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Interleukin-17 (IL-17)-producing CD4M ore than 350 million people worldwide suffer from persistent infection with hepatitis B virus (HBV) and are at risk for developing liver cirrhosis and hepatocellular carcinoma. 1 HBV itself is noncytopathic, but immune-mediated liver damage often occurs in patients with both acute and chronic HBV infection. Such damage has conventionally been attributed to killing of infected hepatocytes by virus-specific cytotoxic CD8 ϩ T cells. [2][3][4] Increasing evidence, however, suggests that non-HBV-specific inflammatory infiltration into the liver is likely responsible for hepatic pathology in patients with chronic hepatitis B (CHB). 5,6 For example, in HBV infection activated HBV-specific CD8 ϩ T cells are often present at high levels in the livers of patients without evident liver inflammation; by contrast, nonantigen-specific lymphocytes were found to be massively infiltrated into the livers of patients with hepatic inflammation. 7 An HBV transgenic mouse model further reinforced the concept that liver inflammation initiated by virus-specific CD8 ϩ T cells is amplified by other lymphocytes. 4,8 Indeed, a large number of immune cells, including myeloid dendritic cells (mDCs), plasmacytoid dendritic cells, and FoxP3-positive regulatory T cells can

CD4+CD25+ regulatory T cells (Treg) have been shown to maintain immune tolerance against self and foreign Ags, but their role in persistent viral infection has not been well-defined. In this study, we investigated whether and where CD4+CD25+ Treg contribute to the development of chronic hepatitis B (CHB). One hundred twenty-one patients were enrolled, including 16 patients with acute hepatitis B, 76 with CHB, and 29 with chronic severe hepatitis B. We demonstrated that in chronic severe hepatitis B patients, the frequencies of CD4+CD25+ Treg in both PBMC and liver-infiltrating lymphocytes were significantly increased and there was a dramatic increase of FoxP3+-cell and inflammatory cell infiltration in the liver compared with healthy controls. In CHB patients, circulating CD4+CD25+ Treg frequency significantly correlates with serum viral load. In acute hepatitis B patients, circulating CD4+CD25+ Treg frequency was initially low and with time, the profile reversed to exhibit an increased number of circulating Treg in the convalescent phase and restored to normal levels upon resolution. In PBMC taken from infected patients, depletion of CD4+CD25+ Treg led to an increase of IFN-γ production by HBV-Ag-stimulated PBMC. In addition, CD4+CD25+ Treg were capable of suppressing proliferation of autologous PBMC mediated by HBV Ags, which probably reflects the generation of HBV-Ag-specific Treg in circulation and in the liver of HBV-infected patients. Together, our findings suggest that CD4+CD25+ Treg play an active role not only in modulating effectors of immune response to HBV infection, but also in influencing the disease prognosis in patients with hepatitis B.

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was −13.31%, 95% CI −29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: −15.45%; 95% CI −30.82%, −0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.

The immunoreceptor PD-1 is significantly up-regulated on exhausted CD8 ؉ T cells during chronic viral infections such as HIV-1. However, it remains unknown whether PD-1 expression on CD8 ؉ T cells differs between typical progressors (TPs) and long-term nonprogressors (LTNPs). In this report, we examined PD-1 expression on HIV-specific CD8 ؉ T cells from 63 adults with chronic HIV infection. We found that LTNPs exhibited functional HIV-specific memory CD8 ؉ T cells with markedly lower PD-1 expression. TPs, in contrast, showed significantly up-regulated PD-1 expression that was closely correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load. Importantly, PD-1 up-regulation was also associated with reduced perforin and IFN-␥ production, as well as decreased HIV-specific effector memory CD8 ؉ T-cell proliferation in TPs but not LTNPs. Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8 ؉ T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 up-regulation mediates HIV-specific CD8 ؉ T-cell exhaustion. IntroductionCD8 ϩ T cells play a critical role in clearing human immunodeficiency virus (HIV) infection in vivo. 1 In general, typical progressors (TPs) have insufficient CD8 ϩ T-cell responses to HIV and fail to maintain durable control of the HIV load, whereas long-term nonprogressors (LTNPs) preferentially maintain functional HIVspecific CD8 ϩ T cells that can persistently control viral replication. [2][3][4][5][6][7][8][9][10] During the CD8 ϩ T-cell response to HIV, there is a complex process of memory CD8 ϩ T-cell differentiation. 11 On the basis of CD45RA and CCR7 surface marker expression and relative function, 4 subpopulations of memory CD8 ϩ T cells are proposed to exist: naive CD45RA ϩ CCR7 ϩ T cells, central memory CD45RA Ϫ CCR7 ϩ T (T CM ) cells, effector memory CD45RA Ϫ CCR7 Ϫ T (T EM ) cells, and terminally differentiated effector CD45RA ϩ CCR7 Ϫ T (T EM RA) cells. [12][13][14][15] The T CM subpopulation readily differentiates into proliferating effector cells and homes to T-cell areas of the secondary lymphoid organs, but it has little or no effector function. The T EM subset has selectively lost constitutive CCR7 expression and produces high levels of perforin, IFN-␥, and IL-4 within hours of antigenic stimulation. The T EM RA subset, the T EM subpopulation that expresses CD45RA, can produce high levels of perforin. Thus, T EM cells are characterized by rapid effector function. Champagne et al 16 have demonstrated that chronic HIV-1 infection affects the differentiation pattern of different CD8 ϩ T-cell subsets; however, the molecular mechanisms of how this process occurs remain undefined.Memory T-cell responses are an important component of protective immunity against viral infection. However, memory T-cell responses generated during chronic viral infection often show defects in antiviral function and skewed differentiation of the memory T-cell subsets. [16][17][18] For example, the proportion ...

Decompensated liver cirrhosis (LC), a life-threatening complication of chronic liver disease, is one of the major indications for liver transplantation. Recently, mesenchymal stem cell (MSC) transfusion has been shown to lead to the regression of liver fibrosis in mice and humans. This study examined the safety and efficacy of umbilical cord-derived MSC (UC-MSC) in patients with decompensated LC. A total of 45 chronic hepatitis B patients with decompensated LC, including 30 patients receiving UC-MSC transfusion, and 15 patients receiving saline as the control, were recruited; clinical parameters were detected during a 1-year follow-up period. No significant side-effects and complications were observed in either group. There was a significant reduction in the volume of ascites in patients treated with UC-MSC transfusion compared with controls (P < 0.05). UC-MSC therapy also significantly improved liver function, as indicated by the increase of serum albumin levels, decrease in total serum bilirubin levels, and decrease in the sodium model for end-stage liver disease scores. UC-MSC transfusion is clinically safe and could improve liver function and reduce ascites in patients with decompensated LC. UC-MSC transfusion, therefore, might present a novel therapeutic approach for patients with decompensated LC.

Acute-on-chronic liver failure (ACLF) is a severe, life-threatening complication, and new and efficient therapeutic strategies for liver failure are urgently needed. Mesenchymal stem cell (MSC) transfusions have been shown to reverse fulminant hepatic failure in mice and to improve liver function in patients with end-stage liver diseases. We assessed the safety and initial efficacy of umbilical cordderived MSC (UC-MSC) transfusions for ACLF patients associated with hepatitis B virus (HBV) infection. A total of 43 ACLF patients were enrolled for this open-labeled and controlled study; 24 patients were treated with UC-MSCs, and 19 patients were treated with saline as controls. UC-MSC therapy was given three times at 4-week intervals. The liver function, adverse events, and survival rates were evaluated during the 48-week or 72-week follow-up period. No significant side effects were observed during the trial. The UC-MSC transfusions significantly increased the survival rates in ACLF patients; reduced the model for end-stage liver disease scores; increased serum albumin, cholinesterase, and prothrombin activity; and increased platelet counts. Serum total bilirubin and alanine aminotransferase levels were significantly decreased after the UC-MSC transfusions. UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients. STEM CELLS TRANSLATIONAL MEDICINE 2012;1:725-731

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