Pd(II)/N,N'-Disulfonyl Bisimidazoline-Catalyzed Enantioselective Synthesis of Cyclic Quaternary Centers and Mechanistic Investigations.

A Pd(II)/N,N'-disulfonyl bisimidazoline-catalyzed asymmetric 1,4-conjugate addition reaction of low-cost arylboronic acids with readily available ß-substituted cyclic enones is described, providing a straightforward way of constructing cyclic all-carbon quaternary stereocenters with high enantioselectivity, in which ≥96% ee was obtained in most cases. The reaction proceeded without the protection of inert gas, making the operation process simple. Theoretical calculations have been applied to understand the origins of enantioselectivity.

Olefin skeletal rearrangement enabling access to multiarylated N-sulfonyl amidines.

A base-promoted olefin skeletal rearrangement strategy from para-quinone methides (p-QMs) and N-fluoroarenesulfonamides is reported, enabling direct nitrogen insertion of olefins to produce a series of multiarylated (Z)-N-sulfonyl amidines with complete stereoselectivity and generally good yields. Using p-QMs without o-hydroxy substituents gave triarylated N-sulfonyl amidines, whereas tetraarylated N,N'-disulfonyl amidines were synthesized with the existence of o-hydroxy groups.

Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice.

BACKGROUND: Acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transplantation of immunosuppressive human mesenchymal stromal cells (hMSCs) can protect against aGvHD post-HSCT; however, their efficacy is limited by poor engraftment and survival. Moreover, infused MSCs can be damaged by activated complement, yet strategies to minimise complement injury of hMSCs and improve their survival are limited. METHODS: Human MSCs were derived from bone marrow (BM), adipose tissue (AT) and umbilical cord (UC). In vitro immunomodulatory potential was determined by co-culture experiments between hMSCs and immune cells implicated in aGvHD disease progression. BM-, AT- and UC-hMSCs were tested for their abilities to protect aGvHD in a mouse model of this disease. Survival and clinical symptoms were monitored, and target tissues of aGvHD were examined by histopathology and qPCR. Transplanted cell survival was evaluated by cell tracing and by qPCR. The transcriptome of BM-, AT- and UC-hMSCs was profiled by RNA-sequencing. Focused experiments were performed to compare the expression of complement inhibitors and the abilities of hMSCs to resist complement lysis. RESULTS: Human MSCs derived from three tissues divergently protected against aGvHD in vivo. AT-hMSCs preferentially suppressed complement in vitro and in vivo, resisted complement lysis and survived better after transplantation when compared to BM- and UC-hMSCs. AT-hMSCs also prolonged survival and improved the symptoms and pathological features of aGvHD. We found that complement-decay accelerating factor (CD55), an inhibitor of complement, is elevated in AT-hMSCs and contributed to reduced complement activation. We further report that atorvastatin and erlotinib could upregulate CD55 and suppress complement in all three types of hMSCs. CONCLUSION: CD55, by suppressing complement, contributes to the improved protection of AT-hMSCs against aGvHD. The use of AT-hMSCs or the upregulation of CD55 by small molecules thus represents promising new strategies to promote hMSC survival to improve the efficacy of transplantation therapy. As complement injury is a barrier to all types of hMSC therapy, our findings are of broad significance to enhance the use of hMSCs for the treatment of a wide range of disorders.

Azofuran activation for annulative rearrangement enabled by gold(I)/Brønsted acid relay catalysis.

A novel gold(I)/Brønsted acid relay catalysis enabling azofuran activation to induce annulative rearrangement from 3-yne-1,2-diols and aryldiazonium tetrafluoroborates is reported, producing a series of furan-2-yl-substituted pyrrol-2-ones bearing a quaternary carbon center with good yields. Exchanging aryldiazonium tetrafluoroborate for azofuran led to skeletally identical but substituent-diverse furan-2-yl-containing pyrrol-2-ones with good yields, supporting the key azofuran activation and annulative rearrangement by gold/Brønsted acid relay catalysis.

Prevalence, risk factors, and prediction of inappropriate use of non-vitamin K antagonist oral anticoagulants in elderly Chinese patients with atrial fibrillation: A study protocol.

Background: Atrial fibrillation (AF) is an arrhythmia that is prevalent globally, and its incidence grows exponentially with aging. Non-vitamin K antagonist oral anticoagulants (NOACs) have been developed in recent years, and it challenges the supremacy of warfarin for thromboembolism prophylaxis in AF. Nevertheless, there are limited data specifically evaluating the real-life use of NOACs in elderly patients with AF in China. Methods: This is a national, multicenter, non-interventional, cross-sectional study that enrolls patients with AF aged 75 years and above from 31 institutions across China. Data were collected using the Hospital Information System. The primary outcomes include (1) profiles of NOAC use in the elderly; (2) frequency of inappropriate NOAC use based on guidelines and approved labeling recommendations; (3) exploring potential risk factors related to NOACs inappropriate use; and (4) creating a prediction tool for inappropriate NOACs use. Conclusion: The results of this study reveal the prevalence, risk factors, and corresponding prediction tool of inappropriate NOACs use in older patients with AF in China, as well as provide valuable insights into the clinical application of NOACs in high-risk populations in the real-world setting. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT05361889.

The relationship between absolute counts of lymphocyte subsets and clinical features in patients with pulmonary tuberculosis.

BACKGROUND: The aim of the present study is to investigate the clinical value and characteristics of peripheral blood lymphocyte subsets in patients with pulmonary tuberculosis (PTB) using flow cytometry. METHODS: The absolute counts of T, CD4+ T, CD8+ T, natural killer (NK), NKT and B lymphocytes in 217 cases of PTB were detected, and the variations in lymphocyte subset counts between different ages and genders and between aetiological detection results and chest radiography results were analysed. RESULTS: In 75.3% of the patients with PTB, six subset counts were lower than the normal reference range, and 44% showed lower-than-normal CD4+ T lymphocyte levels. The counts of T, CD4+ T, CD8+ T and B lymphocytes were significantly lower in patients aged >60 years, and the NKT cell counts were significantly lower in female patients than in male patients. Among the patients with positive aetiological results, 40.8% had reduced CD8+ T counts; these were significantly lower than those in patients with negative aetiological results (P = 0.0295). The cell counts of T, CD4+ T, CD8+ T and B lymphocytes reduced as lesion lobe numbers increased. The counts of T, CD4+ T and CD8+ T lymphocytes were significantly higher in the group with lesions affecting one lobe than in the groups with two to three lobes or four to five lobes, and the counts of B lymphocytes were significantly higher in the group with one lobe and the group with two to three lobes than in the group with four to five lobes. The counts of CD4+ T and CD8+ T lymphocytes were highest in the no cavity group and showed a downward trend with the increase in cavities; the T lymphocyte count was significantly higher in the no cavity group than in the group with five or more cavities (P = 0.014), and the CD8+ T lymphocyte count was significantly higher in the no cavity group than in the group with one to two cavities and the group with five or more cavities (P = 0.001 and 0.01, respectively). CONCLUSIONS: In most patients with tuberculosis, immune function is impaired. The absolute counts of peripheral blood lymphocyte subsets are closely related to the aetiological results and lesion severity in patients with PTB; this could be used as evidence for immune intervention and monitoring curative effects.

RNA sequencing analysis reveals apoptosis induction by hydrogen treatment in endometrial cancer via TNF and NF-κB pathways.

BACKGROUND: To evaluate the activity of hydrogen in endometrial cancer and elucidate its underlying molecular mechanisms. METHODS: Ishikawa, HEC1A and AN3CA cells were incubated in DMEM medium with or without hydrogen. RNA sequencing was used to explore the association of hydrogen treatment with signaling pathways and functional genes in endometrial cancer cells. The apoptotic rates of the three endometrial cancer cells were evaluated by fluorescein isothiocyanate (FITC) Annexin V and Annexin V-allophycocyanin (APC)/propidium iodide double staining. RESULTS: RNA sequencing analysis revealed that hydrogen induced TNF/NF-κB and apoptosis pathways in endometrial cancer cells. The gene sets between hydrogen treatment groups and non-treated groups were mapped in accordance with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) terms. Hydrogen treatment significantly increased the apoptotic rates of endometrial cancer cells. CONCLUSIONS: Taken together, our data indicate that hydrogen can serve as a therapeutic target for endometrial cancer via TNF/NF-κB pathway and apoptosis induction.

Immunosuppressive mechanisms of human bone marrow derived mesenchymal stromal cells in BALB/c host graft versus host disease murine models.

BACKGROUND: Mesenchymal stromal cells (MSCs) are proven to have immunosuppressive functions via various mechanisms. These mechanisms were demonstrated by administering bone marrow derived human MSCs (hMSCs) to graft versus host disease (GVHD) murine models. METHODS: BALB/c host mice were irradiated prior to receiving C57BL/6 donor T cell depleted bone marrow (TCDBM) cells (negative control) and donor CD4+ T lymphocyte with (treatment group) or without hMSCs (positive control). The presence of hMSCs in target tissues and lymphoid organs was documented by using in vivo imaging and measuring the expression of EphB2 and ephrin-B2 by RTqPCR. Survival rate and GVHD score were also monitored. Tissue sections were obtained for histopathologic analysis. Flow cytometry was used to document donor T cell alloreactivity and expression of CCR5, CXCR3 and CCR7. ELISA was utilized to determine levels of proinflammatory cytokines, RANTES (CCL5) and phosphorylated STAT 5A/B. RTqPCR was performed to quantify expression of CCL3 and CXCL9. Western blotting was performed to qualitatively measure iNOS expression. RESULTS: Survival rate and GVHD score improved with hMSC treatment. Pathologic changes of GVHD were abrogated. Documentation of suppression of RANTES, CCL3, CXCL9, CCR5 and CXCR3 with simultaneous decrease of donor T cell alloreactivity was demonstrated 6 days after transplantation, along with reduction of levels of inflammatory cytokines, suppression of STAT 5A/B phosphorylation, increased expression of CCR7 and increased production of nitrous oxide by hMSCs. Documentation of homing of hMSCs to lymphoid organs and target tissues was also performed. CONCLUSIONS: These mechanisms contribute to the current understanding of MSC mechanisms of immunosuppression and forms a comprehensive picture of how they exert immunosuppression in an in vivo model of immune dysregulation.

A pharmacodynamic simulation to evaluate tigecycline in treatment of nosocomial pneumonia caused by multidrug-resistant Acinetobacter baumannii.

The shortage of effective antibiotics against multidrug-resistant Acinetobacter baumannii (MDR-Ab) has posed great threat to the public health. But the advent of tigecycline gives us new hope. The goal of our research was to assess the clinical efficacy of tigecycline at different doses by using a pharmacokinetic/pharmacodynamic (PK/PD) model which can incorporate pharmacokinetic data of tigecycline from patients with pneumonia and MICs of MDR-Ab from a tertiary hospital. A 10000-patient Monte-Carlo Simulation based on the PK/PD model was conducted to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of tigecycline. 97% isolates displayed susceptibility and 3% were tigecycline-intermediate strains and the values of MIC ranged from 0.125 to 4 µ g/ml. A CFR of 61.62% was predicted for tigecycline at current dosage (50 mg q12h). When the dosage was increased, the predicted CFRs for 75 mg q12h, 100 mg q12h, 125 mg q12h, 150 mg q12h were 81.00%, 89.86%, and 94.57%, 96.77%, respectively. Despite presented higher susceptibility, the CFR obtained was not optimal at current dosage. A higher CFR indicating a better clinical efficacy can be gained by the increased dosage.

[The human body burden of polychlorinated dibenzo-p-dioxins and dibenzofurans and dioxin-like polychlorinated biphenyls in residents' human breast milk from Beijing in 2007].

OBJECTIVE: To investigate contamination levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) in human breast milk from Beijing residents, and evaluate the human body burden of PCDD/Fs and dl-PCBs of general population. METHODS: A total of 110 human milk samples were collected from 11 regions in Beijing in 2007. After 11 pooled samples were made, concentrations of PCDD/Fs and dl-PCBs in breast milk pooled samples were measured by a high resolution gas chromatography - high resolution mass spectrometry (HRCG-HRMS) with isotope dilution. RESULTS: For congeners of PCDD/Fs and dl-PCBs in human breast milk from Beijing, the highest content of congeners was octachlorodibenzo-p-dioxin (OCDD), polychlorinated biphenyl (PCB)-118, and PCB-105 with the median of 20.6 pg/g fat, 4.07 ng/g fat and 1.63 ng/g fat, respectively. The concentration median of total dioxins in 11 pooled human milk samples from Beijing was 7.4 pg TEQ/g fat. The highest was 13.5 pg TEQ/g fat from Tongzhou, and the lowest was 4.3 pg TEQ/g fat from Pinggu. CONCLUSION: The contamination level of PCDD/Fs and dl-PCBs in human milk from Beijing is relatively low. However, with the rapid industrialization in China, the human body burden of PCDD/Fs and dl-PCBs will be likely to rise. Thus, further studies should be conducted to continuously monitor the trend of contamination level.

Multicomponent synthesis of poly-substituted benzo[a]pyrano[2,3-c]phenazine derivatives under microwave heating.

A new one-pot two-step tandem synthesis of highly functionalized benzo[a]pyrano[2,3-c]phenazine derivatives via microwave-assisted multicomponent reactions of 2-hydroxynaphthalene-1,4-dione, diamines, aldehydes, and malononitrile is reported. The procedures are facile, avoiding time-consuming and costly syntheses, tedious workup, and purifications of precursors, as well as protection/deprotection of functional groups. The method is expected to find application in the combinatorial synthesis of biologically active compounds, since phenazine and chromene motifs have a broad spectrum of biological activities.

Polybrominated diphenyl ethers (PBDEs) and indicator polychlorinated biphenyls (PCBs) in marine fish from four areas of China.

The levels of polybrominated diphenyl ethers (PBDEs) and indicator polychlorinated biphenyls (PCBs) were determined in marine fish from four areas of China (South China Sea, Bohai Sea, East China Sea, and Yellow Sea) using GC/NCI-MS and GC/ITMS, respectively. Total concentrations of eight PBDEs (BDE-28, 47, 99, 100, 153, 154, 183 and 209) in all samples ranged from 0.3ngg(-1)ww (wet weight) to 700 ng g(-1)ww, with median and mean values of 85 ng g(-1)ww and 200 ng g(-1)ww, respectively. BDE-209 and BDE-47 were the major congeners in all samples, contributing 54% and 19% to the total concentration, respectively. The sum of seven indicator PCB levels (CB-28, 52, 101, 118, 138, 153, and 180) ranged from 0.3 ng g(-1)ww to 3.1 µg g(-1)ww, with median and mean values of 6.4 ng g(-1)ww and 398 ng g(-1)ww, respectively. High contributions of CB-138 (32%) and CB-153 (25%) were found in all samples. In general, pollutants measured in this study were at high levels when compared with previous studies from other regions in the world. The relative abundance of BDE-209 may suggest that deca-BDE sources existed in studied area. And principal component analysis (PCA) showed that there were other PBDE sources in Yellow Sea. The pattern and PCA showed that PCB pollutions came from similar sources in the studied areas. In addition, concentrations of ∑(7)PBDEs (u/209) were strongly correlated with those of ∑(7)PCBs in all fish (r=0.907, n=44).

Proteomic analysis of human serum from diabetic retinopathy.

AIM: To establish and compare serum proteomic of diabetic retinopathy (DR) patients in various phases and discuss pathogenesis of DR so as to find out possible serum specific molecular markers for early diagnosis of DR. METHODS: Thirty-two subjects were divided into four groups: one group of eight type 2 diabetes mellitus (T2DM) patients without apparent DR (No-DR, NDR), one group of eight T2DM patients with non-proliferative diabetic retinopathy (NPDR), one group of eight T2DM patients with proliferative diabetic retinopathy (PDR) and one group of eight healthy volunteer participants. Two dimensional fluorescence difference gel electrophoresis (2D-DIGE) was applied to establish differential protein expression profiles in four groups. Matrix-assisted laser desorption/ionization time of flight tandem mass spectrometry (MALDI-TOF-TOF MS) was applied to identify mass spectrometry of differential proteins and analyze follow-up bioinformatics. RESULTS: 2D-DIGE maps of serum protein were satisfactory obtained from NDR, NPDR, PDR and normal control groups. Twenty-six different proteins spots were screened (the volume ratio was >1.5 based on DeCyder software analysis). Twenty-four of them were verified and two of them were not. Fifteen proteins were verified. Most of them were high-abundant proteins in serum. The four relatively low-abundant ones were beta 2-glycoprotein I (ß(2)-GPI), alpha2-HS-glycoprotein(AHSG), alpha1-acid glycoprotein(α(1)-AGP) and apolipoprotein A-1(apo A-1). ß(2)-GPI expression was gradually increased in the development of DR but unrelated to the severity of DR. The volume ratio of ß(2)-GPI is 1.54, 2.43, and 2.84 in NDR, NPDR and PDR group respectively compared with normal control group. CONCLUSION: Serum proteomic analysis of 2D-DIGE combined with MALDI-TOF-TOF MS is feasible to be applied in the study of DR. ß(2)-GPI probably takes part in the process of DR occurrence and development and it could be a candidate biomarker on DR diagnosis in early phase.

Determination of aflatoxins in edible oil from markets in Hebei Province of China by liquid chromatography-tandem mass spectrometry.

Analysis of aflatoxin B1 (AFB1), B2 (AFB2), G1 (AFG1) and G2 (AFG2) in 76 edible oil samples (peanut oil, soybean oil, corn embryo oil and blended oil) was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The oils were sampled from three areas (Shijiazhuang, Baoding and Tangshan) of Hebei Province of China. AFB1 was detected in 22 samples representing 28.9%, followed by AFB2 (7.89%) and AFG1 (3.95%), while no AFG2 contamination was detected in any samples. AFB1 levels in oil samples ranged 0.14-2.72 µg kg(-1) and AFB2 ranged 0.15-0.36 µg kg(-1), while lower levels of 0.01-0.02 µg kg(-1) for AFG1 were recorded. The paper is part of an on-going investigation of aflatoxin contamination in Chinese edible oils.

Fast analysis of polybrominated diphenyl ethers in eggs using selective pressurized liquid extraction coupled with online GPC-GC/MS.

This article reports the applicability of online gel permeation chromatography (GPC)-GC/MS for the determination of seven predominant polybrominated diphenyl ethers (PBDEs) in eggs to effectively eliminate matrix interference. Selective pressurized liquid extraction using acidic alumina as a fat retainer was used for cleanup of the PBDEs in eggs. It was selected because of its advantages: simpler operation, minimum time spent on sample handing to get fat-free extracts, and low volume of solvent consumption. After concentration, the extract was directly injected for online GC/MS operated in the negative ion chemical ionization mode with a 15 m capillary column. Recoveries of spiked samples were between 75.1 and 102.0%, with RSDs (n=3) ranging from 3.69-11.47% when spiked at levels of 2 and 20 ng/g, dry mass. The LOD varied from 0.25-34 ng/g, dry mass. The proposed method was proven to be rapid, efficient, and reliable for the trace determination of PBDEs in eggs.

Simultaneous protection against allograft rejection and graft-versus-host disease after total lymphoid irradiation: role of natural killer T cells.

BACKGROUND: The use of combined organ and bone marrow transplantation has been studied extensively in rodent models to induce immune tolerance to organ grafts. However, bone marrow transplants with mature donor T cells can induce graft-versus-host disease even in human leukocyte antigen-matched humans. We determined whether total lymphoid irradiation can simultaneously protect against graft-versus-host disease while facilitating tolerance. METHODS: To more closely model clinical studies, we added mature donor T cells to bone marrow grafts combined with heart grafts, and compared murine graft and host survival after conditioning with nonmyeloablative total body or total lymphoid irradiation and depletive anti-T-cell antibodies. RESULTS: Conditioning with total lymphoid irradiation protected hosts against both graft-versus-host disease and organ graft rejection. Although nonmyeloblative total body irradiation prevented organ graft rejection, all hosts succumbed to lethal graft-versus host disease. Induction of tolerance with total lymphoid irradiation and anti-T-cell antibodies was dependent on the presence of regulatory host natural killer T cells, and expression of CD1d on donor marrow but not heart graft cells. CONCLUSION: Conditioning with total lymphoid irradiation and anti-T-cell antibodies prevented host-versus-donor and donor-versus-host alloimmune responses. Tolerance required host natural killer T-cell recognition of CD1d on donor marrow cells.

Naive and memory T cells induce different types of graft-versus-host disease.

The goal of this study was to compare the ability of donor naive and alloantigen-primed effector memory T cells to induce graft-vs-host disease after bone marrow transplantation in MHC-mismatched irradiated host mice. Purified CD4(+) naive (CD62L(high)CD44(low)) T cells and CD4(+) effector memory (CD62L(low)CD44(high)) T cells obtained from unprimed donors and donors primed to host alloantigens, respectively, were injected into host mice, and the rapidity, severity, and pattern of tissue injury of graft-vs-host disease was assessed. Unexpectedly, the naive T cells induced a more acute and severe colitis than the primed memory cells. Whereas the naive T cells expressing CD62L and CCR7 lymph node homing receptors vigorously expanded in mesenteric lymph nodes and colon by day 6 after transplantation, the primed memory T cells without these receptors had 20- to 100-fold lower accumulation at this early time point. These differences were reflected in the significantly more rapid decline in survival and weight loss induced by naive T cells. The primed memory T cells had a greater capacity to induce chronic colitis and liver injury and secrete IL-2 and IFN-gamma in response to alloantigenic stimulation compared with memory T cells from unprimed donors. Nevertheless, the expected increase in potency as compared with naive T cells was not observed due to differences in the pattern and kinetics of tissue injury.

[Treatment of mandibular retrusion patients with Forsus appliance following growth spurts].

PURPOSE: To evaluate the clinical effects of Forsus appliance in treatment of patients with mandibular retrusion after the growth spurts. METHODS: 15 cases of Class II malocclusion with small lower jaw were treated with Forsus appliance. Cephalogram pre-and post-treatment was taken,the width of dental arch was measured, and questionnaire were collected from the patients. SPSS10.0 software package was used for paired t test. RESULTS: SNB increased 1.42 degrees, ANB reduced 1.65 degrees, and Forsus appliance brought about 2.12 degrees reduction of the facial soft tissue profile convexity. The width of dental arch was extended. Overbite reduced and overjet went down 4.98 mm. CONCLUSIONS: Forsus appliance can improve sagittal discrepancy and soft tissue profile convexity of patients with Class II malocclusion.

Protective conditioning for acute graft-versus-host disease.

BACKGROUND: Conditioning with total lymphoid irradiation plus antithymocyte serum protects mice against acute graft-versus-host disease (GVHD) after hematopoietic-cell transplantation. We tested this strategy in humans. METHODS: Thirty-seven patients with lymphoid malignant diseases or acute leukemia underwent an experimental conditioning regimen with 10 doses of total lymphoid irradiation (80 cGy each) plus antithymocyte globulin, followed by an infusion of HLA-matched peripheral-blood mononuclear cells from related or unrelated donors who received granulocyte colony-stimulating factor. RESULTS: Of the 37 transplant recipients, only 2 had acute GVHD after hematopoietic-cell transplantation. Potent antitumor effects in patients with lymphoid malignant diseases were shown by the change from partial to complete remission. In the transplant recipients who underwent conditioning with total lymphoid irradiation and antithymocyte globulin, the fraction of donor CD4+ T cells that produced interleukin-4 after in vitro stimulation increased by a factor of five, and the proliferative response to alloantigens in vitro was reduced, as compared with normal control subjects and control subjects who underwent conditioning with a single dose of total-body irradiation (200 cGy). CONCLUSIONS: A regimen of total lymphoid irradiation plus antithymocyte globulin decreases the incidence of acute GVHD and allows graft antitumor activity in patients with lymphoid malignant diseases or acute leukemia treated with hematopoietic-cell transplantation.

L-selectin and beta7 integrin on donor CD4 T cells are required for the early migration to host mesenteric lymph nodes and acute colitis of graft-versus-host disease.

The homing receptors L-selectin and alpha4beta7 integrin facilitate entry of T cells into the gut-associated organized lymphoid tissues such as the mesenteric lymph nodes and Peyer patches. We studied the impact of inactivation of genes encoding these receptors on the ability of purified donor CD4+ T cells to induce acute lethal graft-versus-host disease (GVHD) associated with severe colitis in irradiated major histocompatibility complex (MHC)-mismatched mice. Whereas lack of expression of a single receptor had no significant impact on the severity of colitis and GVHD, the lack of expression of both receptors markedly ameliorated colitis and early deaths observed with wild-type (WT) T cells. The changes in colitis and GVHD were reflected in a marked reduction in the early accumulation of donor T cells in the mesenteric lymph nodes and subsequently in the colon. The purified WT donor CD4+ T cells did not accumulate early in the Peyer patches and failed to induce acute injury to the small intestine. In conclusion, the combination of CD62L and beta7 integrin is required to induce acute colitis and facilitate entry of CD4+ donor T cells in the mesenteric nodes associated with lethal GVHD in allogeneic hosts.