Harnessing and honing mesenchymal stem/stromal cells for the amelioration of graft-versus-host disease

Allogeneic hematopoietic stem cell transplantation is a deterministic curative procedure for various hematologic disorders and congenital immunodeficiency.Despite its increased use,the mortality rate for patients undergoing this procedure remains high,mainly due to the perceived risk of exacerbating graft-versushost disease(GVHD).However,even with immunosuppressive agents,some patients still develop GVHD.Advanced mesenchymal stem/stromal cell(MSC)strategies have been proposed to achieve better therapeutic outcomes,given their immunosuppressive potential.However,the efficacy and trial designs have varied among the studies,and some research findings appear contradictory due to the challenges in characterizing the in vivo effects of MSCs.This review aims to provide real insights into this clinical entity,emphasizing diagnostic,and therapeutic considerations and generating pathophysiology hypotheses to identify research avenues.The indications and timing for the clinical application of MSCs are still subject to debate.

Pathophysiology of acute graft-versus-host disease from the perspective of hemodynamics determined by dielectric analysis

BACKGROUND Numerous reports have demonstrated that the pathophysiology of graft-versushost disease(GVHD)during hematopoietic stem cell transplantation(HSCT)is closely related to vascular endothelial disorders and coagulation abnormalities.We previously presented the discovery of a principle and the development of a novel instrument for measuring whole blood coagulation.This was achieved by assessing the variations in the dielectric properties of whole blood.AIM To investigate how GVHD affects the changes of dielectric properties of whole blood in patients with HSCT.METHODS We examined the changes of dielectric properties of whole blood and erythrocyte proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis sequentially in patients with HSCT and compared it with clinical symptoms and inflammatory parameters of GVHD.RESULTS During severe GVHD,the dielectric relaxation strength markedly increased and expression of band3 decreased.The dielectric relaxation strength normalized with the improvement of GVHD.In vitro analysis confirmed that the increase of relaxation strength was associated with severe erythrocyte aggregates,but not with decreased expression of band3.CONCLUSION Severe erythrocyte aggregates observed in GVHD may cause coagulation abnormalities and circulatory failure,which,together with the irreversible erythrocyte dysfunction we recently reported,could lead to organ failure.

Endoscopic diagnosis of gastrointestinal graft-versus-host disease

AIM:To evaluate the diagnostic value of endoscopy in patients with gastrointestinal graft-versus-host disease (GI GVHD). METHODS:We identified 8 patients with GI GVHD following allogeneic hematopoietic stem cell trans-plantation (HSCT). GVHD was defined histologically as the presence of gland apoptosis, not explained by other inflammatory or infectious etiologies. RESULTS:The symptoms of GI GVHD included anorexia, nausea, vomiting, watery diarrhea, abdominal pain, GI bleeding, etc. Upper endoscopic appearance varied from subtle mucosal edema, hyperemia, erythema to obvious erosion. Colonoscopic examination showed diffuse edema, hyperemia, patchy erosion, scattered ulcer, sloughing and active bleeding. Histological changes in GI GVHD included apoptosis of crypt epithelial cells, dropout of crypts, and lymphocytic infiltration in epithelium and lamina propria. The involvement of stomach and rectocolon varied from diffuse to focal. CONCLUSION:Endoscopy may play a significant role in early diagnosis of GI GVHD patients following allogeneic HSCT, and histologic examination of gastrointestinal biopsies is needed to confirm the final diagnosis.

Cytokines are early diagnostic biomarkers of graft-versus-host disease in liver recipients

BACKGROUND： Graft-versus-host disease （GVHD） is associated with high mortality. Early diagnosis is essential to start treatment and to improve outcomes. Because of the inflammatory nature, we hypothesis that cytokine profile of patients with GVHD may serve as diagnostic markers. The present study was to evaluate the role of cytokine profile in the diagnosis of GVHD. METHODS： An immunoassay was used to detect 29 cytokines simultaneously in the serum; the measuring sensitivity of all cytokines was pg/mL. Healthy subjects undergoing annual routine physical examinations served as negative controls; 23 patients with hepatocellular carcinoma （HCC） who had undergone liver transplantation （the LT group） comprised the test subjects. A total of 22 kidney recipients with biopsyconfirmed GVHD （the RT group） were included for comparison. HCC patients with radical surgery （the HCC group, n=22） served as positive control. The liver contents of the three cytokines, IL-2, IL-18, and IFN-γ, were detected with immunohistochemistry. Serum granzyme B and perforin were measured by flow cytometry.RESULTS： Of the 29 cytokines, the levels of IL-2 and IL-18 were increased significantly in liver recipients with GVHD compared with healthy controls （P〈0.05）. The serum levels of these three cytokines in the healthy, HCC, LT, and RT groups were IL-2： 0.90±0.02, 4.14±0.61, 5.10±0.89, and 1.48±0.09 pg/mL; IL-18： 80.61±9.35, 109.51±10.93, 230.11±12.92, and 61.98±7.88 pg/mL; IFN-γ： 24.06±3.88, 24.84±3.21, 40.37±5.88, and 15.33±4.72 pg/mL, respectively. Immunohistochemistry showed that these 3 cytokines expressions in the liver were parallel to the serum cytokine. After standard anti-GVHD treatment, the expressions of IL-2, IL-18, and IFN-y were de- creased in the liver （P〈0.05）. Serum granzyme B and perforin were significantly increased in GVHD patients （P〈0.05）. CONCLUSIONS： IL-2, IL-18 and IFN-γ were from liver and might serve as biomarkers for monitoring GVHD develop- ment and the effects of anti-GVHD treatment. Granzyme B and perforin may play a role in increasing IL-2, IL-18, and IFN-y levels in GVHD patients.

Umbilical Cord Blood-derived Mesenchymal Stem Cells Ameliorate Graft-Versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation through Multiple Immunoregulations

Summary： Although mesenchymal stem cells （MSCs） are increasingly used to treat graft-versus-host disease （GVHD）, their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs （UCB-hMSCs） on GVHD patients after allogeneic hematopoietic stem cell transplantation （allo-HSCT） and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK ceils, Treg cells and dendritic cells （DCs） and cytokines including interleukin-17 （IL-17） and tumor necrosis factor-alpha （TNF-α） were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3^＋, CD3＋CD4^＋ and CD3＋CD8^＋ cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4^＋ and CD8^＋ Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations.

Comparison of the meibomian gland dysfunction in patients with chronic ocular graft-versus-host disease and Sjogren's syndrome

AIM: To investigate the abnormalities in the meibomian gland in patients with dry eye disease(DED) associated with chronic ocular graft-versus-host disease(coGVHD) in comparison with Sj?gren's syndrome(SS), a major form of aqueous deficient DED and meibomian gland dysfunction(MGD), a common cause of evaporative DED.METHODS: A total 135 eyes of 135 subjects included in this study: patients with DED associated with coGVHD(n=30), patients with SS(n=35), patients with MGD(n=35), and normal controls(n=35). All participants completed the Ocular Surface Disease Index(OSDI) questionnaire, ocular surface examination [Schirmer test, tear film breakup time(TFBUT), and ocular surface staining], and meibomian gland assessment [meiboscore(gland dropout detected on meibography using infrared camera of the Keratograph 5 M), meibum expressibility score(MES), meibum quality score(MQS), lid margin abnormality]. In addition, correlations of meibomian gland characteristics with ocular surface parameters as well as disease severity score were investigated in coGVHD group.RESULTS: The coGVHD group showed significantly higher meiboscore, MES, and MQS than the other 3 groups(all P<0.05). In the coGVHD group, parameters of meibomian gland showed a significant correlation each other and those of ocular surface. The correlation between meibomian gland parameters and severity score of co GVHD was also established(meiboscore, r=0.62; MES, r=0.47; MQS, r=0.47; lid margin abnormality score, r=0.55; all P<0.05).CONCLUSION: Patients with DED associated with co GVHD show poorer gland morphology and worse glandfunction than other types of DED. In addition, meibomian gland damage is not only associated with ocular surface damage but also disease severity of coGVHD.

Diagnosis and treatment of acute graft-versus-host disease after liver transplantation:Report of six cases

BACKGROUND Graft-versus-host disease(GVHD)following liver transplantation(LT)is an unpredictable complication with poor outcome.However,consensus regarding the diagnosis and therapeutic regimen for the disease is yet lacking.The present study summarized the clinical experience on the diagnosis and treatment of acute GVHD(aGVHD)following LT and reviewed the pertinent literature.CASE SUMMARY Between January 1^(st),2000 and December 31^(st),2020,a total of 1053 LT were performed in the First Affiliated Hospital of Xi’an Jiaotong University.Six recipients developed aGVHD with clinical symptoms of fever,rash,diarrhea,and pancytopenia.The incidence of aGVHD was 0.57%.The median time from LT to the clinical presentation of aGVHD was 22.17 d.The median time from the beginning of the clinical symptom to histopathological diagnosis was 7.5 d.All six cases underwent treatment of immunosuppressant adjustment,corticosteroids,human normal immunoglobulin,and antithymocyte globulin/IL-2 antagonists.Despite intensive treatment strategies,4 patients were deceased due to sepsis,multiple organ failure,and cerebral hemorrhage.The remaining two cases were discharged as treatment successfully.However,one died because of tuberculosis infection on the 6 th month of follow-up,the other one was alive healthy during 30 mo of follow-up.CONCLUSION The rapid diagnosis of aGVHD is mainly based on the time from the first symptom,histopathological features,and the donor T-lymphocyte chimerism.Our cases report highlights massive corticosteroid therapy and age difference between donors and recipients could accelerate to aGVHD.Moreover,gut microbial interventions and donor-targeted serotherapy may provide novel therapeutics.

Oral granuloma in a pediatric patient with chronic graft-versus-host disease:A case report

BACKGROUND Oral mucositis is often observed with graft-versus-host disease(GVHD);however,the occurrence of oral granuloma is rare.The rapid increase in granulomatous lesions should be distinguished from malignant tumors in patients with GVHD because malignant diseases can develop in those patients.This case is the youngest pediatric patient with granuloma associated with GVHD.CASE SUMMARY The patient was a 1-year and 5-mo-old girl who presented to our department for the management of oral nodules.At the age of 5 mo,she was diagnosed with primary immunodeficiency disease,cord blood transplant was performed at 11 mo and bone marrow transplant at 1 year of age.After transplantation,GVHD and oral mucositis developed,and tacrolimus was administered.Interestingly,nodules appeared on the lower lip and buccal mucosa,which spontaneously disappeared.Then,a new nodule appeared on the left lateral border of the tongue.Resection was performed and the histopathological diagnosis was granuloma.The origin of these nodules were considered to be the fibroblasts activated under inflammation caused by GVHD because the calcineurin inhibitor tacrolimus acted on their proliferation.CONCLUSION It is very important to distinguish oral granulomatous lesions from malignancies if GVHD is present at the base and if immunosuppressive agents and steroids are being administered.

Expressions of Tissue Factor and Tissue Factor Pathway Inhibitor in Patients with Acute Graft-versus-host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

This study examined the expressions of human serum tissue factor （TF） and tissue factor pathway inhibitor （TFPI） in patients with acute graft-versus-host disease （aGVHD） after allogeneic hematopoietic stem cell transplantation （allo-HSCT） and their clinical significance. The serum TF and TFPI levels were detected by ELISA in 28 allo-HSCT recipients before and after the transplanta-tion and the changes of TF and TFPI levels were dynamically monitored at different phases of the disease. No significant differences in the serum TF and TFPI levels were found in allo-HSCT recipi-ents in the absence of aGVHD or with gradeⅠaGVHD before and after the transplantation. The lev-els of serum TF and TFPI were substantially increased in the patients with gradeⅡ aGVHD at the peak of aGVHD （P〈0.05） and they were even higher in the patients with grade Ⅲ–Ⅳ aGVHD （P〈0.01）. When the conditions became stable after treatment with immunosuppressive agents, the serum TFPI level was decreased to the baseline level （P〉0.05） and the TF level was lowered but still higher than the baseline level （P〈0.05）. It was concluded that the levels of serum TF and TFPI were increased significantly in the patients with grade Ⅱ–Ⅳ aGVHD after allo-HSCT and decreased markedly after the treatment. Monitoring the levels of serum TF and TFPI in the patients with allo-HSCT is important to predict the occurrence, outcome and prognosis of aGVHD.

Gene expression of cytokines after allogeneic peripheral stem cell transplantation and its relationship with acute graft-versus-host disease

Objective: To investigate the role of cytokines IL-2, IL-4, IL-10, IL-12, and IFN-γ in pathogenesis of acute graft-versus-host disease (aGVHD) after allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Methods: Forty-two patients undergoing allo-PBSCT were included in this study. Reverse-transcriptase polymerase chain reaction (RT-PCR) was used to analyze gene expression of cytokines IL-2, IL-4, IL-10, IL-12, and IFN-γ. Results: All patients achieved engraftment, 18 patients developed grade ⅠGVHD, 6 patients developed grade Ⅱ-Ⅳ GVHD. The gene expression of IL-2, IL-12, and IFN-γ increased, the gene expression of IL-4 and IL-10 decreased. Conclusion: Cytokines IL-2, IL-12, and IFN-γ lead to a positive regulation of the development in human aGVHD, and IL-4 and IL-10 play negative regulatory roles.

Experimental study of G-CSF alleviating graft-versus-host disease after mixed bone marrow transplantation in mice

Objective： How to reduce the incidence and severity of acute graft-versus-host disease （aGVHD） is a crucial step to improve the overall survival of allogeneic bone marrow transplantation （allo-BMT）. The low incidence of severe aGVHD observed in allogeneic peripheral blood stem cell transplantation （allo-PBSCT）, which may be related to modulating immune function of T lymphocytes by granulocyte colony-stimulating factor （G-CSF） primed donors. The study aimed to explore whether aGVHD could be alleviated by syngeneic bone marrow mixed with G-CSF-mobilized H-2 haploidentical marrow grafting. Methods： Female BALB/c mice and neonatal BALB/c mice were recipients and male （BALB/c × C57BL/6）F1（BCF1） mice were donor mice respectively. Donor mice were injected subcutaneously with G-CSF daily at 0.01 μg/g body weight or saline for 6 days, and splenocytes were harvested on day 6. Spleen index （SI） represented GVHD in neonatal mice after the intraperitoneal injection of mixed spleen cells. Lethally irradiated （^60Co, 8.5 Gy） adult mice were transplanted with a mixture of syngeneic plus G-CSF-mobilized （control diluents） H-2 haploidentical marrow cells. Survival time and survival rate of the recipients were observed after mixed marrow transplantation （MBMT）. GVHD was assessed by observing signs of weight loss, ruffled fur, diarrhea and histological change of skin, liver and small intestines. Enzyme-linked immunosorbent assay （ELISA） method was used to detect cytokines （IL-2, IL-4 and INF-γ）. Fluorescence-activated cell sorting （FACS） analysis was used to detect T cells phenotype. Results： （1） The neonatal mice subject to injection of 2：1 and 1：1 mixed spleen cells and H-2 haploidentical spleen cells all suffered from aGVHD. The severity of aGVHD in recipient mice receiving G-CSF-mobilized splenocytes was dramatically reduced. （2） The aGVHD signs and histological change were observed in most mice of 2：1 and 1：1 MBMT groups. However, the survival time of G-CSF-mobilized MBMT was longer than in control groups and these mice had signs of moderate GVHD. （3） L3T4^＋ cells and relative ratio in both subsets was significantly reduced in G-CSF-treated donor mice. The total number of Thyl.2 and lyt2^＋ cells was increased after G-CSF pretreatment of donors, but no statistical difference. （4） The supernatants from a primary MLR were collected at 48 h for cytokine measurement. The results showed an increased production of IL-4 and a decreased production of IL-2 and INF-γ after stimulating with concanavalin A for 48 h. Conclusion： The GVHD could be reduced using syngeneic bone marrow mixed with H-2 haploidentical marrow cells. The severity of aGVHD in recipient mice receiving G-CSF-mobilized splenocytes or marrow cells could be further moderated, which is associated with increased IL-4 production and decreased IL-2 and INF-y production.

Modified Vecchietti’s vaginoplasty with Remeex^(■) system in patient with chronic graft-versus-host disease

We present a case report of a chronic graft-versus-host disease manifestation in 33-year-old patient with an unusual complication of vaginal stenosis with complete obstruction after allogeneic bone marrow transplantation for myelocytic leukemia. The patient complained on a progressive dyspareunia and sexual intercourse inability. She has received hormone replacement therapy due to the ovarian failure after the chemotherapy treatment. The hormonal treatment was used in continuous combined manner and hematocolpos wasn’t seen during an abdominal ultrasound examination. The reconstructive surgery was performed by the modified Vecchietti’s neovagina technique with a Remeex&reg;system after histological confirmation of main diagnosis. The immediate postoperative course was uneventful with gradual normalization of sexual function.

Fulminant gastrointestinal graft-versus-host disease concomitant with cytomegalovirus infection:Case report and literature review

Here,we report a case of fulminant gastrointestinal graft-versus-host disease(GI-GVHD) with cytomegalovirus(CMV) infection in 44-year-old woman.Despite the difficulties associated with the treatment of GIGVHD and GI-CMV disease,the mucosal findings and the clinical course showed marked improvements during long-term clinical observation.The endoscopic findings were remarkable,with diffuse sloughing mucosa in the stomach and highly active inflammation and deep discrete ulcers throughout the colon.Changes in the CMV quantitative polymerase chain reaction results were correlated with the endoscopic mucosal findings and were useful for assessing the efficacy of the treatment.Although a definite diagnosis of GI-GVHD is generally made by endoscopy with biopsy,the gross appearance of this disease can vary depending on the endoscopy.In this paper,we also conduct a literature review of patients with GI-GVHD.

Graft-versus-host disease after liver transplantation:A comprehensive literature review

AIM： To determine the factors affecting mortality in pa- tients who developed graft-versus-host disease （GvHD） after liver transplantation （LT）. METHODS： We performed a review of studies of GvHD following LT published in the English literature and ac- cessed the PubMed, Medline, EBSCO, EMBASE, and Google Scholar databases. Using relevant search phras- es, 88 articles were identified. Of these, 62 articles con- raining most of the study parameters were considered eligible for the study. Risk factors were first examined using a univariate Kaplan-Meier model, and variables with a significant association （P 〈 0.05） were then sub- jected to multivariate analyses using a Cox proportional- hazards model. RESULTS： The 61 articles reported 87 patients, 58 male and 29 female, mean age, 40.4 ± 15.5 years （range： 8 mo to 74 years）, who met the inclusion criteria for the present study. Deaths occurred in 59 （67.8%） patients, whereas 28 （32.2%） survived after a mean follow-up period of 280.8 ± 316.2 d （range： 27-2285 d）. Among the most frequent symptoms were rash （94.2%）, fever （66.6%）, diarrhea （54%）, and pancytopenia （54%）. The average time period between LT and first symptom on- set was 60.6 ± 190.1 d （range： 2-1865 d）. The Kaplan- Meier analysis revealed that pancytopenia （42.8% vs 59.3%, P = 0.03）, diarrhea （39.2% vs 61.0%, P = 0.04）, age difference between the recipient and the donor （14.6 ± 3.1 years vs 22.6 ± 2.7 years, P 〈 0.0001）, and time From first symptom occurrence to diagnosis or treatment （13.3 ± 2.6 mo vs 15.0 ± 2.3 mo, P 〈 0.0001） were significant factors affecting mortality, whereas age, sex, presence of rash and fever, use of immunosuppressive agents, acute rejection before GvHD, etiological causes, time of onset, and donor type were not associated with mortality risk. The Cox proportional-hazards model, de- termined that an age difference between the recipient and donor was an independent risk Factor （P = 0.03; hazard ratio, 7.395, 95% confidence interval, 1.2-46.7）. CONCLUSION： This study showed that an age differ- ence between the recipient and donor is an independent risk factor for mortality in patients who develop GvHD after LT.

Immune Regulatory Cell Biology and Clinical Applications to Prevent or Treat Acute Graft-Versus-Host Disease

The most common approaches to prevent and treat graft-versus-host disease (GVHD) are intended to deplete or suppress the T cells capable of mediating or supporting alloresponses;however, this renders the recipients functionally T cell deficient and hence highly susceptible to infections and tumor recurrence. Depletion is often accomplished through the use of broadly reactive antibodies, while functional impairment is typically achieved by pharmacological agents that require long-term administration (usually six months or more), have significant side effects, and may not result in tolerance (i.e., nonresponsiveness) of donor T cells to conditioning regimen-resistant host alloantigen-bearing cells. As our knowledge of immune system homeostasis has increased, cell populations with immune regulatory function have been identified and characterized. Although such cell populations are typically present in low frequencies, methods to isolate and expand these cells have permitted their supplementation to the donor graft or infusion late post-transplant in order to stifle GVHD. This review discusses the biology and preclinical proof of concept of GVHD models, along with GVHD outcomes that focus exclusively on immune regulatory cell therapies that have progressed to clinical testing.

Nanoparticle-encapsulated allogeneic T cells mitigate graft-versus-host disease but retain graft-versus-leukemia activity

Aim Allogeneic hematopoietic stem cell transplantation （HSCT） has curable potential for hematopoietic malignancies through graft-versus-leukemia （GVL） effects but is often associated with life-threatening graft-versus-host disease （GVHD）. Donor T cells play an important role in the pathological process of GVHD. In this study, to determinate immunoisolation through encapsulating T cells with biomaterials could be a promising approach to atten- uate GVHD. Methods T cells were isolated from spleens of donor C57B1/6 mice by magnetic cell separation and coated by layer-by-layer in chitosan and alginate. BALB/c recipient mice were established by GVHD mode and leukemia mode. Xenogen IVIS imaging system was used for live animal imaging. Donor BMCs and T cell subsets were analyzed by flow cytometry. Results In this study, we successfully encapsulated T cells of mice in multilay- ers of chitosan and alginate. In vitro studies showed that the encapsulation did not change the phenotype of T cells as defined through the following parameters： size, viability, proliferation, antibody binding, cytokine secretion, and cytotoxicity. Mice transplanted with encapsulated allogeneic T cells exhibited less severe acute GVHD and pro- longed survival. The mice showed a lower GVHD score, less liver damage, a smaller CD8/CD4 T cell ratio, and a higher number of donor BM-derived cells following transplantation with encapsulated donor T cells. When this GVHD model was combined with implantation of A20 lymphoma cells, GVL of encapsulated T cells was not com- promised, while GVHD was still suppressed and the mouse survival also prolonged. Conclusion These studies demonstrate that encapsulation of T cells with bio-degradable materials could attenuate the severity of GVHD but re- taine GVL, which presents a novel and potentially safer and effective approach of allogeneic HSCT for future clini- cal application.

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.

Severe graft-versus-host disease post allogeneic hematopoietic stem cell transplantation due to loss of HLA heterozygosity in recipient lymphocytes after full graft rejection

Germ cell tumors complicated by hematological malignancy(HM)are a rare clinical phenomenon.Allogeneic hematopoietic stem cell transplantation(allo-HSCT)is a potentially effective therapy,but graft-versus-host disease(GVHD)is a life-threatening complication.We report a case of a 13-year-old female patient diagnosed with germ cell tumors followed by acute lymphoblastic leukemia.After chemotherapy,she received allo-HSCT and her chimerism rate decreased rapidly to near zero by 6 months without evidence of HM recurrence.However,she developed severe,multiorgan GVHD-like manifestations.DNA analysis revealed the pathogenesis of GVHD to be loss of HLA heterozygosity in recipient hematopoietic cells.

Microglial response to aging and neuroinflammation in the development of neurodegenerative diseases

Cellular senescence and chronic inflammation in response to aging are considered to be indicators of brain aging;they have a great impact on the aging process and are the main risk factors for neurodegeneration.Reviewing the microglial response to aging and neuroinflammation in neurodegenerative diseases will help understand the importance of microglia in neurodegenerative diseases.This review describes the origin and function of microglia and focuses on the role of different states of the microglial response to aging and chronic inflammation on the occurrence and development of neurodegenerative diseases,including Alzheimer's disease,Huntington's chorea,and Parkinson's disease.This review also describes the potential benefits of treating neurodegenerative diseases by modulating changes in microglial states.Therefore,inducing a shift from the neurotoxic to neuroprotective microglial state in neurodegenerative diseases induced by aging and chronic inflammation holds promise for the treatment of neurodegenerative diseases in the future.

The role of exosomes in adult neurogenesis:implications for neurodegenerative diseases

Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells.As an important form of intercellular communication,exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids,proteins,mRNAs,and microRNAs between cells,and because they can regulate physiological and pathological processes in the central nervous system.Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits.In the adult brain,neurogenesis is mainly localized in two specialized niches:the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus.An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches.In recent studies,exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo,thereby participating in the progression of neurodegenerative disorders in patients and in various disease models.Here,we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases.We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults.In addition,exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.