No effective drug treatments are available for coronavirus disease 2019(COVID-19).Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage,death,or long-term functi...No effective drug treatments are available for coronavirus disease 2019(COVID-19).Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage,death,or long-term functional disability in survivors require clinical evaluation.We performed a parallel assigned controlled,non-randomized,phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells(UC-MSCs)infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease.The study enrolled 18 hospitalized patients with COVID-19(n=9 for each group).The treatment group received three cycles of intravenous infusion of UC-MSCs(3×107 cells per infusion)on days 0,3,and 6.Both groups received standard COVID-treatment regimens.Adverse events,duration of clinical symptoms,laboratory parameters,length of hospitalization,serial chest computed tomography(CT)images,the PaO2/FiO2 ratio,dynamics of cytokines,and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed.No serious UC-MSCs infusion-associated adverse events were observed.Two patients receiving UC-MSCs developed transient facial flushing and fever,and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion.Mechanical ventilation was required in one patient in the treatment group compared with four in the control group.All patients recovered and were discharged.Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated.Phase 2/3 randomized,controlled,double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.展开更多
γδT cells play important roles in innate immunity as the first-line of defense against infectious diseases. Human immunodeficiency virus (HIV) infection disrupts the balance between Vδ1 T cells and Vδ2 T cells a...γδT cells play important roles in innate immunity as the first-line of defense against infectious diseases. Human immunodeficiency virus (HIV) infection disrupts the balance between Vδ1 T cells and Vδ2 T cells and causes dysfunction among γδ T cells. However, the biological mechanisms and clinical consequences of this disruption require further investigation. In this study, we performed a comprehensive analysis of phenotype and function of memory γδ T cells in cohorts of Chinese individuals with HIV infection. We found a dynamic change in memory Vδ2 γδ T cells, skewed toward an activated and terminally differentiated effector memory phenotype TEMRA Vδ2 γδT cell, which may account for the dysfunction of Vδ2 γδT cells in HIV disease. In addition, we found that IL-17-producing γδ T cells were significantly increased in HIV-infected patients with fast disease progression and positively correlated with HLA-DR+ γδ T cells and CD38+HLA-DR+ γδ T cells. This suggests the IL-17 signaling pathway is involved in γδ T-cell activation and HIV pathogenesis. Our findings provide novel insights into the role of Vδ2 T cells during HIV pathogenesis and represent a sound basis on which to consider immune therapies with these cells.展开更多
Preferential infection and depletion of gut-homing a4β7 CD4+ T cells in the blood are observed in chronic HIV/SIV infection. The dynamic change in gut-homing a4p7 CD4+ T cells and their functional subsets during th...Preferential infection and depletion of gut-homing a4β7 CD4+ T cells in the blood are observed in chronic HIV/SIV infection. The dynamic change in gut-homing a4p7 CD4+ T cells and their functional subsets during the acute stages of HIV-1 infection are less documented. Therefore, we conducted a cohort study to investigate whether acute HIV-1 infection induced abnormalities in gut-homing a4β7 CD4+ T cells and their functional subsets. We examined the frequency, absolute number, and functionality of gut-homing a4β7 CD4+ T cells in 26 acute HIV-l-infected patients compared with 20 healthy individuals. We found that circulating gut-homing a4β7 CD4+ T cells were preferentially depleted during acute HIV-1 infection and were positively correlated with absolute CD4+ T-cell count in blood. Notably, Th17 and Thl cell subsets of gut-homing CD4+ T cells were also decreased, which resulted in an imbalance of T helper cells (Th 1)-regulatory T cells (Treg) and Treg.Th 17 ratios. Gut-homing Th17 and Thl cells were also positively correlated with the absolute number of total CD4+ T cells and gut-homing CD4+ T cells. The gut-homing Treg:Th17 ratio was inversely correlated with the CD4+ T-cell count. Taken together, the analyses of our acute HIV-1 cohort demonstrate that gut-homing a4β7 CD4+ T cells and their functional subsets were profoundly depleted during acute HIV-1 infection, which may have resulted in the persistent loss of circulating CD4+ T cells and an imbalance of Thl-Treg and Treg.Th17 ratios and contribute to HIV-1 disease pathogenesis.展开更多
Plasmacytoid dendritic cells(pDCs)are decreased in number and are functionally impaired in HIV act reasons for pDCs depletion are still unknown.It was recently reported that pDCs can be divided into two functionally d...Plasmacytoid dendritic cells(pDCs)are decreased in number and are functionally impaired in HIV act reasons for pDCs depletion are still unknown.It was recently reported that pDCs can be divided into two functionally distinct populations based on their CD2 expression level.To determine how the CD2high and CD2^(low) populations are affected by HIV infection,we analyzed their frequencies in the peripheral blood of HIV-infected subjects and healthy controls.We found that the CD2^(low) pDC subset was preferentially depleted in infected individuals.The frequency of CD2^(low) pDCs correlated with the CD41 T-cell count but not with the plasma viral load.This finding furthers our understanding of the causes and consequences of pDC depletion during HIV infection.展开更多
基金supported by The National Key R&D Program of China(2020YFC0841900,2020YFC0844000)The Innovation Groups of the National Natural Science Foundation of China(81721002)+2 种基金The National Science and Technology Major Project(2017YFA0105703)The Military Emergency Research Project for COVID-19(BWS20J006)The Project for Innovation of Military Medicine of China(16CXZ045).
文摘No effective drug treatments are available for coronavirus disease 2019(COVID-19).Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage,death,or long-term functional disability in survivors require clinical evaluation.We performed a parallel assigned controlled,non-randomized,phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells(UC-MSCs)infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease.The study enrolled 18 hospitalized patients with COVID-19(n=9 for each group).The treatment group received three cycles of intravenous infusion of UC-MSCs(3×107 cells per infusion)on days 0,3,and 6.Both groups received standard COVID-treatment regimens.Adverse events,duration of clinical symptoms,laboratory parameters,length of hospitalization,serial chest computed tomography(CT)images,the PaO2/FiO2 ratio,dynamics of cytokines,and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed.No serious UC-MSCs infusion-associated adverse events were observed.Two patients receiving UC-MSCs developed transient facial flushing and fever,and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion.Mechanical ventilation was required in one patient in the treatment group compared with four in the control group.All patients recovered and were discharged.Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated.Phase 2/3 randomized,controlled,double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.
文摘γδT cells play important roles in innate immunity as the first-line of defense against infectious diseases. Human immunodeficiency virus (HIV) infection disrupts the balance between Vδ1 T cells and Vδ2 T cells and causes dysfunction among γδ T cells. However, the biological mechanisms and clinical consequences of this disruption require further investigation. In this study, we performed a comprehensive analysis of phenotype and function of memory γδ T cells in cohorts of Chinese individuals with HIV infection. We found a dynamic change in memory Vδ2 γδ T cells, skewed toward an activated and terminally differentiated effector memory phenotype TEMRA Vδ2 γδT cell, which may account for the dysfunction of Vδ2 γδT cells in HIV disease. In addition, we found that IL-17-producing γδ T cells were significantly increased in HIV-infected patients with fast disease progression and positively correlated with HLA-DR+ γδ T cells and CD38+HLA-DR+ γδ T cells. This suggests the IL-17 signaling pathway is involved in γδ T-cell activation and HIV pathogenesis. Our findings provide novel insights into the role of Vδ2 T cells during HIV pathogenesis and represent a sound basis on which to consider immune therapies with these cells.
文摘Preferential infection and depletion of gut-homing a4β7 CD4+ T cells in the blood are observed in chronic HIV/SIV infection. The dynamic change in gut-homing a4p7 CD4+ T cells and their functional subsets during the acute stages of HIV-1 infection are less documented. Therefore, we conducted a cohort study to investigate whether acute HIV-1 infection induced abnormalities in gut-homing a4β7 CD4+ T cells and their functional subsets. We examined the frequency, absolute number, and functionality of gut-homing a4β7 CD4+ T cells in 26 acute HIV-l-infected patients compared with 20 healthy individuals. We found that circulating gut-homing a4β7 CD4+ T cells were preferentially depleted during acute HIV-1 infection and were positively correlated with absolute CD4+ T-cell count in blood. Notably, Th17 and Thl cell subsets of gut-homing CD4+ T cells were also decreased, which resulted in an imbalance of T helper cells (Th 1)-regulatory T cells (Treg) and Treg.Th 17 ratios. Gut-homing Th17 and Thl cells were also positively correlated with the absolute number of total CD4+ T cells and gut-homing CD4+ T cells. The gut-homing Treg:Th17 ratio was inversely correlated with the CD4+ T-cell count. Taken together, the analyses of our acute HIV-1 cohort demonstrate that gut-homing a4β7 CD4+ T cells and their functional subsets were profoundly depleted during acute HIV-1 infection, which may have resulted in the persistent loss of circulating CD4+ T cells and an imbalance of Thl-Treg and Treg.Th17 ratios and contribute to HIV-1 disease pathogenesis.
基金supported in part by grants from the National Natural Science Foundation of China 30872365(LZ)the Beijing Municipal of Science and Technology Major Project D09050703590901the National Key Technologies R&DProgram for the 11th Five-Year Plan 2008ZX10001-001 and 2008ZX10001-006(HW).
文摘Plasmacytoid dendritic cells(pDCs)are decreased in number and are functionally impaired in HIV act reasons for pDCs depletion are still unknown.It was recently reported that pDCs can be divided into two functionally distinct populations based on their CD2 expression level.To determine how the CD2high and CD2^(low) populations are affected by HIV infection,we analyzed their frequencies in the peripheral blood of HIV-infected subjects and healthy controls.We found that the CD2^(low) pDC subset was preferentially depleted in infected individuals.The frequency of CD2^(low) pDCs correlated with the CD41 T-cell count but not with the plasma viral load.This finding furthers our understanding of the causes and consequences of pDC depletion during HIV infection.