Incomplete immune reconstitution occurs in 10%-40%of antiretroviral therapy(ART)-treated human immunodeficiency virus(HIV)patients.This subset of immunological non-responders(INRs)has yet to undergo a comprehensive an...Incomplete immune reconstitution occurs in 10%-40%of antiretroviral therapy(ART)-treated human immunodeficiency virus(HIV)patients.This subset of immunological non-responders(INRs)has yet to undergo a comprehensive analysis of immunological profiles,and no definitive cytological diag-nosis has been established.In this study,we comparatively analyzed the immunological profiles of INRs,immunological responders(IRs),and healthy control individuals(HCs)via single-cell RNA sequencing(scRNA-seq)and single-cell T-cell receptor(TCR)repertoire sequencing of peripheral blood mononuclear cells(PBMCs),and identified a relatively small population of mucosal-associated invariant T(MAIT)cells in INRs.This finding was recapitulated in rhesus macaques infected with simian immunodeficiency virus(SIV).Specifically,the population of the naïve MAIT cell subtype was significantly lower in INRs than in IRs,and the majority of MAIT cells were CD8^(+)cell subsets.Further characteristic analysis of MAIT cells via the transcriptome revealed decreased expression of cytotoxicity-related genes in INRs,while displaying increased expression of genes involved in TGF-β receptor signaling.In summary,by conducting a comparative analysis,this study revealed a corre-lation between the decreased proportion of naïve MAIT cells and impaired immune reconstitution in INRs.This finding highlights a particular cell subset that may play a pivotal role in the incomplete immune reconstitution,and suggests a plausible cellular target for the modulation of INRs.展开更多
Objective To explore the effect of α-galactosyleramide （α-GalCer） on immune reconstitution under acute graft-versus-host disease （aGVHD）. Methods BALB/c mice were transplanted with allogeneic C57BL/6 bone marro...Objective To explore the effect of α-galactosyleramide （α-GalCer） on immune reconstitution under acute graft-versus-host disease （aGVHD）. Methods BALB/c mice were transplanted with allogeneic C57BL/6 bone marrow cells and splenocytes （both 1 × 10^7） after receiving lethal total-body irradiation, α-GalCer （100 ug/kg） or vehicle （dimethyl- sulfoxide） was administered intraperitoneally immediately after transplantation. The effects of α-GalCer on immune reconstitufion, proliferation of T cells and B cells, hematopoiesis, and thymic microenvironment were assessed. Results The α-GalCer group exhibited higher percentages of CD3^＋, CD4^＋, CD8^＋, B220^＋, CD40＋, and CD86＋cells compared with the vehicle group. The number of colony forming unit per 1000 CD34^＋ cells in the et-GalCer group was higher than in the vehicle group （P=0.0012）. In vitro proliferation assays showed that the α-GalCer group had higher percentages of CD3^＋, CD4^＋, CD8^＋, and B220^＋ cells compared with the vehicle group. As for the results of in vivo proliferation assays, the numbers of CD3^＋, CD4^＋, CD8^＋, and B220^＋ cells were higher in the α-GalCer group than in the normal group, especially the number of B220^＋ cells （P=0.007）. Significant difference was not found in thymocyte count between the α-GalCer group and the vehicle group, nor in the percentages of CD3^＋, CD4^＋, and CD8^＋ cells. Conclusion Administration of tl-GalCer after allogeneic bone marrow transplantation may promote immune reconstitution in the presence of aGVHD.展开更多
The mouse genome has a high degree of homology with the human genome,and its physiological,biochemical,and developmental regulation mechanisms are similar to those of humans;therefore,mice are widely used as experimen...The mouse genome has a high degree of homology with the human genome,and its physiological,biochemical,and developmental regulation mechanisms are similar to those of humans;therefore,mice are widely used as experimental animals.However,it is undeniable that interspecies differences between humans and mice can lead to experimental errors.The differences in the immune system have become an impor-tant factor limiting current immunological research.The application of immunodefi-cient mice provides a possible solution to these problems.By transplanting human immune cells or tissues,such as peripheral blood mononuclear cells or hematopoietic stem cells,into immunodeficient mice,a human immune system can be reconstituted in the mouse body,and the engrafted immune cells can elicit human-specific immune responses.Researchers have been actively exploring the development and differen-tiation conditions of host recipient animals and grafts in order to achieve better im-mune reconstitution.Through genetic engineering methods,immunodeficient mice can be further modified to provide a favorable developmental and differentiation microenvironment for the grafts.From initially only being able to reconstruct single T lymphocyte lineages,it is now possible to reconstruct lymphoid and myeloid cells,providing important research tools for immunology-related studies.In this review,we compare the differences in immune systems of humans and mice,describe the devel-opment history of human immune reconstitution from the perspectives of immuno-deficient mice and grafts,and discuss the latest advances in enhancing the efficiency of human immune cell reconstitution,aiming to provide important references for im-munological related researches.展开更多
Despite continuous progress,the prevention and treatment of human immunodeficiency virus(HIV)/acquired immune deficiency syndrome(AIDS)remain the world’s most serious public health challenges.A key problem is the deg...Despite continuous progress,the prevention and treatment of human immunodeficiency virus(HIV)/acquired immune deficiency syndrome(AIDS)remain the world’s most serious public health challenges.A key problem is the degree of immune function reconstruction after antiretroviral therapy.Antiretroviral therapy has enriched the treatment of HIV/AIDS and improved the present conditions and the life quality of HIV/AIDS patients.However,some patients still fail to achieve normalization of CD4+T lymphocyte counts although persistent virological suppression.These patients are referred to as immunological non-responders,and usually present with severe immunological dysfunction.To date,since the underlying mechanism of incomplete immune reconstitution in HIV/AIDS has not been fully elucidated,remaining to be the focus and difficulties of current research.It is still a challenge to explore a safe,effective,and reliable therapeutic method for immunological non-responders.Due to fewer side effects and lower drug resistance,traditional Chinese medicine is often sought to provide alternative pharmacotherapy for regulating the immunity of immunological non-responders in China.In this review,we aimed at summarizing the latest and most comprehensive information on traditional Chinese medicine therapeutic methods for promoting immune reconstruction.In addition,outlooks and perspectives for possible future research that related are also discussed.展开更多
To observe potential effect of the engineered bone marrow stromal cell line QXMSC1 secreting IL-6 (QXMSCIL-6) on accelerating immune reconstitution in syngeneic bone marrow transplantation in mice, QXMSC1 was transfec...To observe potential effect of the engineered bone marrow stromal cell line QXMSC1 secreting IL-6 (QXMSCIL-6) on accelerating immune reconstitution in syngeneic bone marrow transplantation in mice, QXMSC1 was transfected with the eukaryocytic expression vector pcDNAIL-6, which contained hIL-6 cDNA by liposome-mediated gene transfecting technique. G418-resistance clone was selected by limiting dilution. The highest secreting clone was selected by ELISA assay and used in animal experiments. The recipient mice (BALB/c) were lethally irradiated and cotransplanted syngeneic bone marrow (10 7/mice) and the QXMSC1IL-6 (5×10 5/mice). Lymphocyte proliferation induced by ConA and LPS, helper T lymphocyte precursor (HTLp), cytotoxic T lymphocyte precursor (CTLp), plaque-forming cell (PFC), delayed type hypersensitivity (DTH) were examined 30, 60 days in post transplantation respectively. The results showed that lymphocytes proliferation to ConA and LPS, HTLp, CTLp increased, DTH and PFC were improved by cografted stromal cells QXMSC1IL-6 on 30, 60 days after BMT. These results demonstrated that the bone marrow stromal cell line QXMSC1IL-6 transfected with IL-6 (QXMSC1IL-6) accelerated immune reconstitution in syngeneic bone marrow transplantation.展开更多
Allogeneic hematopoietic stem cell transplantation(allo-HSCT)represents a curative therapy for hematological malignancies,with T-cell immune reconstitution playing a pivotal role in determining clinical outcomes.This ...Allogeneic hematopoietic stem cell transplantation(allo-HSCT)represents a curative therapy for hematological malignancies,with T-cell immune reconstitution playing a pivotal role in determining clinical outcomes.This review comprehensively illustrates the processes and influencing factors of T-cell recovery post-HSCT,highlighting the dual pathways of reconstitution:thymus-independent peripheral expansion and thymus-dependent central regeneration.Key factors such as recipient and donor age,human leukocyte antigen disparity,conditioning regimens,immunosuppressive therapies,cytomegalovirus reactivation,and graft-versus-host disease(GVHD)significantly impact T-cell reconstitution dynamics and functional recovery.Furthermore,the article discusses the critical balance between graft-versus-leukemia(GVL)effects and GVHD,emphasizing how T-cell exhaustion,inhibitory receptor overexpression,and clonal dynamics contribute to relapse.Emerging technologies,including single-cell multi-omics,spatially resolved proteomics,T cell receptor repertoire analysis,and artificial intelligence-driven modeling,are explored for their potential to deepen mechanistic understanding and enable personalized therapeutic strategies.Ultimately,enhancing T-cell reconstitution through optimized transplantation protocols and targeted interventions is essential for reducing complications and improving long-term survival.展开更多
Immune reconstitution inflammatory syndrome(IRIS)is a collection of inflammatory disorders characterized by the paradoxical worsening of preexisting infections processes following the initiation of antiretroviral ther...Immune reconstitution inflammatory syndrome(IRIS)is a collection of inflammatory disorders characterized by the paradoxical worsening of preexisting infections processes following the initiation of antiretroviral therapy in human immunodeficiency virus(HIV)-infected individuals.Diagnosing IRIS accurately and promptly remains challenging in areas with limited medical resources.Herpes simplex virus-2(HSV-2)is highly endemic in sub-Saharan Africa and is one of the primary opportunistic pathogens underlying IRIS,manifesting as mucocutaneous lesions.Here,we report a case of HSV-2-associated IRIS presenting as a genital ulcer,confirmed through nanopore high-throughput sequencing and successfully treated with acyclovir antiviral therapy.This study emphasizes the importance of clinicians maintaining proficiency in recognizing IRIS manifestations and being aware of region-specific opportunistic pathogens,both essential for timely diagnosis and etiology-directed therapy.展开更多
Objective： To observe the Immune No. 2（免疫2号方）on the immune reconstitution in patients with human immunodeficiency virus or acquired immune deficiency syndrome （HIV/AIDS） after highly active antiretroviral the...Objective： To observe the Immune No. 2（免疫2号方）on the immune reconstitution in patients with human immunodeficiency virus or acquired immune deficiency syndrome （HIV/AIDS） after highly active antiretroviral therapy （HAART）. Methods： A randomized, double-blind, placebo-controlled clinical trial was designed. 233 patients falling immune reconstitution after HAART were randomly divided into treatment group （116 cases） and control group （117 cases）, respectively using Immune No. 2 plus HAART and placebo combined with HAART for 6 months. CD4, CD45RA, CD45RO cell numbers, as well as the symptoms, signs and integral improvement rates were observed in order to evaluate the immune reconstitution efficiency. Results： after the intervention for 1 month, the effective rate of the treatment group （18.97%, 22/116） was significantly higher than that of the control group （9.40%, 11/117） （P=0.02）; 3 months after treatment, the effective rate of the treatment group （27.59%, 32/116） was no difference from that of the control group （22.22%, 26/117） （P=0.31）; 6 months after treatment, the effective rate of the treatment group （34.48%, 40/116） was significantly superior to the control group （21.37%, 25/117） （P=0.02）. CD4, CD45RA, CD45RO count of the treatment group was significantly higher than that of the control group （P〈0.05）. The total score of symptoms and signs in the treatment group was significantly lowered compared with the control group （P=0.02）, and the improvement of fatigue, muscle and joint pain, pruritus and shortness of breath in the treatment group was better than the control group （P〈0.05）. Conclusion： Immune No. 2 can effectively improve the numbers of CD4 cells and its subgroups, as well as the main clinical symptoms and signs of patients after HAART, thereby promoting the immune reconstitution.展开更多
Background Highly active antiretroviral therapy （HAART） produces profound suppression of HIV replication, substantial increase in CD4^＋ T cells, and partial reconstitution of the immune system. However, the numbers...Background Highly active antiretroviral therapy （HAART） produces profound suppression of HIV replication, substantial increase in CD4^＋ T cells, and partial reconstitution of the immune system. However, the numbers of subjects were small in previous Chinese studies. This study evaluated the efficacy and side effects of HAART in Chinese advanced AIDS patients.Methods One hundred and three antiretroviral drug naive AIDS patients were enrolled in this study and were divided into two groups by their baseline CD4^＋ count： 〈 100 cells/μl or ≥ 100 cells/μl. Clinical, virological and immunological outcomes were monitored at baseline and at 1, 3, 6, 9 and 12 months during the course of treatment with HAART.Results One patient died and another was lost from the follow-up. For the remaining 101 HIV/AIDS patients at the 12th month during the HAART, the plasma viral load （VL） was reduced to （3.2±0.7） lg copies/ml, the CD4^＋ count increased to （168 ±51） cells/μl [among which the naive phenotype （CD45RA^＋CD62L^＋） increased to （49 ±27） cells/μl and the memory phenotype （CD45RA^-） increased to （119 ±55） cells/μl], and the percentage of CD4^＋CD28^＋ cells increased. At the same time, there was a significant reduction of CD8^＋ T cell activation. In the 69 patients with the baseline CD4^＋ count 〈100 cells/μl, 37 had a VL 〈50 copies/ml; while in the 34 patients with the baseline CD4^＋ count ≥ 100 cells/μl, 25 had a VL 〈50 copies/ml, the difference between the two groups was statistically significant. The CD4^＋ T cell count showed a two-phase increase during HAART and a significant positive correlation was shown between the change of CD4^＋ count and plasma VL. Over 12 months of HAART, 10 patients had gastrointestinal side effects, 13 peripheral neuritis, 7 hepatic lesions, 8 hematological side effects, 8 skin rashes, 10 lipodystrophy and 1 renal calculus.Conclusions Immune reconstitution as well as the significantly improved clinical outcomes is observed in Chinese advanced AIDS patients after HAART. Side effects are common during HAART and require clinical attention.展开更多
Background:Women comprise more than half of people living with human immunodeficiency virus/acquired immune deficiency syndrome(HIV/AIDS)worldwide and incomplete immune recovery and metabolic abnormalities affect them...Background:Women comprise more than half of people living with human immunodeficiency virus/acquired immune deficiency syndrome(HIV/AIDS)worldwide and incomplete immune recovery and metabolic abnormalities affect them deeply.Studies of HIV antiretroviral therapy(ART)have a low female representation in China.We aimed to investigate immune reconstitution and metabolic changes of female HIV-positive cohort in China longitudinally.Methods:HIV-positive women who initiated ART from January 2005 to June 2021 and were followed up regularly at least once a year were included in this study.Immunological indicators(cluster of differentiation 4[CD4]counts and CD8 counts),viral load(VL),and metabolic indicators were collected at follow-up.All data were collected from the China Disease Prevention and Control Information System(CDPCIS).VL was tested half a year,1 year after receiving ART,and every other year subsequently according to local policy.CD4/CD8 ratio normalization was considered as the primary outcome and defined as a value≥1.Incidence rate and probability of CD4/CD8 ratio normalization were estimated through per 100 person-years follow-up(PYFU)and Kaplan-Meier curve,respectively.Multivariate Cox regression was used to identify independent risk factors associated with CD4/CD8 ratio normalization.We further studied the rate of dyslipidemia,hyperuricemia,diabetes,liver injury,and renal injury after ART initiation with the chi-squared tests or Fisher’s exact probability tests,and a generalized estimating equation model was used to analyze factors of dyslipidemia and hyperuricemia.Results:A total of 494 female patients with HIV/AIDS started ART within 16 years from January 2005 to June 2021,out of which 301 women were enrolled with a median duration of ART for 4.1 years(interquartile range,2.3-7.0 years).The overall incidence rate of CD4/CD8 ratio normalization was 8.9(95%confidence interval[CI],7.4-10.6)per 100 PYFU,and probabilities of CD4/CD8 normalization after initiating ART at 1 year,2 years,5 years,and 10 years follow-up were 11.7%,23.2%,44.0%,and 59.0%,respectively.Independent risk factors associated with CD4/CD8 normalization were baseline CD4 cell counts<200 cells/μL,CD8 counts>1000 cells/μL,and more than 6 months from the start of combined ART(cART)to first virological suppression.Longitudinally,the rate of hypercholesterolemia(total cholesterol[TC])and high triglyceride(TG)showed an increasing trend,while the rate of low high-density lipoprotein cholesterol(HDL)showed a decreasing trend.The rate of hyperuricemia presented a downtrend at follow-up.Although liver and renal injury and diabetes persisted during ART,the rate was not statistically significant.Older age and protease inhibitors were independent risk factors for increase of TC and TG,and ART duration was an independent factor for elevation of TC and recovery of HDL-C.Conclusions:This study showed that women were more likely to normalize CD4/CD8 ratio in comparison with findings reported in the literature even though immune reconstruction was incomplete.展开更多
Acquired immune deficiency syndrome （AIDS） is a chronic infectious disease,which the patients are infected with human immunodeficiency virus （HIV）.HIV damages the human＇s immune function and causes CD4 cell decli...Acquired immune deficiency syndrome （AIDS） is a chronic infectious disease,which the patients are infected with human immunodeficiency virus （HIV）.HIV damages the human＇s immune function and causes CD4 cell decline in the number and function.Immune reconstitution is an important treatment to AIDS.Bone marrow transplantation,adoptive immune cell therapy and cytokines infusion can all assist the immune reconstitution;highly active antiretroviral therapy （HAART） can effectively control the virus replication and benefit the immune reconstitution.HAART combined with immunotherapy is an important method of immune reconstitution in AIDS patients.Chinese medicine is playing a more and more important role in immune reconstitution.Immune reconstitution has always been effective in the whole treatment of AIDS.展开更多
Incomplete immune reconstitution remains a global challenge for human immunodeficiency virus(HIV)treatment in the present era of potent antiretroviral therapy(ART),especially for those individuals referred to as immun...Incomplete immune reconstitution remains a global challenge for human immunodeficiency virus(HIV)treatment in the present era of potent antiretroviral therapy(ART),especially for those individuals referred to as immunological non-responders(INRs),who exhibit dramatically low CD4^(+)T-cell counts despite the use of effective antiretroviral therapy,with long-term inhibition of viral replication.In this review,we provide a critical overview of the concept of ART-treated HIV-positive immunological non-response,and also explain the known mechanisms which could potentially account for the emergence of immunological non-response in some HIV-infected individuals treated with appropriate and effective ART.We found that immune cell exhaustion,combined with chronic inflammation and the HIV-associated dysbiosis syndrome,may represent strategic aspects of the immune response that may be fundamental to incomplete immune recovery.Interestingly,we noted from the literature that metformin exhibits properties and characteristics that may potentially be useful to specifically target immune cell exhaustion,chronic inflammation,and HIV-associated gut dysbiosis syndrome,mechanisms which are now recognized for their critically important complicity in HIV disease-related incomplete immune recovery.In light of evidence discussed in this review,it can be seen that metformin may be of particularly favorable use if utilized as adjunctive treatment in INRs to potentially enhance immune reconstitution.The approach described herein may represent a promising area of therapeutic intervention,aiding in significantly reducing the risk of HIV disease progression and mortality in a particularly vulnerable subgroup of HIV-positive individuals.展开更多
Background:Even with long-term complete suppression of the virus through antiretroviral therapy(ART),people infected with HIV cannot attain optimal immune reconstitution.This phenomenon is called immune reconstitution...Background:Even with long-term complete suppression of the virus through antiretroviral therapy(ART),people infected with HIV cannot attain optimal immune reconstitution.This phenomenon is called immune reconstitution deficiency,there are no effective therapeutic interventions for immune reconstitution deficiency in modern medicine.Objective:To evaluate the efficacy and safety of ART with Shenling Guben Granules Traditional Chinese medicine in boosting immunological reconstitution compared with ART alone.Methods:This was a randomized,double-blind,placebo-controlled,multicenter clinical trial evaluating the efficacy and safety of ART combined with Chinese medicine.The individuals aged 18–65 years with poor immune reconstitution following ART were included in this trial.The primary outcome was a change in the absolute value of CD4^(+)T lymphocytes after 72 weeks of combined ART and Chinese medicine administration.Secondary outcomes included changes in CD4^(+)T lymphocyte functional subpopulations,activated T lymphocyte subpopulations,CD4^(+)T lymphocyte proliferation,and T lymphocyte apoptosis from baseline to after 72 weeks.We also evaluated efficacy at 24-and 48-week intervals to better understand the dynamics of the trial drug’s efficacy.Results:There was a significant increase in CD4^(+)cell counts in groups treated with the Shenling Guben Granules after 24,48,and 72 weeks of treatment(P<0.05),and the difference in CD4^(+)cell counts at 24 weeks of treatment was statistically significant(P=0.010).After 48 and 72 weeks of therapy,the CD4^(+)CD38^(+)cell counts in the Shenling Guben Granules group were significantly higher than in the control group(P<0.05).In the subgroup analysis of CD4^(+)cell counts≥200 cells/mm^(3),the CD4^(+)cell counts in the treatment group were higher than the control group after treatment for 24,48,and 72 weeks(P<0.05).Discussion:CD4 cell counts in HIV/AIDS patients with immunological reconstitution insufficiency can be improved to a certain extent using Shenling Guben Granules.The greater the CD4 cell count at the start,the better the therapy response.Furthermore,Shenling Guben Granules have the efficacy and safety to prevent aberrant immunological activation.A large sample size,long-term follow-up,and multiple efficacy indicators were employed to assess the therapy’s safety.Our findings will lead to new therapeutic alternatives for HIV/AIDS patients suffering from immune reconstitution deficiency.Clinical Trial Registry:Name of the registry:Sundy on promote the reconstruction of Inadequate responders in HIV/AIDS patients after combined antiretroviral therapy by Shen Ling Gu Ben Granules;Chictr.org.cn Identifier:ChiCTR1800015290,registered on March 21,2018(http://www.chictr.org.cn/registry.aspx).展开更多
BACKGROUND Patients with acute-on-chronic liver failure(ACLF)experience severe immune dysfunction.Liver transplantation(LT)significantly improves survival outcomes.However,the characteristics of peripheral blood lymph...BACKGROUND Patients with acute-on-chronic liver failure(ACLF)experience severe immune dysfunction.Liver transplantation(LT)significantly improves survival outcomes.However,the characteristics of peripheral blood lymphocyte subsets(PBLSs)in this patient population are not well defined,and the dynamics of immune reconstitution post-LT are insufficiently understood.AIM To characterize PBLSs in patients with ACLF prior to LT and to evaluate PBLS reconstitution after LT.METHODS Clinical data from patients undergoing LT in the Transplantation Center,The Third Xiangya Hospital from January 2022 to December 2023 were analyzed retrospectively.Our cohort comprised 44 patients with ACLF,16 patients with acute decompensation of cirrhosis,and 23 patients with compensated cirrhosis.Twenty healthy volunteers were included as controls.PBLSs were evaluated across all groups.The relationship between PBLSs and post-LT prognosis was assessed,and dynamic changes in PBLSs among patients with ACLF were analyzed at different time points.RESULTS Patients with ACLF exhibited a marked reduction in PBLSs compared with healthy volunteers.Natural killer(NK)cell counts were further reduced in patients with ACLF when compared with patients with compensated cirrhosis.PBLSs did not correlate with the etiology or severity of ACLF or with established liver failure scores.Following LT,a rapid restoration of NK cells and B cells was observed in patients with ACLF.However,the cluster of differentiation(CD)3+T cell and CD4+T cell counts decreased 14 days post-LT and subsequently returned to preoperative levels by day 21.CONCLUSION Patients with ACLF exhibited markedly reduced PBLSs,with decreased NK cells potentially linked to progression from compensated cirrhosis to liver failure.NK and B cell were rapidly restored after LT.展开更多
Cytomegalovirus (CMV) retinitis is a significant yet infrequent complication inpediatric hematopoietic stem cell transplant recipients, occurring in approximately4% of cases. Its presentation typically coincides with ...Cytomegalovirus (CMV) retinitis is a significant yet infrequent complication inpediatric hematopoietic stem cell transplant recipients, occurring in approximately4% of cases. Its presentation typically coincides with immune reconstitution,between 6 weeks to 6 months post-transplant, emphasizing the need fortimely detection. Symptoms often develop insidiously, underscoring the role offundus examinations during episodes of CMV viremia. However, the low incidencechallenges the necessity of routine screenings, as they may strain clinicalresources without clear benefits to patient outcomes. Management includes systemicand intravitreal antivirals, such as ganciclovir and foscarnet, and adoptiveT-cell therapy for refractory cases. Tailored follow-up strategies are crucial, withconsiderations for lesion activity and CMV viremia status to determine theduration of therapy. Baseline and post-transplant screenings remain a topic ofdebate, with evolving guidelines needed to balance patient safety and clinicalfeasibility. Future research is needed to address optimal screening intervals andinvestigate the role of pre-existing CMV serostatus in transplant eligibility andoutcomes.展开更多
Hematopoietic cell transplantation（HCT） is widely performed for neoplastic and non-neoplastic diseases. HCT involves intravenous infusion of hematopoietic progenitor cells from human leukocyte antigen（HLA）-matched...Hematopoietic cell transplantation（HCT） is widely performed for neoplastic and non-neoplastic diseases. HCT involves intravenous infusion of hematopoietic progenitor cells from human leukocyte antigen（HLA）-matched donor（allogeneic） or from the patient（autologous）. Before HCT, the patient is prepared with high dose chemotherapy and/or radiotherapy to destroy residual malignant cells and to reduce immunologic resistance. After HCT, chemotherapy is used to prevent graft rejection and graft versus host disease（Gv HD）. Neurological complications are related to the type of HCT, underlying disease, toxicity of the conditioning regimens, immunosuppression caused by conditioning regimens, vascular complications generated by thrombocytopenia and/or coagulopathy, Gv HD and inappropriate immune response. In this review, neurological complications are presented according to time of onset after HCT：（1） early complications（in the first month）-related to harvesting of stem cells, during conditioning（drug toxicity, posterior reversible encephalopathy syndrome）, related to pancytopenia,（2） intermediate phase complications（second to sixth month）-central nervous system infections caused by prolonged neutropenia and progressive multifocal leukoencephalopathy due to JC virus,（3） late phase complications（after sixth month）-neurological complications of Gv HD, second neoplasms and relapses of the original disease.展开更多
Objective To investigate the response on late stage Chinese AIDS patients after highly active antiretroviral therapy （HAART）. Methods From October 2002 to March 2004, 20 cases of late stage Chinese AIDS patients we...Objective To investigate the response on late stage Chinese AIDS patients after highly active antiretroviral therapy （HAART）. Methods From October 2002 to March 2004, 20 cases of late stage Chinese AIDS patients were selected to participate in this opened and randomised study, we purposely chose those with CD4＋ T cell counts 〈 100/mm^3. All of them had one or two opportunistic infections and none had been treated with anti-HIV drugs. All patients were tested with CD4＋ （naive CD4＋ T cell defined by CD45RA＋ and CD62L＋, memory CD4＋ T cell defined by CD45RA-）, CD8＋ T cell, plasma HIV viral load, and clinical manifestations on before, during, and after HAART （5 different regimes） on 1, 3, 6, 9, and 12 months. Before HAART mean CD4＋ T cell counts were 32 ± 31 （range 2-91）/mm^3, and plasma HIV viral load were 5.07 ± 0.85（range 2.04-5.70） log copies/mL. In 1 month＇s time patients treated with HAAT had mean CD4＋ and CD8＋ T cell counts increasing rapidly. After 1 month the increasing speed turned to slow down, but HIV viral load decreased predominantly within the first 3 months. The major part of increasing CD4＋ T cells were memory CD4＋ T cells, as for naive CD4＋ T cells increasing low and slow. Clinical symptoms and signs improved, and opportunistic infections reduced. The quality of life will be far much better than before. Each patient was followed for 12 months, and had finished 12 months＇ HAAT. Conclusion This is the first report in China that late stage Chinese AIDS patients after HAART could have their immune reconstitution. The regular pattern is similar to what had been reported in Western countries and also in China. So it is worth to treat late stage Chinese AIDS patients with HAAT.展开更多
Background: Mucosal-associated invariant T(MAIT) cells are systemically depleted in human immunodeficiency virus type 1(HIV-1) infected patients and are not replenished even after successful combined antiretroviral th...Background: Mucosal-associated invariant T(MAIT) cells are systemically depleted in human immunodeficiency virus type 1(HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy(cART).This study aimed to identify the mechanism underlying MAIT cell depletion.Methods: In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.Results: Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D(GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12(IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro.Conclusions: Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients,which could potentiate disease progression and poor immune reconstitution.展开更多
BACKGROUND Angioimmunoblastic T-cell lymphoma(AITL), a unique subtype of peripheral Tcell lymphoma, has relatively poor outcomes. High-dose chemotherapy with autologous stem cell transplantation(ASCT) can achieve comp...BACKGROUND Angioimmunoblastic T-cell lymphoma(AITL), a unique subtype of peripheral Tcell lymphoma, has relatively poor outcomes. High-dose chemotherapy with autologous stem cell transplantation(ASCT) can achieve complete remission and improve outcomes. Unfortunately, subsequent T-cell lymphoma-triggered hemophagocytic lymphohistiocytosis(HLH) has a worse prognosis than B-cell lymphoma-triggered HLH.CASE SUMMARY We here report a 50-year-old woman with AITL who achieved a favorable outcome after developing HLH 2 mo after receiving high-dose chemotherapy/ASCT. The patient was initially admitted to our hospital because of multiple enlarged lymph nodes. The final pathologic diagnosis, made on biopsy of a left axillary lymph node was AITL(Stage Ⅳ, Group A). Four cycles of the following chemotherapy regimen were administered: Cyclophosphamide 1.3 g, doxorubicin 86 mg, and vincristine 2 mg on day 1;prednisone 100 mg on days 1-5;and lenalidomide 25 mg on days 1-14. The interval between each cycle was 21 d. The patient received a conditioning regimen(busulfan, cyclophosphamide, and etoposide) followed by peripheral blood stem cell infusion. Unfortunately, she developed sustained fever and a low platelet count 17 d after ACST, leading to a diagnosis of HLH after ASCT. During treatment, she experienced thrombocytopenia and Pneumocystis carinii pneumonia. The patient was successfully treated with etoposide and glucocorticoids.CONCLUSION It is possible that development of HLH is related to immune reconstitution after ASCT.展开更多
Objective To investigate the association between earlyimmune reconstitution and Epstein-Barrrvirus(EBV)reactivation by analyzing changes in natural killer(NK),B,and T cells and their functional status in the periphera...Objective To investigate the association between earlyimmune reconstitution and Epstein-Barrrvirus(EBV)reactivation by analyzing changes in natural killer(NK),B,and T cells and their functional status in the peripheral blood during the early post-transplant period.Methods This study included 23 patients who underwent haplo-hematopoietic stem cell transplantation(HSCT).The immune reconstitution of NK cells,T cells,and B cells as well as the expression levels of NK and T cell exhaustion markers(PD-1,TIM-3,and CTLA-4)and cytotoxic function at 1,2,and 3 months post-transplantation were compared between patients with EBV activation(EBV+group)and those without activation(EBV-group)post-transplantation.Results EBV activation occurredinninepatients posttransplantation(EBV+group),whereas 14 patients demonstrated no activation(EBV-group).All patients with EBV activation exhibited EBV viremia,and no EBV-associateddiseasesoccurred.No significant differences in the clinical characteristicswereffound between the two ggroupsof patients.The median proportion of CD3^(+)CD8^(+)T cells in the EBV+group was significantly lower than that in the EBV-group at 1 month post-transplantation(P=0.033).The median proportion of the CD3^(-)CD16^(neg)CD56^(bri)subset in the EBV+group was significantly higher than that in the EBV-group at 2 months postransplantation(P=0.046).No significant differences in the median proportions of CD3^(-)CD19^(+)B cells were observed between the two groups at 1,2,and 3 months post-transplantation.The expression of CTLA-4 on CD3^(-)CD16^(bri)CD56^(dim)NK cells in the EBV+group was significantly higher than that in the EBV-group at 1 month post-transplantation(P=0.033).The expression of TIM-3 on CD3^(+)CD8^(+)T cells in the EBV+group was significantly higher than that in the EBV-group(P=0.009).The expression level of TIM-3 on CD3^(-)CD16^(neg)CD56^(dim)NK cells in the EBV+group was significantly lower than that in the EBV-group at 2 months post-transplantation(P=0.023).The expression levels of TIM-3 on CD3^(+)CD4^(+)T cells in the EBV+group than those in the EBV-group at 1 and 3 months post-transplantation(P=0.002,P=0.043).The median positive rate of Granzyme B expression in CD3^(+)CD8^(+)T cells and CD3^(+)CD4^(+)T cells in the EBV+group was significantly lower than that in the EBV-group at 1-month post-transplantation(P=0.033,P=0.016).The median positive rate of Granzyme B expression in the CD3^(-)CD16^(bri)CD56^(neg)cell subset in the EBV+group was higher than that in the EBV-group at 2 months post-transplantation(P=0.012).The median positive rate of Granzyme B expression in CD3^(+)CD4^(+)T cells in the EBV+group remained significantly lower than that in the EBV-ggroup at 2 months posttransplantation(P=0.049).The median positive rate of perforin expression in the CD3^(-)CD16^(bri)CD56^(dim)cell subset was significantly higher in the EBV+group than in the EBV-group at 3 months post-transplantation(P=0.003).The median positive rate of IFNexpression in CD3^(+)CD8^(+)T cells in the EBV+group was significantly lower than that in the EBV-group at 3 months post-transplantation(P=0.036).Conclusion Delayed NK cell and T lymphocyte reconstitution,high exhaustion marker expression,and weakened cytotoxic functions may be related to EBV reactivation after haploidentical HSCT.展开更多
基金supported by the National Natural Science Foundation of China(82460391,82260397,32060177,82360328,82472266)the Yunnan Revitalization Talent Support Program(RLQB20220013,RLQN20230007)+7 种基金the Yunnan Health Training Project of High Level Talents(L-2024027)the Joint Special Fund of Science and Technology of Yunnan Province-Kunming Medical University(202201AY070001-046,202301AY070001-139,202401AY070001-237)the Yunnan Fundamental Research Projects(202201AT070292,202301AT070127)the 535 Talent Project of the First Affiliated Hospital of Kunming Medical University(2023535Q09,2024535Q01)the Fund of Beijing Key Laboratory for HIV/AIDS Research(BJYAHKF2021001)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0490000)the First-Class Discipline Team of Kunming Medical University(2024XKTDYS09)Yunnan Key Laboratory of Organ Transplantation(202449CE340016).
文摘Incomplete immune reconstitution occurs in 10%-40%of antiretroviral therapy(ART)-treated human immunodeficiency virus(HIV)patients.This subset of immunological non-responders(INRs)has yet to undergo a comprehensive analysis of immunological profiles,and no definitive cytological diag-nosis has been established.In this study,we comparatively analyzed the immunological profiles of INRs,immunological responders(IRs),and healthy control individuals(HCs)via single-cell RNA sequencing(scRNA-seq)and single-cell T-cell receptor(TCR)repertoire sequencing of peripheral blood mononuclear cells(PBMCs),and identified a relatively small population of mucosal-associated invariant T(MAIT)cells in INRs.This finding was recapitulated in rhesus macaques infected with simian immunodeficiency virus(SIV).Specifically,the population of the naïve MAIT cell subtype was significantly lower in INRs than in IRs,and the majority of MAIT cells were CD8^(+)cell subsets.Further characteristic analysis of MAIT cells via the transcriptome revealed decreased expression of cytotoxicity-related genes in INRs,while displaying increased expression of genes involved in TGF-β receptor signaling.In summary,by conducting a comparative analysis,this study revealed a corre-lation between the decreased proportion of naïve MAIT cells and impaired immune reconstitution in INRs.This finding highlights a particular cell subset that may play a pivotal role in the incomplete immune reconstitution,and suggests a plausible cellular target for the modulation of INRs.
基金Supported by National Natural Science Foundation of China (30670898, 30572108)National Basic Research Program of China (973 Program) (2005CB522400)Capital Research Fund for Medical Development (2007-2040)
文摘Objective To explore the effect of α-galactosyleramide （α-GalCer） on immune reconstitution under acute graft-versus-host disease （aGVHD）. Methods BALB/c mice were transplanted with allogeneic C57BL/6 bone marrow cells and splenocytes （both 1 × 10^7） after receiving lethal total-body irradiation, α-GalCer （100 ug/kg） or vehicle （dimethyl- sulfoxide） was administered intraperitoneally immediately after transplantation. The effects of α-GalCer on immune reconstitufion, proliferation of T cells and B cells, hematopoiesis, and thymic microenvironment were assessed. Results The α-GalCer group exhibited higher percentages of CD3^＋, CD4^＋, CD8^＋, B220^＋, CD40＋, and CD86＋cells compared with the vehicle group. The number of colony forming unit per 1000 CD34^＋ cells in the et-GalCer group was higher than in the vehicle group （P=0.0012）. In vitro proliferation assays showed that the α-GalCer group had higher percentages of CD3^＋, CD4^＋, CD8^＋, and B220^＋ cells compared with the vehicle group. As for the results of in vivo proliferation assays, the numbers of CD3^＋, CD4^＋, CD8^＋, and B220^＋ cells were higher in the α-GalCer group than in the normal group, especially the number of B220^＋ cells （P=0.007）. Significant difference was not found in thymocyte count between the α-GalCer group and the vehicle group, nor in the percentages of CD3^＋, CD4^＋, and CD8^＋ cells. Conclusion Administration of tl-GalCer after allogeneic bone marrow transplantation may promote immune reconstitution in the presence of aGVHD.
基金Scientific and Technological Resources Coordination Project of Shaanxi Province,Grant/Award Number:2020PT-002,2022PT-43 and CX-PT-18Special Fund for Military Laboratory Animals,Grant/Award Number:SYDW_KY(2021)13State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers,Grant/Award Number:CBSKL2022ZZ28。
文摘The mouse genome has a high degree of homology with the human genome,and its physiological,biochemical,and developmental regulation mechanisms are similar to those of humans;therefore,mice are widely used as experimental animals.However,it is undeniable that interspecies differences between humans and mice can lead to experimental errors.The differences in the immune system have become an impor-tant factor limiting current immunological research.The application of immunodefi-cient mice provides a possible solution to these problems.By transplanting human immune cells or tissues,such as peripheral blood mononuclear cells or hematopoietic stem cells,into immunodeficient mice,a human immune system can be reconstituted in the mouse body,and the engrafted immune cells can elicit human-specific immune responses.Researchers have been actively exploring the development and differen-tiation conditions of host recipient animals and grafts in order to achieve better im-mune reconstitution.Through genetic engineering methods,immunodeficient mice can be further modified to provide a favorable developmental and differentiation microenvironment for the grafts.From initially only being able to reconstruct single T lymphocyte lineages,it is now possible to reconstruct lymphoid and myeloid cells,providing important research tools for immunology-related studies.In this review,we compare the differences in immune systems of humans and mice,describe the devel-opment history of human immune reconstitution from the perspectives of immuno-deficient mice and grafts,and discuss the latest advances in enhancing the efficiency of human immune cell reconstitution,aiming to provide important references for im-munological related researches.
基金the Science and Technology Project of Sichuan Province(No.2020YFS0333).
文摘Despite continuous progress,the prevention and treatment of human immunodeficiency virus(HIV)/acquired immune deficiency syndrome(AIDS)remain the world’s most serious public health challenges.A key problem is the degree of immune function reconstruction after antiretroviral therapy.Antiretroviral therapy has enriched the treatment of HIV/AIDS and improved the present conditions and the life quality of HIV/AIDS patients.However,some patients still fail to achieve normalization of CD4+T lymphocyte counts although persistent virological suppression.These patients are referred to as immunological non-responders,and usually present with severe immunological dysfunction.To date,since the underlying mechanism of incomplete immune reconstitution in HIV/AIDS has not been fully elucidated,remaining to be the focus and difficulties of current research.It is still a challenge to explore a safe,effective,and reliable therapeutic method for immunological non-responders.Due to fewer side effects and lower drug resistance,traditional Chinese medicine is often sought to provide alternative pharmacotherapy for regulating the immunity of immunological non-responders in China.In this review,we aimed at summarizing the latest and most comprehensive information on traditional Chinese medicine therapeutic methods for promoting immune reconstruction.In addition,outlooks and perspectives for possible future research that related are also discussed.
基金This work was supported by a grant from the National Natural Science Foundation of China (No. 30170895)
文摘To observe potential effect of the engineered bone marrow stromal cell line QXMSC1 secreting IL-6 (QXMSCIL-6) on accelerating immune reconstitution in syngeneic bone marrow transplantation in mice, QXMSC1 was transfected with the eukaryocytic expression vector pcDNAIL-6, which contained hIL-6 cDNA by liposome-mediated gene transfecting technique. G418-resistance clone was selected by limiting dilution. The highest secreting clone was selected by ELISA assay and used in animal experiments. The recipient mice (BALB/c) were lethally irradiated and cotransplanted syngeneic bone marrow (10 7/mice) and the QXMSC1IL-6 (5×10 5/mice). Lymphocyte proliferation induced by ConA and LPS, helper T lymphocyte precursor (HTLp), cytotoxic T lymphocyte precursor (CTLp), plaque-forming cell (PFC), delayed type hypersensitivity (DTH) were examined 30, 60 days in post transplantation respectively. The results showed that lymphocytes proliferation to ConA and LPS, HTLp, CTLp increased, DTH and PFC were improved by cografted stromal cells QXMSC1IL-6 on 30, 60 days after BMT. These results demonstrated that the bone marrow stromal cell line QXMSC1IL-6 transfected with IL-6 (QXMSC1IL-6) accelerated immune reconstitution in syngeneic bone marrow transplantation.
基金supported by grants from the Ministry of Science and Technology of China(2021YFA1100902)the National Natural Science Foundation of China(NSFC)(82370222,92368202)+3 种基金the Haihe Laboratory of Cell Ecosystem Innovation Fund(HH24KYZX0001)CAMS Innovation Fund for Medical Sciences(CIFMS)(2024-I2M-ZD-010)Science,Technology&Innovation Project of Xiong’an New Area(2022XAGG0142)Tianjin Municipal Science and Technology Commission Grant(24ZXRKSY00030,24ZXZSSS00250).
文摘Allogeneic hematopoietic stem cell transplantation(allo-HSCT)represents a curative therapy for hematological malignancies,with T-cell immune reconstitution playing a pivotal role in determining clinical outcomes.This review comprehensively illustrates the processes and influencing factors of T-cell recovery post-HSCT,highlighting the dual pathways of reconstitution:thymus-independent peripheral expansion and thymus-dependent central regeneration.Key factors such as recipient and donor age,human leukocyte antigen disparity,conditioning regimens,immunosuppressive therapies,cytomegalovirus reactivation,and graft-versus-host disease(GVHD)significantly impact T-cell reconstitution dynamics and functional recovery.Furthermore,the article discusses the critical balance between graft-versus-leukemia(GVL)effects and GVHD,emphasizing how T-cell exhaustion,inhibitory receptor overexpression,and clonal dynamics contribute to relapse.Emerging technologies,including single-cell multi-omics,spatially resolved proteomics,T cell receptor repertoire analysis,and artificial intelligence-driven modeling,are explored for their potential to deepen mechanistic understanding and enable personalized therapeutic strategies.Ultimately,enhancing T-cell reconstitution through optimized transplantation protocols and targeted interventions is essential for reducing complications and improving long-term survival.
基金supported by National key R&D Program of China(2024YFC2311100)the National Social Science Fund of China(2022-SKJJ-B-069).
文摘Immune reconstitution inflammatory syndrome(IRIS)is a collection of inflammatory disorders characterized by the paradoxical worsening of preexisting infections processes following the initiation of antiretroviral therapy in human immunodeficiency virus(HIV)-infected individuals.Diagnosing IRIS accurately and promptly remains challenging in areas with limited medical resources.Herpes simplex virus-2(HSV-2)is highly endemic in sub-Saharan Africa and is one of the primary opportunistic pathogens underlying IRIS,manifesting as mucocutaneous lesions.Here,we report a case of HSV-2-associated IRIS presenting as a genital ulcer,confirmed through nanopore high-throughput sequencing and successfully treated with acyclovir antiviral therapy.This study emphasizes the importance of clinicians maintaining proficiency in recognizing IRIS manifestations and being aware of region-specific opportunistic pathogens,both essential for timely diagnosis and etiology-directed therapy.
基金Supported by Chinese Ministry of Science and Technology(No. 2008ZX10005-004)
文摘Objective： To observe the Immune No. 2（免疫2号方）on the immune reconstitution in patients with human immunodeficiency virus or acquired immune deficiency syndrome （HIV/AIDS） after highly active antiretroviral therapy （HAART）. Methods： A randomized, double-blind, placebo-controlled clinical trial was designed. 233 patients falling immune reconstitution after HAART were randomly divided into treatment group （116 cases） and control group （117 cases）, respectively using Immune No. 2 plus HAART and placebo combined with HAART for 6 months. CD4, CD45RA, CD45RO cell numbers, as well as the symptoms, signs and integral improvement rates were observed in order to evaluate the immune reconstitution efficiency. Results： after the intervention for 1 month, the effective rate of the treatment group （18.97%, 22/116） was significantly higher than that of the control group （9.40%, 11/117） （P=0.02）; 3 months after treatment, the effective rate of the treatment group （27.59%, 32/116） was no difference from that of the control group （22.22%, 26/117） （P=0.31）; 6 months after treatment, the effective rate of the treatment group （34.48%, 40/116） was significantly superior to the control group （21.37%, 25/117） （P=0.02）. CD4, CD45RA, CD45RO count of the treatment group was significantly higher than that of the control group （P〈0.05）. The total score of symptoms and signs in the treatment group was significantly lowered compared with the control group （P=0.02）, and the improvement of fatigue, muscle and joint pain, pruritus and shortness of breath in the treatment group was better than the control group （P〈0.05）. Conclusion： Immune No. 2 can effectively improve the numbers of CD4 cells and its subgroups, as well as the main clinical symptoms and signs of patients after HAART, thereby promoting the immune reconstitution.
基金This study was supported by the grants from the National Key Technologies R&D Program for the 10th Five-Year Plan (No. 2004BA719A10), the HIV/AIDS Prevention and Treatment Project of Ministry of Health (No. WA2003-05), and the Critical Clinical Project of Ministry of Health.
文摘Background Highly active antiretroviral therapy （HAART） produces profound suppression of HIV replication, substantial increase in CD4^＋ T cells, and partial reconstitution of the immune system. However, the numbers of subjects were small in previous Chinese studies. This study evaluated the efficacy and side effects of HAART in Chinese advanced AIDS patients.Methods One hundred and three antiretroviral drug naive AIDS patients were enrolled in this study and were divided into two groups by their baseline CD4^＋ count： 〈 100 cells/μl or ≥ 100 cells/μl. Clinical, virological and immunological outcomes were monitored at baseline and at 1, 3, 6, 9 and 12 months during the course of treatment with HAART.Results One patient died and another was lost from the follow-up. For the remaining 101 HIV/AIDS patients at the 12th month during the HAART, the plasma viral load （VL） was reduced to （3.2±0.7） lg copies/ml, the CD4^＋ count increased to （168 ±51） cells/μl [among which the naive phenotype （CD45RA^＋CD62L^＋） increased to （49 ±27） cells/μl and the memory phenotype （CD45RA^-） increased to （119 ±55） cells/μl], and the percentage of CD4^＋CD28^＋ cells increased. At the same time, there was a significant reduction of CD8^＋ T cell activation. In the 69 patients with the baseline CD4^＋ count 〈100 cells/μl, 37 had a VL 〈50 copies/ml; while in the 34 patients with the baseline CD4^＋ count ≥ 100 cells/μl, 25 had a VL 〈50 copies/ml, the difference between the two groups was statistically significant. The CD4^＋ T cell count showed a two-phase increase during HAART and a significant positive correlation was shown between the change of CD4^＋ count and plasma VL. Over 12 months of HAART, 10 patients had gastrointestinal side effects, 13 peripheral neuritis, 7 hepatic lesions, 8 hematological side effects, 8 skin rashes, 10 lipodystrophy and 1 renal calculus.Conclusions Immune reconstitution as well as the significantly improved clinical outcomes is observed in Chinese advanced AIDS patients after HAART. Side effects are common during HAART and require clinical attention.
基金Beijing Municipal Administration of Hospitals’Ascent Plan(No.DFL20191802)Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support(No.ZYLX202126)
文摘Background:Women comprise more than half of people living with human immunodeficiency virus/acquired immune deficiency syndrome(HIV/AIDS)worldwide and incomplete immune recovery and metabolic abnormalities affect them deeply.Studies of HIV antiretroviral therapy(ART)have a low female representation in China.We aimed to investigate immune reconstitution and metabolic changes of female HIV-positive cohort in China longitudinally.Methods:HIV-positive women who initiated ART from January 2005 to June 2021 and were followed up regularly at least once a year were included in this study.Immunological indicators(cluster of differentiation 4[CD4]counts and CD8 counts),viral load(VL),and metabolic indicators were collected at follow-up.All data were collected from the China Disease Prevention and Control Information System(CDPCIS).VL was tested half a year,1 year after receiving ART,and every other year subsequently according to local policy.CD4/CD8 ratio normalization was considered as the primary outcome and defined as a value≥1.Incidence rate and probability of CD4/CD8 ratio normalization were estimated through per 100 person-years follow-up(PYFU)and Kaplan-Meier curve,respectively.Multivariate Cox regression was used to identify independent risk factors associated with CD4/CD8 ratio normalization.We further studied the rate of dyslipidemia,hyperuricemia,diabetes,liver injury,and renal injury after ART initiation with the chi-squared tests or Fisher’s exact probability tests,and a generalized estimating equation model was used to analyze factors of dyslipidemia and hyperuricemia.Results:A total of 494 female patients with HIV/AIDS started ART within 16 years from January 2005 to June 2021,out of which 301 women were enrolled with a median duration of ART for 4.1 years(interquartile range,2.3-7.0 years).The overall incidence rate of CD4/CD8 ratio normalization was 8.9(95%confidence interval[CI],7.4-10.6)per 100 PYFU,and probabilities of CD4/CD8 normalization after initiating ART at 1 year,2 years,5 years,and 10 years follow-up were 11.7%,23.2%,44.0%,and 59.0%,respectively.Independent risk factors associated with CD4/CD8 normalization were baseline CD4 cell counts<200 cells/μL,CD8 counts>1000 cells/μL,and more than 6 months from the start of combined ART(cART)to first virological suppression.Longitudinally,the rate of hypercholesterolemia(total cholesterol[TC])and high triglyceride(TG)showed an increasing trend,while the rate of low high-density lipoprotein cholesterol(HDL)showed a decreasing trend.The rate of hyperuricemia presented a downtrend at follow-up.Although liver and renal injury and diabetes persisted during ART,the rate was not statistically significant.Older age and protease inhibitors were independent risk factors for increase of TC and TG,and ART duration was an independent factor for elevation of TC and recovery of HDL-C.Conclusions:This study showed that women were more likely to normalize CD4/CD8 ratio in comparison with findings reported in the literature even though immune reconstruction was incomplete.
基金Supported by the National Key Technologies Special-purpose Program (No.2008ZX10005-004)
文摘Acquired immune deficiency syndrome （AIDS） is a chronic infectious disease,which the patients are infected with human immunodeficiency virus （HIV）.HIV damages the human＇s immune function and causes CD4 cell decline in the number and function.Immune reconstitution is an important treatment to AIDS.Bone marrow transplantation,adoptive immune cell therapy and cytokines infusion can all assist the immune reconstitution;highly active antiretroviral therapy （HAART） can effectively control the virus replication and benefit the immune reconstitution.HAART combined with immunotherapy is an important method of immune reconstitution in AIDS patients.Chinese medicine is playing a more and more important role in immune reconstitution.Immune reconstitution has always been effective in the whole treatment of AIDS.
基金Chongqing Talent Cultivation Program(No.cstc2021ycjh-bgzxm0275)Key Project of the Chongqing Science&Technology Bureau(No.cstc2020jscx-cylhX0001)
文摘Incomplete immune reconstitution remains a global challenge for human immunodeficiency virus(HIV)treatment in the present era of potent antiretroviral therapy(ART),especially for those individuals referred to as immunological non-responders(INRs),who exhibit dramatically low CD4^(+)T-cell counts despite the use of effective antiretroviral therapy,with long-term inhibition of viral replication.In this review,we provide a critical overview of the concept of ART-treated HIV-positive immunological non-response,and also explain the known mechanisms which could potentially account for the emergence of immunological non-response in some HIV-infected individuals treated with appropriate and effective ART.We found that immune cell exhaustion,combined with chronic inflammation and the HIV-associated dysbiosis syndrome,may represent strategic aspects of the immune response that may be fundamental to incomplete immune recovery.Interestingly,we noted from the literature that metformin exhibits properties and characteristics that may potentially be useful to specifically target immune cell exhaustion,chronic inflammation,and HIV-associated gut dysbiosis syndrome,mechanisms which are now recognized for their critically important complicity in HIV disease-related incomplete immune recovery.In light of evidence discussed in this review,it can be seen that metformin may be of particularly favorable use if utilized as adjunctive treatment in INRs to potentially enhance immune reconstitution.The approach described herein may represent a promising area of therapeutic intervention,aiding in significantly reducing the risk of HIV disease progression and mortality in a particularly vulnerable subgroup of HIV-positive individuals.
基金Supported by the State Major Science&Technology Specific Projects(2017ZX10205501)National Nature Science Foundation of China(82174221).
文摘Background:Even with long-term complete suppression of the virus through antiretroviral therapy(ART),people infected with HIV cannot attain optimal immune reconstitution.This phenomenon is called immune reconstitution deficiency,there are no effective therapeutic interventions for immune reconstitution deficiency in modern medicine.Objective:To evaluate the efficacy and safety of ART with Shenling Guben Granules Traditional Chinese medicine in boosting immunological reconstitution compared with ART alone.Methods:This was a randomized,double-blind,placebo-controlled,multicenter clinical trial evaluating the efficacy and safety of ART combined with Chinese medicine.The individuals aged 18–65 years with poor immune reconstitution following ART were included in this trial.The primary outcome was a change in the absolute value of CD4^(+)T lymphocytes after 72 weeks of combined ART and Chinese medicine administration.Secondary outcomes included changes in CD4^(+)T lymphocyte functional subpopulations,activated T lymphocyte subpopulations,CD4^(+)T lymphocyte proliferation,and T lymphocyte apoptosis from baseline to after 72 weeks.We also evaluated efficacy at 24-and 48-week intervals to better understand the dynamics of the trial drug’s efficacy.Results:There was a significant increase in CD4^(+)cell counts in groups treated with the Shenling Guben Granules after 24,48,and 72 weeks of treatment(P<0.05),and the difference in CD4^(+)cell counts at 24 weeks of treatment was statistically significant(P=0.010).After 48 and 72 weeks of therapy,the CD4^(+)CD38^(+)cell counts in the Shenling Guben Granules group were significantly higher than in the control group(P<0.05).In the subgroup analysis of CD4^(+)cell counts≥200 cells/mm^(3),the CD4^(+)cell counts in the treatment group were higher than the control group after treatment for 24,48,and 72 weeks(P<0.05).Discussion:CD4 cell counts in HIV/AIDS patients with immunological reconstitution insufficiency can be improved to a certain extent using Shenling Guben Granules.The greater the CD4 cell count at the start,the better the therapy response.Furthermore,Shenling Guben Granules have the efficacy and safety to prevent aberrant immunological activation.A large sample size,long-term follow-up,and multiple efficacy indicators were employed to assess the therapy’s safety.Our findings will lead to new therapeutic alternatives for HIV/AIDS patients suffering from immune reconstitution deficiency.Clinical Trial Registry:Name of the registry:Sundy on promote the reconstruction of Inadequate responders in HIV/AIDS patients after combined antiretroviral therapy by Shen Ling Gu Ben Granules;Chictr.org.cn Identifier:ChiCTR1800015290,registered on March 21,2018(http://www.chictr.org.cn/registry.aspx).
基金Supported by the National Natural Science Foundation of China,No.82300857.
文摘BACKGROUND Patients with acute-on-chronic liver failure(ACLF)experience severe immune dysfunction.Liver transplantation(LT)significantly improves survival outcomes.However,the characteristics of peripheral blood lymphocyte subsets(PBLSs)in this patient population are not well defined,and the dynamics of immune reconstitution post-LT are insufficiently understood.AIM To characterize PBLSs in patients with ACLF prior to LT and to evaluate PBLS reconstitution after LT.METHODS Clinical data from patients undergoing LT in the Transplantation Center,The Third Xiangya Hospital from January 2022 to December 2023 were analyzed retrospectively.Our cohort comprised 44 patients with ACLF,16 patients with acute decompensation of cirrhosis,and 23 patients with compensated cirrhosis.Twenty healthy volunteers were included as controls.PBLSs were evaluated across all groups.The relationship between PBLSs and post-LT prognosis was assessed,and dynamic changes in PBLSs among patients with ACLF were analyzed at different time points.RESULTS Patients with ACLF exhibited a marked reduction in PBLSs compared with healthy volunteers.Natural killer(NK)cell counts were further reduced in patients with ACLF when compared with patients with compensated cirrhosis.PBLSs did not correlate with the etiology or severity of ACLF or with established liver failure scores.Following LT,a rapid restoration of NK cells and B cells was observed in patients with ACLF.However,the cluster of differentiation(CD)3+T cell and CD4+T cell counts decreased 14 days post-LT and subsequently returned to preoperative levels by day 21.CONCLUSION Patients with ACLF exhibited markedly reduced PBLSs,with decreased NK cells potentially linked to progression from compensated cirrhosis to liver failure.NK and B cell were rapidly restored after LT.
文摘Cytomegalovirus (CMV) retinitis is a significant yet infrequent complication inpediatric hematopoietic stem cell transplant recipients, occurring in approximately4% of cases. Its presentation typically coincides with immune reconstitution,between 6 weeks to 6 months post-transplant, emphasizing the need fortimely detection. Symptoms often develop insidiously, underscoring the role offundus examinations during episodes of CMV viremia. However, the low incidencechallenges the necessity of routine screenings, as they may strain clinicalresources without clear benefits to patient outcomes. Management includes systemicand intravitreal antivirals, such as ganciclovir and foscarnet, and adoptiveT-cell therapy for refractory cases. Tailored follow-up strategies are crucial, withconsiderations for lesion activity and CMV viremia status to determine theduration of therapy. Baseline and post-transplant screenings remain a topic ofdebate, with evolving guidelines needed to balance patient safety and clinicalfeasibility. Future research is needed to address optimal screening intervals andinvestigate the role of pre-existing CMV serostatus in transplant eligibility andoutcomes.
文摘Hematopoietic cell transplantation（HCT） is widely performed for neoplastic and non-neoplastic diseases. HCT involves intravenous infusion of hematopoietic progenitor cells from human leukocyte antigen（HLA）-matched donor（allogeneic） or from the patient（autologous）. Before HCT, the patient is prepared with high dose chemotherapy and/or radiotherapy to destroy residual malignant cells and to reduce immunologic resistance. After HCT, chemotherapy is used to prevent graft rejection and graft versus host disease（Gv HD）. Neurological complications are related to the type of HCT, underlying disease, toxicity of the conditioning regimens, immunosuppression caused by conditioning regimens, vascular complications generated by thrombocytopenia and/or coagulopathy, Gv HD and inappropriate immune response. In this review, neurological complications are presented according to time of onset after HCT：（1） early complications（in the first month）-related to harvesting of stem cells, during conditioning（drug toxicity, posterior reversible encephalopathy syndrome）, related to pancytopenia,（2） intermediate phase complications（second to sixth month）-central nervous system infections caused by prolonged neutropenia and progressive multifocal leukoencephalopathy due to JC virus,（3） late phase complications（after sixth month）-neurological complications of Gv HD, second neoplasms and relapses of the original disease.
文摘Objective To investigate the response on late stage Chinese AIDS patients after highly active antiretroviral therapy （HAART）. Methods From October 2002 to March 2004, 20 cases of late stage Chinese AIDS patients were selected to participate in this opened and randomised study, we purposely chose those with CD4＋ T cell counts 〈 100/mm^3. All of them had one or two opportunistic infections and none had been treated with anti-HIV drugs. All patients were tested with CD4＋ （naive CD4＋ T cell defined by CD45RA＋ and CD62L＋, memory CD4＋ T cell defined by CD45RA-）, CD8＋ T cell, plasma HIV viral load, and clinical manifestations on before, during, and after HAART （5 different regimes） on 1, 3, 6, 9, and 12 months. Before HAART mean CD4＋ T cell counts were 32 ± 31 （range 2-91）/mm^3, and plasma HIV viral load were 5.07 ± 0.85（range 2.04-5.70） log copies/mL. In 1 month＇s time patients treated with HAAT had mean CD4＋ and CD8＋ T cell counts increasing rapidly. After 1 month the increasing speed turned to slow down, but HIV viral load decreased predominantly within the first 3 months. The major part of increasing CD4＋ T cells were memory CD4＋ T cells, as for naive CD4＋ T cells increasing low and slow. Clinical symptoms and signs improved, and opportunistic infections reduced. The quality of life will be far much better than before. Each patient was followed for 12 months, and had finished 12 months＇ HAAT. Conclusion This is the first report in China that late stage Chinese AIDS patients after HAART could have their immune reconstitution. The regular pattern is similar to what had been reported in Western countries and also in China. So it is worth to treat late stage Chinese AIDS patients with HAAT.
基金supported by the Peking University Clinical Scientist Program Special(BMU2019LCKXJ013)the National Natural Science Foundation Innovation Research Group Project(81721002)+2 种基金the Sanming Project of Medicine Project in Shenzhen(SZSM201612014)the Yunnan Applied Basic Research Projects-Union Foundation by Yunnan Provincial Department of Science and Technology and Kunming Medical University(202001AY070001-154)the Scientific Research Fund of Education Department of Yunnan Province(2021J0297)。
文摘Background: Mucosal-associated invariant T(MAIT) cells are systemically depleted in human immunodeficiency virus type 1(HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy(cART).This study aimed to identify the mechanism underlying MAIT cell depletion.Methods: In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.Results: Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D(GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12(IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro.Conclusions: Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients,which could potentiate disease progression and poor immune reconstitution.
基金Supported by the Jinan Clinical Medical Science and Technology Innovation Plan,No.202019141Norman Bethune Foundation-Feifan Iron Supplement Project,No.ffbt-C-2022-010.
文摘BACKGROUND Angioimmunoblastic T-cell lymphoma(AITL), a unique subtype of peripheral Tcell lymphoma, has relatively poor outcomes. High-dose chemotherapy with autologous stem cell transplantation(ASCT) can achieve complete remission and improve outcomes. Unfortunately, subsequent T-cell lymphoma-triggered hemophagocytic lymphohistiocytosis(HLH) has a worse prognosis than B-cell lymphoma-triggered HLH.CASE SUMMARY We here report a 50-year-old woman with AITL who achieved a favorable outcome after developing HLH 2 mo after receiving high-dose chemotherapy/ASCT. The patient was initially admitted to our hospital because of multiple enlarged lymph nodes. The final pathologic diagnosis, made on biopsy of a left axillary lymph node was AITL(Stage Ⅳ, Group A). Four cycles of the following chemotherapy regimen were administered: Cyclophosphamide 1.3 g, doxorubicin 86 mg, and vincristine 2 mg on day 1;prednisone 100 mg on days 1-5;and lenalidomide 25 mg on days 1-14. The interval between each cycle was 21 d. The patient received a conditioning regimen(busulfan, cyclophosphamide, and etoposide) followed by peripheral blood stem cell infusion. Unfortunately, she developed sustained fever and a low platelet count 17 d after ACST, leading to a diagnosis of HLH after ASCT. During treatment, she experienced thrombocytopenia and Pneumocystis carinii pneumonia. The patient was successfully treated with etoposide and glucocorticoids.CONCLUSION It is possible that development of HLH is related to immune reconstitution after ASCT.
文摘Objective To investigate the association between earlyimmune reconstitution and Epstein-Barrrvirus(EBV)reactivation by analyzing changes in natural killer(NK),B,and T cells and their functional status in the peripheral blood during the early post-transplant period.Methods This study included 23 patients who underwent haplo-hematopoietic stem cell transplantation(HSCT).The immune reconstitution of NK cells,T cells,and B cells as well as the expression levels of NK and T cell exhaustion markers(PD-1,TIM-3,and CTLA-4)and cytotoxic function at 1,2,and 3 months post-transplantation were compared between patients with EBV activation(EBV+group)and those without activation(EBV-group)post-transplantation.Results EBV activation occurredinninepatients posttransplantation(EBV+group),whereas 14 patients demonstrated no activation(EBV-group).All patients with EBV activation exhibited EBV viremia,and no EBV-associateddiseasesoccurred.No significant differences in the clinical characteristicswereffound between the two ggroupsof patients.The median proportion of CD3^(+)CD8^(+)T cells in the EBV+group was significantly lower than that in the EBV-group at 1 month post-transplantation(P=0.033).The median proportion of the CD3^(-)CD16^(neg)CD56^(bri)subset in the EBV+group was significantly higher than that in the EBV-group at 2 months postransplantation(P=0.046).No significant differences in the median proportions of CD3^(-)CD19^(+)B cells were observed between the two groups at 1,2,and 3 months post-transplantation.The expression of CTLA-4 on CD3^(-)CD16^(bri)CD56^(dim)NK cells in the EBV+group was significantly higher than that in the EBV-group at 1 month post-transplantation(P=0.033).The expression of TIM-3 on CD3^(+)CD8^(+)T cells in the EBV+group was significantly higher than that in the EBV-group(P=0.009).The expression level of TIM-3 on CD3^(-)CD16^(neg)CD56^(dim)NK cells in the EBV+group was significantly lower than that in the EBV-group at 2 months post-transplantation(P=0.023).The expression levels of TIM-3 on CD3^(+)CD4^(+)T cells in the EBV+group than those in the EBV-group at 1 and 3 months post-transplantation(P=0.002,P=0.043).The median positive rate of Granzyme B expression in CD3^(+)CD8^(+)T cells and CD3^(+)CD4^(+)T cells in the EBV+group was significantly lower than that in the EBV-group at 1-month post-transplantation(P=0.033,P=0.016).The median positive rate of Granzyme B expression in the CD3^(-)CD16^(bri)CD56^(neg)cell subset in the EBV+group was higher than that in the EBV-group at 2 months post-transplantation(P=0.012).The median positive rate of Granzyme B expression in CD3^(+)CD4^(+)T cells in the EBV+group remained significantly lower than that in the EBV-ggroup at 2 months posttransplantation(P=0.049).The median positive rate of perforin expression in the CD3^(-)CD16^(bri)CD56^(dim)cell subset was significantly higher in the EBV+group than in the EBV-group at 3 months post-transplantation(P=0.003).The median positive rate of IFNexpression in CD3^(+)CD8^(+)T cells in the EBV+group was significantly lower than that in the EBV-group at 3 months post-transplantation(P=0.036).Conclusion Delayed NK cell and T lymphocyte reconstitution,high exhaustion marker expression,and weakened cytotoxic functions may be related to EBV reactivation after haploidentical HSCT.
