Against all odds:The road to success in the development of human immune reconstitution mice

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.

Alpha-GalCer Administration after Allogeneic Bone Marrow Transplantation Improves Immune Reconstitution in Mice

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.

Role of traditional Chinese medicine in incomplete immune reconstitution of HIV/AIDS:a review

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.

Acceleration of Immune Reconstitution after Bone Marrow Transplantation in Mice by Bone Marrow Stromal Cell Line Transfected with IL-6 Gene

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.

Longitudinal analysis of immune reconstitution and metabolic changes in women living with HIV:A real-world observational study

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.

Metformin may be a viable adjunctive therapeutic option to potentially enhance immune reconstitution in HIV-positive immunological non-responders

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.

Effect of Immune No.2(免疫2号方) on the Immune Reconstitution in Patients with HIV/AIDS after Highly Active Antiretroviral Treatment:A Randomized Double Blind Placebo Controlled Clinical Trial

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.

Clinical outcomes and immune reconstitution in 103 advanced AIDS patients undergoing 12-month highly active antiretroviral therapy

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.

Immune Reconstitution of Acquired Immune Deficiency syndrome

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.

Activation-induced pyroptosis contributes to the loss of MAIT cells in chronic HIV-1 infected patients

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.

Hemophagocytic lymphohistiocytosis after autologous stem cell transplantation in angioimmunoblastic T-cell lymphoma:A case report

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.

Reconstitution of double-negative T cells after cord blood transplantation and its predictive value for acute graft-versus-host disease

Background:With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation(UCBT),the correlation between immune reconstitution(IR)after UCBT and graft-versus-host disease(GVHD)has been reported successively,but reports on double-negative T(DNT)cell reconstitution and its association with acute GVHD(aGVHD)after UCBT are lacking.Methods:A population-based observational study was conducted among 131 patients with hematological malignancies who underwent single-unit UCBT as their first transplant at the Department of Hematology,the First Affiliated Hospital of USTC,between August 2018 and June 2021.IR differences were compared between the patients with and without aGVHD.Results:The absolute number of DNT cells in the healthy Chinese population was 109(70-157)/μL,accounting for 5.82(3.98-8.19)%of lymphocytes.DNT cells showed delayed recovery and could not reach their normal levels even one year after transplantation.Importantly,the absolute number and percentage of DNT cells were significantly higher in UCBT patients without aGVHD than in those with aGVHD within one year(F=4.684,P=0.039 and F=5.583,P=0.026,respectively).In addition,the number of DNT cells in the first month after transplantation decreased significantly with the degree of aGVHD increased,and faster DNT cell reconstitution in the first month after UCBT was an independent protective factor for aGVHD(HR=0.46,95%confidence interval[CI]:0.23-0.93;P=0.031).Conclusions:Compared to the number of DNT cells in Chinese healthy people,the reconstitution of DNT cells in adults with hematological malignancies after UCBT was slow.In addition,the faster reconstitution of DNT cells in the early stage after transplantation was associated with a lower incidence of aGVHD.

Dendritic nanomedicine enhances chemoimmunotherapy by disturbing metabolism of cancer-associated fibroblasts for deep penetration and activating function of immune cells

Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic epirubicin(Epi)prodrug(Epi-P4D)to regulate the metabolism of cancer-associated fibroblasts(CAFs),thus enhancing Epi penetration into both multicellular tumor spheroids(MTSs)and tumor tissues in mouse colon cancer(CT26),mouse breast cancer(4T1)and human breast cancer(MDA-MB-231)models.Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin,α-SMA,and collagen secretion.Besides,thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell(DC)maturation and subsequent immune activation,including elevating the CD4^(+)T cell population,reducing CD4^(+)and CD8^(+)T cell hyperactivation and exhaustion,and amplifying the natural killer(NK)cell proportion and effectively activating them.As a result,this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.

Neurological complications of hematopoietic cell transplantation in children and adults

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.

T-CELL RESPONSE OF ADVANCED AIDS PATIENTS AFTER HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

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.

Effectiveness and safety of traditional Chinese medicine in treating acquired immune deficiency syndrome: 2004–2014

Substantial progress has been made in China in using traditional Chinese medicine(TCM)to treat acquired immune deficiency syndrome(AIDS).Our objective was to review the latest developments in TCM treatment of AIDS in China between 2004 and 2014.We reviewed the content of original articles investigating the efficacy and safety of TCM for treating AIDS published in Chinese and English language journals.Relevant references from 2004 to 2014 were found using PubMed and the China National Knowledge Infrastructure Database.We found that TCM has been widely used for treating AIDS and its complications in China.The number of TCM studies has increased,which indicates efficacy and safety.Measures of efficacy in the reviewed articles included the alleviation of human immunodeficiency virus(HIV)-related signs and symptoms,improvements in quality of life,improvements in long-term survival,counteraction of the adverse side effects of antiviral drugs,promotion of immune reconstitution,and improvement of laboratory results.In sum,the literature indicates that TCM is safe.TCM plays an important role in the treatment of AIDS.Some studies have attempted to measure the efficacy and safety of TCM for treating AIDS,but more evidence is needed.Therefore,more research on this topic is required in the future.

Comparison of reference values for immune recovery between event-free patients receiving haploidentical allografts and those receiving human leukocyte antigen-matched sibling donor allografts

To establish optimal reference values for recovered immune cell subsets, we prospectively investigated post-transplant immune reconstitution （IR） in 144 patients who received allogeneic stem ceil transplantation （alio- SCT） and without showing any of the following events： poor graft function, grades II-IV acute graft-versus-host disease （GVHD）, serious chronic GVHD, serious bacterial infection, invasive fungal infection, or relapse or death in the first year after transplantation. IR was rapid in monocytes, intermediate in lymphocytes, CD3~ T cells, CD8~ T cells, and CD19~ B cells, and very slow in CD4~ T cells in the entire patient cohort. Immune recovery was generally faster under HLA-matched sibling donor transplantation than under haploidentical transplantation. Results suggest that patients with an IR comparable to the reference values display superior survival, and the levels of recovery in immune ceils need not reach those in healthy donor in the first year after transplantation. We suggest that data from this recipient cohort should be used as reference values for post-transplant immune ceil counts in patients receiving HSCT.

Increased early activation of CD56^(dim)CD16^(dim)/-natural killer cells in immunological non-responders correlates with CD4^(+)T-cell recovery

Background:Natural killer(NK)cells play a critical role in suppressing human immunodeficiency virus-1(HIV-1)infection,but knowledge on whether and how NK cells affect immune reconstitution in HIV-1-infected individuals who receive antiretroviral therapy(ART)is limited.Methods:We performed a case-control study with 35 healthy individuals and 66 HIV-1-infected patients including 32 immunological non-responders(INRs)with poor CD4+T-cell recovery(<500 cells/μL after 4 years of ART)and 34 immunological responders(IRs)with improved CD4+T-cell recovery(>500 cells/μL after 4 years of ART).NK cell phenotype,receptor repertoire,and early activation in INRs and IRs were investigated by flow cytometry.Results:A significantly higher proportion of CD56dimCD16dim/-NK cells was observed in INRs than IRs before ART and after 4 years of ART.The number of CD56dimCD16dim/-NK cells was inversely correlated with CD4+T-cell counts in INRs before ART(r=-0.344,P=0.050).The more CD69-expressing NK cells there were,the lower the CD4+T-cell counts andΔCD4,and these correlations were observed in INRs after ART(r=-0.416,P=0.019;r=-0.509,P=0.003,respectively).Additionally,CD69-expressing CD56dimCD16dim/-NK cells were more abundant in INRs than those in IRs(P=0.018)after ART,both of which had an inverse association trend towards significance with CD4+T-cell counts.The expression of the activating receptors NKG2C,NKG2D,and NKp46 on CD56dimCD16dim/-NK cell subsets were higher in IRs than that in INRs after 4 years of ART(all P<0.01).Strong inverse correlations were observed between CD69 expression and NKG2C,NKG2A-NKG2C+,NKG2D,and NKp46 expression on CD56dimCD16dim/-NK cells in INRs after ART(NKG2C:r=-0.491,P=0.004;NKG2A-NKG2C+:r=-0.434,P=0.013;NKG2D:r=-0.405,P=0.021;NKp46:r=-0.457,P=0.008,respectively).Conclusions:INRs had a larger number of CD56dimCD16dim/-NK cells characterized by higher activation levels than did IRs after ART.The increase in the CD56dimCD16dim/-NK cell subset may play an adverse role in immune reconstitution.Further functional studies of CD56dimCD16dim/-NK cells in INRs are urgently needed to inform targeted interventions to optimize immune recovery.

Safety and efficacy of allogeneic natural killer cell immunotherapy on human immunodeficiency virus type 1 immunological non-responders:a brief report

Background:Allogeneic natural killer(NK)cell immunotherapy is recognized as a promising anti-tumor strategy,but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1(HIV-1)infected patients is unknown.This study aimed to investigate the safety and effectiveness of allogeneic NK cells immunotherapy on HIV-1 immunological non-responders(INRs)receiving antiretroviral therapy(ART).Methods:From February to April 2018,a prospective,randomized,controlled,open-label clinical trial,which enrolled 20 HIV-1 INRs following specific inclusion criteria,was conducted at Nankai University Second People’s Hospital.Participants were randomly allocated(simple randomization 1:1)to either the combined treatment(NK+ART)group(n=10)or the control(ART)group(n=10).The allogenic highly activated NK cells from killer cell immunoglobulin-like receptor(KIR)/human leukocyte antigen(HLA)-Cw mismatched healthy donor were prepared(108 cells in each injection)and intravenously infused to each recruited patient of NK+ART group in three courses.Key immune parameters(CD4 count,CD8 count,CD4/CD8 ratio),laboratory tests(count of blood cells,biochemistry panel)and symptoms at baseline and at month 1,3,6,9,12,and 24 were measured/collected to analyze the safety and efficacy of the therapy.Comparisons were between the seven time-points of both groups using repeated measurement analysis of variance(ANOVA)test.Generalized estimating equations(GEE)model was performed to evaluate the overall effect of the NK+ART group vs.the ART group.Results:From baseline to 24 months,we noted a mean CD4 count augmentation(139 to 243 cells/μL)in the NK+ART group and(144 to 176 cells/μL)in the ART group(difference,67;95%CI,10 to 124;P=0.024).Our estimations revealed that NK+ART group could improve CD4 level(β=54.59,P=0.006)and CD8 level(β=322.47,P=0.010)on average among the six measurements compared with the ART group.Only two(2/10,20%)participants in the NK+ART group developed a transient mild fever after the first course.Conclusions:This preliminary study informs that HIV-1 INRs,allogenic NK cells immunotherapy is safe and could significantly improve CD4 recovery but not CD4/CD8 ratio.The practical effects,however,need long-term follow-up observations.Further study on the potential underlying mechanism is warranted.Registration info:www.chictr.org.cn/showproj.aspx?proj=34912(No.ChiCTR1900020634).

Bone marrow stromal cell line co-transfected with IL-2 and IL-3 genes can accelerate restoration of T-cell immunity in allo-BMT mice

Background After T-cell depleted allogeneic bone marrow transplantation, impaired immune reconstitution is a major cause of morbidity and mortality in the recipient The purpose of this study was to observe the effects of the gene-engineered bone marrow stromal cell line QXMSC1-IL-2+IL-3 on the reconstitution of T-cell immunity in allo-BMT mice Methods The bone marrow stromal cell line QXMSC1 was co-transfected with IL-2 and IL-3 genes using a Tet-on gene expression system T lymphocyte subset counts per spleen were analyzed by flow cytometry Lymphocyte proliferation response to ConA was examined to evaluate T-cell function CDR3 spectratyping techniques were performed to evaluate TCR repertoire diversity at various time points post-transplantation Results Gene engineered bone marrow stromal cell line QXMSC1-IL-2+IL-3 could express IL-2 and IL-3 (1300 ng·day -1 ·10 -6 cells and 1100 ng·day -1 ·10 -6 cells, respectively) under the control of doxycycline QXMSC1-IL-2+IL-3 in combination with allogeneic bone marrow could significantly increase the counts of CD4 + and CD8 + T cell, 1.72 and 1.27-fold respectively at week 3 compared with TCD-BMT group ( P <0.01); make CD4 +/CD8 + ratio return to normal level at week 4; enhance splenocytes mitotic response to ConA ( P <0.01), and accelerate restoration of TCR repertoire diversity in the lethally irradiated mice ( P <0.05) KH*2/5DConclusion The gene transduced stromal cell line QXMSC1-IL-2+IL-3 is able to accelerate T-cell immunity in allo-BMT mice