue-specific apoptosis and caspase-mediated α-fodrin proteolysis are involved in the progression of autoimmune lesions in Sjögren's syndrome. Moreover, Fas ligand (FasL) and its receptor Fas are essential in the homeostasis of the peripheral immune system. It is considered that a defect in activation-induced cell death (AICD) of effector T cells may result in the development of autoimmune exocrinopathy in Sjögren's syndrome.