Osteoporosis(OP)is a common age-related disease characterized by a deterioration of bone mass and structure that predisposes patients to fragility fractures.Pharmaceutical therapies that promote anabolic bone formatio...Osteoporosis(OP)is a common age-related disease characterized by a deterioration of bone mass and structure that predisposes patients to fragility fractures.Pharmaceutical therapies that promote anabolic bone formation in OP patients and OP-induced fracture are needed.We investigated whether a neutralizing antibody against Siglec-15 can simultaneously inhibit bone resorption and stimulate bone formation.We found that the multinucleation of osteoclasts was inhibited in SIGLEC-15 conditional knockout mice and mice undergoing Siglec-15 neutralizing antibody treatment.The secretion of platelet-derived growth factor-BB(PDGF-BB),the number of tartrate-resistant acid phosphatase-positive(TRAP+)mononuclear cells,and bone formation were significantly increased in the SIGLEC-15 conditional knockout mice and antibody-treated mice.The anabolic effect of the Siglec-15 neutralizing antibody on bone formation was blunted in mice with Pdgfb deleted in TRAP-1"cells.These findings showed that the anabolic effect of the Siglec-15 neutralizing antibody was mediated by elevating PDGF-BB production of TRAP4 mononuclear cells.To test the therapeutic potential of the Siglec-15 neutralizing antibody,we injected the antibody in an ovariectomy-induced osteoporotic mouse model,which mimics postmenopausal osteoporosis in women,and in two fracture healing models because fracture is the most serious health consequence of osteoporosis.The Siglec-15 neutralizing antibody effectively reduced bone resorption and stimulated bone formation in estrogen deficiency-induced osteoporosis.Of note,the Siglec-15 neutralizing antibody promoted intramembranous and endochondral ossification at the damaged area of cortical bone in fracture healing mouse models.Thus,the Siglec-15 neutralizing antibody shows significant translational potential as a novel therapy for OP and bone fracture.展开更多
In the Acknowledgement section of this article,NIH grants numbered P50 CA196530 and P30 CA016359 were incorrectly attributed to author Lieping Chen and should not have been cited.The original article has been corrected.
The role of B7-DC in T-cell responses remains controversial because both coinhibitory and costimulatory functions have been reported in various experimental systems in vitro and in vivo.In addition to interacting with...The role of B7-DC in T-cell responses remains controversial because both coinhibitory and costimulatory functions have been reported in various experimental systems in vitro and in vivo.In addition to interacting with the coinhibitory receptor PD-1,B7-DC has also been shown to bind repulsive guidance molecule b(RGMb).The functional consequences of the B7-DC/RGMb interaction,however,remain unclear.More than a decade ago,we reported that replacement of a murine B7-DC mutant lysine with serine(K113S)at positive 113 resulted in a loss of binding capacity to PD-1.Nevertheless,K113S remained costimulatory for T cells in vitro,implicating a dual functionality for B7-DC in T-cell responses.Here we show that recombinant K113S protein interacts with RGMb with a similar affinity to wild-type B7-DC.More importantly,K113S costimulates CD4^(+)T-cell responses via RGMb and promotes Th1 polarization.RGMb is expressed on the surface of naive mouse T cells,macrophages,neutrophils and dendritic cells.Finally,K113S/RGMb costimulation suppresses Th2-mediated asthma and ameliorates small airway inflammation and lung pathology in an experimental mouse model.Our findings indicate that RGMb is a costimulatory receptor for B7-DC.These findings from the K113S variant provide not only a possible explanation for the B7-DC-triggered contradictory effects on T-cell responses,but also a novel approach to investigate the B7-DC/PD-1/RGMb axis.Recombinant K113S or its derivatives could potentially be developed as an agonist for RGMb to costimulate the Th1 response without triggering PD-1-mediated T-cell inhibition.展开更多
Programmed death one homolog (PD-1H) is a cell surface molecule of the B7/CD28 immune modulatory genefamily. Although PD-1H has been shown to function as a coinhibitory receptor on T cells to limit naive T-cellactivat...Programmed death one homolog (PD-1H) is a cell surface molecule of the B7/CD28 immune modulatory genefamily. Although PD-1H has been shown to function as a coinhibitory receptor on T cells to limit naive T-cellactivation and proliferation, its role in the regulation of the T-cell response to allergens is unknown. We report herethat genetic ablation or blockade of PD-1H drastically promotes pulmonary inflammation with massive accumulationof eosinophils in a mouse model of experimental asthma, indicating a suppressive function of PD-1H in allergicinflammation. The loss of PD-1H led to elevated production of both innate cytokines (IL-6, MCP-1 and TNFα) andTh2 cytokines (IL-5 and IL-13) in the lung, indicating a critical role of PD-1H in suppressing the production ofairway inflammatory cytokines. In addition, the loss of PD-1H also impaired the expansion of systemic andpulmonary regulatory T cells during asthma induction. These findings support a critical role of intrinsic PD-1H inthe regulation of inflammatory responses to allergens. Finally, we showed that treatment with a PD-1H agonisticmonoclonal antibody reduced the severity of asthma, which was accompanied by suppressed lung inflammation.Our findings support PD-1H as a potential target and suggest a possible strategy for the treatment of allergicasthma in humans.展开更多
T cell activation-induced cell death(AICD),that involves the induction of Fas-mediated apoptosis,is very important for the maintenance of immune homeostasis.TOSO was firstly described as an inhibitor of Fasmediated ap...T cell activation-induced cell death(AICD),that involves the induction of Fas-mediated apoptosis,is very important for the maintenance of immune homeostasis.TOSO was firstly described as an inhibitor of Fasmediated apoptosis and overexpressed in chronic lymphocytic leukemia.Recently,TOSO was identified as IgM FcR.In this study,we produced anti-TOSO monoclonal antibody(mAb)that could block the binding of IgM to TOSO and found that T cell apoptosis is negatively correlated with TOSO expression during T cell activation.Treatment of activated T cells with anti-TOSO blocking mAb promoted T cell AICD in in vitro AICD model,and treatment of xenogeneic-GVHD mice with the antibody also increased the sensitivity of activated T cells to Fasinduced apoptosis,which was accompanied by reduction of c-FLIPL expression and up-regulation of AP-1 complex.In summary,our data indicate the anti-apoptotic effect of TOSO in T cell AICD and open up new therapeutic prospects for the treatment of hematologic malignancies and immune disorders.展开更多
It has been reported that the ratio of CD41 to CD81 T cells has no bias in a few class I major histocompatibility complex(MHC-I)-restricted T-cell receptor(TCR)-transgenic mice specific for alloantigens or autoantigen...It has been reported that the ratio of CD41 to CD81 T cells has no bias in a few class I major histocompatibility complex(MHC-I)-restricted T-cell receptor(TCR)-transgenic mice specific for alloantigens or autoantigens,in which most CD41 T cells express an MHC-I-restricted TCR.In this study,we further showed that more than 50%of CD41 T cells in MHC-I-restricted P1A tumor antigen-specific TCR(P1ATCR)-transgenic mice could specifically bind to MHC-I/P1A peptide complex.P1A peptide could stimulate the transgenic CD41 T cells to proliferate and secrete both type 1 helper T cell and type 2 helper T cell cytokines.The activated CD41 T cells also showed cytotoxicity against P1A-expressing tumor cells.The analysis of TCR a-chains showed that these CD41 T cells were selected by co-expressing endogenous TCRs.Our results show that CD41 T cells from P1ATCR transgenic mice co-expressed an MHC-I-restricted transgenic TCR and another rearranged endogenous TCRs,both of which were functional.展开更多
基金This research was partially supported by a grant from NextCure,Inc.and the NIH National Institute on Aging under Award Number P01AG066603.
文摘Osteoporosis(OP)is a common age-related disease characterized by a deterioration of bone mass and structure that predisposes patients to fragility fractures.Pharmaceutical therapies that promote anabolic bone formation in OP patients and OP-induced fracture are needed.We investigated whether a neutralizing antibody against Siglec-15 can simultaneously inhibit bone resorption and stimulate bone formation.We found that the multinucleation of osteoclasts was inhibited in SIGLEC-15 conditional knockout mice and mice undergoing Siglec-15 neutralizing antibody treatment.The secretion of platelet-derived growth factor-BB(PDGF-BB),the number of tartrate-resistant acid phosphatase-positive(TRAP+)mononuclear cells,and bone formation were significantly increased in the SIGLEC-15 conditional knockout mice and antibody-treated mice.The anabolic effect of the Siglec-15 neutralizing antibody on bone formation was blunted in mice with Pdgfb deleted in TRAP-1"cells.These findings showed that the anabolic effect of the Siglec-15 neutralizing antibody was mediated by elevating PDGF-BB production of TRAP4 mononuclear cells.To test the therapeutic potential of the Siglec-15 neutralizing antibody,we injected the antibody in an ovariectomy-induced osteoporotic mouse model,which mimics postmenopausal osteoporosis in women,and in two fracture healing models because fracture is the most serious health consequence of osteoporosis.The Siglec-15 neutralizing antibody effectively reduced bone resorption and stimulated bone formation in estrogen deficiency-induced osteoporosis.Of note,the Siglec-15 neutralizing antibody promoted intramembranous and endochondral ossification at the damaged area of cortical bone in fracture healing mouse models.Thus,the Siglec-15 neutralizing antibody shows significant translational potential as a novel therapy for OP and bone fracture.
文摘In the Acknowledgement section of this article,NIH grants numbered P50 CA196530 and P30 CA016359 were incorrectly attributed to author Lieping Chen and should not have been cited.The original article has been corrected.
基金supported by grants from Guangdong Province Innovative Research Program Project(No.2011Y035)863 Project grants to Sun Yat-sen University and the United Technologies Corporation endowed chair from Yale University.
文摘The role of B7-DC in T-cell responses remains controversial because both coinhibitory and costimulatory functions have been reported in various experimental systems in vitro and in vivo.In addition to interacting with the coinhibitory receptor PD-1,B7-DC has also been shown to bind repulsive guidance molecule b(RGMb).The functional consequences of the B7-DC/RGMb interaction,however,remain unclear.More than a decade ago,we reported that replacement of a murine B7-DC mutant lysine with serine(K113S)at positive 113 resulted in a loss of binding capacity to PD-1.Nevertheless,K113S remained costimulatory for T cells in vitro,implicating a dual functionality for B7-DC in T-cell responses.Here we show that recombinant K113S protein interacts with RGMb with a similar affinity to wild-type B7-DC.More importantly,K113S costimulates CD4^(+)T-cell responses via RGMb and promotes Th1 polarization.RGMb is expressed on the surface of naive mouse T cells,macrophages,neutrophils and dendritic cells.Finally,K113S/RGMb costimulation suppresses Th2-mediated asthma and ameliorates small airway inflammation and lung pathology in an experimental mouse model.Our findings indicate that RGMb is a costimulatory receptor for B7-DC.These findings from the K113S variant provide not only a possible explanation for the B7-DC-triggered contradictory effects on T-cell responses,but also a novel approach to investigate the B7-DC/PD-1/RGMb axis.Recombinant K113S or its derivatives could potentially be developed as an agonist for RGMb to costimulate the Th1 response without triggering PD-1-mediated T-cell inhibition.
基金This work is supported in part by the 985 project grant from Sun Yat-Sen University,Guangdong Province Innovative Research Program Project 2011Y035,PRCNational Institutes of Health grants P50 CA196530 and P30 CA016359.
文摘Programmed death one homolog (PD-1H) is a cell surface molecule of the B7/CD28 immune modulatory genefamily. Although PD-1H has been shown to function as a coinhibitory receptor on T cells to limit naive T-cellactivation and proliferation, its role in the regulation of the T-cell response to allergens is unknown. We report herethat genetic ablation or blockade of PD-1H drastically promotes pulmonary inflammation with massive accumulationof eosinophils in a mouse model of experimental asthma, indicating a suppressive function of PD-1H in allergicinflammation. The loss of PD-1H led to elevated production of both innate cytokines (IL-6, MCP-1 and TNFα) andTh2 cytokines (IL-5 and IL-13) in the lung, indicating a critical role of PD-1H in suppressing the production ofairway inflammatory cytokines. In addition, the loss of PD-1H also impaired the expansion of systemic andpulmonary regulatory T cells during asthma induction. These findings support a critical role of intrinsic PD-1H inthe regulation of inflammatory responses to allergens. Finally, we showed that treatment with a PD-1H agonisticmonoclonal antibody reduced the severity of asthma, which was accompanied by suppressed lung inflammation.Our findings support PD-1H as a potential target and suggest a possible strategy for the treatment of allergicasthma in humans.
基金supported by the National Key Basic Research Program of China(2012CB917101)the National Natural Science Foundation of China(30771968 and 81000920)
文摘T cell activation-induced cell death(AICD),that involves the induction of Fas-mediated apoptosis,is very important for the maintenance of immune homeostasis.TOSO was firstly described as an inhibitor of Fasmediated apoptosis and overexpressed in chronic lymphocytic leukemia.Recently,TOSO was identified as IgM FcR.In this study,we produced anti-TOSO monoclonal antibody(mAb)that could block the binding of IgM to TOSO and found that T cell apoptosis is negatively correlated with TOSO expression during T cell activation.Treatment of activated T cells with anti-TOSO blocking mAb promoted T cell AICD in in vitro AICD model,and treatment of xenogeneic-GVHD mice with the antibody also increased the sensitivity of activated T cells to Fasinduced apoptosis,which was accompanied by reduction of c-FLIPL expression and up-regulation of AP-1 complex.In summary,our data indicate the anti-apoptotic effect of TOSO in T cell AICD and open up new therapeutic prospects for the treatment of hematologic malignancies and immune disorders.
基金grants from the National Natural Science Foundation of China under contract no.30771968.
文摘It has been reported that the ratio of CD41 to CD81 T cells has no bias in a few class I major histocompatibility complex(MHC-I)-restricted T-cell receptor(TCR)-transgenic mice specific for alloantigens or autoantigens,in which most CD41 T cells express an MHC-I-restricted TCR.In this study,we further showed that more than 50%of CD41 T cells in MHC-I-restricted P1A tumor antigen-specific TCR(P1ATCR)-transgenic mice could specifically bind to MHC-I/P1A peptide complex.P1A peptide could stimulate the transgenic CD41 T cells to proliferate and secrete both type 1 helper T cell and type 2 helper T cell cytokines.The activated CD41 T cells also showed cytotoxicity against P1A-expressing tumor cells.The analysis of TCR a-chains showed that these CD41 T cells were selected by co-expressing endogenous TCRs.Our results show that CD41 T cells from P1ATCR transgenic mice co-expressed an MHC-I-restricted transgenic TCR and another rearranged endogenous TCRs,both of which were functional.
