RESUMO
Antibodies reactive to self-antigens are an important component of posttransplant immune responses. The generation requirements and functions of autoantibodies, as well as the mechanisms of their influence on alloimmune responses, still remain to be determined. Our study investigated the contribution of autoimmunity during rejection of renal allografts. We have previously characterized a mouse model in which the acute rejection of a life-supporting kidney allograft is mediated by antibodies. At rejection, recipient sera screening against >4000 potential autoantigens revealed DNA topoisomerase I peptide 205-219 (TI-I205-219) as the most prominent epitope. Subsequent analysis showed TI-I205-219-reactive autoantibodies are induced in nonsensitized recipients of major histocompatibility complex-mismatched kidney allografts in a T cell-dependent manner. Immunization with TI-I205-219 broke self-tolerance, elicited TI-I205-219 immunoglobin G autoantibodies, and resulted in acute rejection of allogeneic but not syngeneic renal transplants. The graft loss was associated with increased priming of donor-reactive T cells but not with donor-specific alloantibodies elevation. Similarly, passive transfer of anti-TI-I205-219 sera following transplantation increased donor-reactive T cell activation with minimal effects on donor-specific alloantibody levels. The results identify DNA topoisomerase I as a novel self-antigen in transplant settings and demonstrate that autoantibodies enhance activation of donor-reactive T cells following renal transplantation.
Assuntos
Transplante de Rim , Linfócitos T , Camundongos , Animais , Transplante de Rim/efeitos adversos , DNA Topoisomerases Tipo I , Autoanticorpos , Rejeição de Enxerto , Aloenxertos , RimRESUMO
PURPOSE: Patients with functional constipation (FCon) often suffer from mental and psychological problems. To explore the possible neurological interaction, we used resting-state functional magnetic imaging (RS-fMRI) to compare the alterations in intrinsic brain functional networks at multiple levels between patients with FCon and healthy controls (HC). METHODS: Twenty-eight patients with FCon and twenty-nine HC were recruited for a series of examinations and RS-fMRI. Both graph theory analysis and functional connectivity (FC) analysis were used to investigate brain functional alterations between the two groups. Correlation analyses were performed among neuropsychological scores, clinical indexes, and neuroimaging data. RESULTS: Compared with the HC, the assortativity showed significantly increased in global level in patients with FCon. In regional level, we found obviously increased nodal degree and nodal efficiency in somatosensory network (SMN), decreased nodal degree, and increased nodal efficiency in default mode network (DMN) in the FCon group. Furthermore, FC analysis demonstrated several functional alterations within and between the networks, particularly including the SMN and visual network (VN) in sub-network and large-scale network analysis. Moreover, correlation analysis indicated that nodal metrics and aberrant FC among functional brain networks were associated with emotion and scores of constipation in patients with FCon. CONCLUSION: All these findings reflect the differences in intrinsic brain functional networks between FCon and HC. Our study highlighted SMN, DMN, and VN as critical network and may be involved in the neurophysiology of FCon, which may contribute to improve personalized treatment in patients with FCon.
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Mapeamento Encefálico , Imageamento por Ressonância Magnética , Humanos , Mapeamento Encefálico/métodos , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Neuroimagem , Constipação Intestinal/diagnóstico por imagemRESUMO
Diminishing homeostatic proliferation of memory T cells is essential for improving the efficacy of lymphoablation in transplant recipients. Our previous studies in a mouse heart transplantation model established that B lymphocytes secreting proinflammatory cytokines are critical for T cell recovery after lymphoablation. The goal of the current study was to identify mediators of B cell activation following lymphoablation in allograft recipients. Transcriptome analysis revealed that macrophage-inducible C-type lectin (Mincle, Clec4e) expression is up-regulated in B cells from heart allograft recipients treated with murine anti-thymocyte globulin (mATG). Recipient Mincle deficiency diminishes B cell production of pro-inflammatory cytokines and impairs T lymphocyte reconstitution. Mixed bone marrow chimeras lacking Mincle only in B lymphocytes have similar defects in T cell recovery. Conversely, treatment with a synthetic Mincle ligand enhances T cell reconstitution after lymphoablation in non-transplanted mice. Treatment with agonistic CD40 mAb facilitates T cell reconstitution in CD4 T cell-depleted, but not in Mincle-deficient, recipients indicating that CD40 signaling induces T cell proliferation via a Mincle-dependent pathway. These findings are the first to identify an important function of B cell Mincle as a sensor of damage-associated molecular patterns released by the graft and demonstrate its role in clinically relevant settings of organ transplantation.
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Linfócitos B , Transplante de Coração , Aloenxertos , Animais , Linfócitos B/metabolismo , Citocinas/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Allogeneic transplants elicit dynamic T cell responses that are modulated by positive and negative co-stimulatory receptors. Understanding mechanisms that intrinsically modulate the immune responses to transplants is vital to develop rational treatment for rejection. Here, we have investigated the impact of programed cell death-1 (PD-1) protein, a negative co-stimulatory receptor, on the rejection of MHC incompatible kidney transplants in mice. T cells were found to rapidly infiltrate the kidneys of A/J mice transplanted to C57BL/6 mice, which peaked at six days and decline by day 14. The T cells primarily encircled tubules with limited infiltration of the tubular epithelium. Lipocalin 2 (LCN2), a marker of tubular injury, also peaked in the urine at day six and then declined. Notably, flow cytometry demonstrated that most of the T cells expressed PD-1 (over 90% of CD8 and about 75% of CD4 cells) at day six. Administration of blocking antibody to PD-L1, the ligand for PD-1, before day six increased T cell infiltrates and urinary LCN2, causing terminal acute rejection. In contrast, blocking PD-1/PD-L1 interactions after day six caused only a transient increase in urinary LCN2. Depleting CD4 and CD8 T cells virtually eliminated LCN2 in the urine in support of T cells injuring tubules. Thus, our data indicate that PD-1/PD-L1 interactions are not just related to chronic antigenic stimulation of T cells but are critical for the regulation of acute T cell responses to renal transplants.
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Transplante de Rim , Receptor de Morte Celular Programada 1 , Animais , Antígeno B7-H1 , Linfócitos T CD8-Positivos , Morte Celular , Ligantes , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Understanding the mechanisms of T cell homeostatic expansion is crucial for clinical applications of lymphoablative therapies. We previously established that T cell recovery in mouse heart allograft recipients treated with anti-thymocyte globulin (mATG) critically depends on B cells and is mediated by B cell-derived soluble factors. B cell production of interleukin (IL)-1ß and IL-6 is markedly upregulated after heart allotransplantation and lymphoablation. Neutralizing IL-1ß or IL-6 with mAb or the use of recipients lacking mature IL-1ß, IL-6, IL-1R, MyD88, or IL-6R impair CD4+ and CD8+ T cell recovery and significantly enhance the graft-prolonging efficacy of lymphoablation. Adoptive co-transfer experiments demonstrate a direct effect of IL-6 but not IL-1ß on T lymphocytes. Furthermore, B cells incapable of IL-1ß or IL-6 production have diminished capacity to mediate T cell reconstitution and initiate heart allograft rejection upon adoptive transfer into mATG treated B cell deficient recipients. These findings reveal the essential role of B cell-derived IL-1ß and IL-6 during homeostatic T cell expansion in a clinically relevant model of lymphoablation.
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Transplante de Coração , Interleucina-6 , Animais , Linfócitos B , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Rejeição de Enxerto/prevenção & controle , Interleucina-1beta , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: The mechanisms underlying the effects of prolonged cold-ischemia storage on kidney allografts are poorly understood. METHODS: To investigate effects of cold ischemia on donor-reactive immune responses and graft pathology, we used a mouse kidney transplantation model that subjected MHC-mismatched BALB/c kidney allografts to cold-ischemia storage for 0.5 or 6 hours before transplant into C57BL/6 mice. RESULTS: At day 14 post-transplant, recipients of allografts subjected to 6 versus 0.5 hours of cold-ischemia storage had increased levels of anti-MHC class II (but not class I) donor-specific antibodies, increased donor-reactive T cells, and a significantly higher proportion of transplant glomeruli infiltrated with macrophages. By day 60 post-transplant, allografts with a 6 hour cold-ischemia time developed extensive glomerular injury compared with moderate pathology in allografts with 0.5 hour of cold-ischemia time. Pathology was associated with increased serum levels of anti-class 2 but not anti-class 1 donor-specific antibodies. Recipient B cell depletion abrogated early macrophage recruitment, suggesting augmented donor-specific antibodies, rather than T cells, increase glomerular pathology after prolonged cold ischemia. Lymphocyte sequestration with sphingosine-1-phosphate receptor 1 antagonist FTY720 specifically inhibited anti-MHC class II antibody production and abrogated macrophage infiltration into glomeruli. Adoptive transfer of sera containing anti-donor MHC class II antibodies or mAbs against donor MHC class II restored early glomerular macrophage infiltration in FTY720-treated recipients. CONCLUSIONS: Post-transplant inflammation augments generation of donor-specific antibodies against MHC class II antigens. Resulting MHC class II-reactive donor-specific antibodies are essential mediators of kidney allograft glomerular injury caused by prolonged cold ischemia.
Assuntos
Isquemia Fria/efeitos adversos , Antígenos de Histocompatibilidade Classe II/imunologia , Isoanticorpos/imunologia , Glomérulos Renais/patologia , Transplante de Rim , Animais , Anticorpos Monoclonais/imunologia , Cloridrato de Fingolimode/uso terapêutico , Histocompatibilidade , Imunidade Celular , Imunidade Humoral , Imunoglobulina G/imunologia , Imunoglobulina G/uso terapêutico , Isoanticorpos/biossíntese , Glomérulos Renais/imunologia , Depleção Linfocítica , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Especificidade do Receptor de Antígeno de Linfócitos T , Transplante HomólogoRESUMO
Prolonged cold ischemia storage (CIS) is a leading risk factor for poor transplant outcome. Existing strategies strive to minimize ischemia-reperfusion injury in transplanted organs, yet there is a need for novel approaches to improve outcomes of marginal allografts and expand the pool of donor organs suitable for transplantation. Aquaporins (AQPs) are a family of water channels that facilitate homeostasis, tissue injury, and inflammation. We tested whether inhibition of AQP4 improves the survival of fully MHC-mismatched murine cardiac allografts subjected to 8 hours of CIS. Administration of a small molecule AQP4 inhibitor during donor heart collection and storage and for a short-time posttransplantation improves the viability of donor graft cells, diminishes donor-reactive T cell responses, and extends allograft survival in the absence of other immunosuppression. Furthermore, AQP4 inhibition is synergistic with cytotoxic T lymphocyte-associated antigen 4-Ig in prolonging survival of 8-hour CIS heart allografts. AQP4 blockade markedly reduced T cell proliferation and cytokine production in vitro, suggesting that the improved graft survival is at least in part mediated through direct effects on donor-reactive T cells. These results identify AQPs as a promising target for diminishing donor-specific alloreactivity and improving the survival of high-risk organ transplants.
Assuntos
Aquaporina 4/antagonistas & inibidores , Isquemia Fria/efeitos adversos , Transplante de Coração/mortalidade , Disfunção Primária do Enxerto/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Abatacepte/farmacologia , Aloenxertos , Animais , Apoptose , Antígeno CTLA-4/antagonistas & inibidores , Feminino , Terapia de Imunossupressão , Imunossupressores/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Disfunção Primária do Enxerto/etiologia , Disfunção Primária do Enxerto/mortalidade , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/mortalidade , Taxa de Sobrevida , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Ab-mediated lymphoablation is commonly used in solid organ and hematopoietic cell transplantation. However, these strategies fail to control pathogenic memory T cells efficiently and to improve long-term transplant outcomes significantly. Understanding the mechanisms of T cell reconstitution is critical for enhancing the efficacy of Ab-mediated depletion in sensitized recipients. Using a murine analog of anti-thymocyte globulin (mATG) in a mouse model of cardiac transplantation, we previously showed that peritransplant lymphocyte depletion induces rapid memory T cell proliferation and only modestly prolongs allograft survival. We now report that T cell repertoire following depletion is dominated by memory CD4 T cells. Additional depletion of these residual CD4 T cells severely impairs the recovery of memory CD8 T cells after mATG treatment. The CD4 T cell help during CD8 T cell recovery depends on the presence of B cells expressing CD40 and intact CD40/CD154 interactions. The requirement for CD4 T cell help is not limited to the use of mATG in heart allograft recipients, and it is observed in nontransplanted mice and after CD8 T cell depletion with mAb instead of mATG. Most importantly, limiting helper signals increases the efficacy of mATG in controlling memory T cell expansion and significantly extends heart allograft survival in sensitized recipients. Our findings uncover the novel role for helper memory CD4 T cells during homeostatic CD8 T cell proliferation and open new avenues for optimizing lymphoablative therapies in allosensitized patients.
Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/imunologia , Ativação Linfocitária/imunologia , Linfopenia/imunologia , Aloenxertos , Animais , Linfócitos B/metabolismo , Transplante de Medula Óssea , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD40/genética , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica , Transplante de Coração , Memória Imunológica , Depleção Linfocítica , Linfopenia/genética , Linfopenia/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Quimeras de TransplanteRESUMO
Cognate T-B cell interactions and CD40-CD154 costimulation are essential for productive humoral immunity against T-dependent Ags. We reported that memory CD4 T cells can deliver help to B cells and induce pathogenic IgG alloantibodies in the absence of CD40-CD154 interactions. To determine cytokine requirements for CD40-independent help, we used CD40(-/-) mice containing differentiated subsets of donor-reactive memory Th cells as heart allograft recipients. Th1 and Th17, but not Th2, memory CD4 T cells elicited high titers of anti-donor Ab. Abs induced by Th17 memory CD4 T cells had decreased reactivity against donor MHC class I molecules and inferior ability to cause complement deposition in heart allografts compared with Abs induced by Th1 cells, suggesting a requirement for IFN-γ during CD40-independent help. IFN-γ neutralization inhibited helper functions of memory CD4 T cells in both CD40(-/-) recipients and wild type recipients treated with anti-CD154 mAb. Our results suggest that IFN-γ secreted by pre-existing memory helper cells determines both isotype and specificity of donor-reactive alloantibodies and can thus affect allograft pathology. This information may be valuable for identifying transplant patients at risk for de novo development of pathogenic alloantibodies and for preventing alloantibody production in T cell-sensitized recipients.
Assuntos
Antígenos CD40/metabolismo , Memória Imunológica , Interferon gama/biossíntese , Isoanticorpos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Antígenos CD40/genética , Comunicação Celular , Diferenciação Celular , Proteínas do Sistema Complemento/imunologia , Citocinas/metabolismo , Feminino , Expressão Gênica , Transplante de Coração , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Humoral , Masculino , Camundongos , Camundongos Transgênicos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Doadores de Tecidos , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
Despite advances in immunosuppression, antibody-mediated rejection is a serious threat to allograft survival. Alloreactive memory helper T cells can induce potent alloantibody responses and often associate with poor graft outcome. Nevertheless, the ability of memory T cells to elicit well characterized manifestations of antibody-mediated rejection has not been tested. We investigated helper functions of memory CD4 T cells in a mouse model of renal transplantation. Whereas the majority of unsensitized C57Bl/6 recipients spontaneously accepted fully MHC-mismatched A/J renal allografts, recipients containing donor-reactive memory CD4 T cells rapidly lost allograft function. Increased serum creatinine levels, high serum titers of donor-specific alloantibody, minimal T cell infiltration, and intense C4d deposition in the grafts of sensitized recipients fulfilled all diagnostic criteria for acute renal antibody-mediated rejection in humans. IFNγ neutralization did not prevent the renal allograft rejection induced by memory helper T cells, and CD8 T cell depletion at the time of transplantation or depletion of both CD4 and CD8 T cells also did not prevent the renal allograft rejection induced by memory helper T cells starting at day 4 after transplantation. However, B cell depletion inhibited alloantibody generation and significantly extended allograft survival, indicating that donor-specific alloantibodies (not T cells) were the critical effector mechanism of renal allograft rejection induced by memory CD4 T cells. Our studies provide direct evidence that recipient T cell sensitization may result in antibody-mediated rejection of renal allografts and introduce a physiologically relevant animal model with which to investigate mechanisms of antibody-mediated rejection and novel therapeutic approaches for its prevention and treatment.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Rejeição de Enxerto/imunologia , Isoanticorpos/imunologia , Transplante de Rim , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Memória Imunológica , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses.
Assuntos
Plaquetas/fisiologia , Rejeição de Enxerto/imunologia , Transplante de Rim , Animais , Isoanticorpos/fisiologia , Masculino , Camundongos SCID , Ativação PlaquetáriaRESUMO
14-3-3η can regulate the cell cycle, immunity, inflammation and the secretion of matrix metalloproteinases, while it may also be involved in the development of rheumatoid arthritis (RA) and promote bone injury. Therefore, the present meta-analysis focused on the dysregulated serum levels of 14-3-3η and its association with osteoporosis in patients with RA. Studies comparing the serum levels of 14-3-3η between patients with RA and healthy controls (HCs) or patients with RA with different bone mineral densities were retrieved from the EMBASE, Web of Science, PubMed and Cochrane databases. A total of 14 studies comprising 2,164 patients with RA and 1,136 HCs were included and analysed. Pooled analyses showed that the serum levels of 14-3-3η were enhanced in patients with RA compared with HCs [standardized mean difference (SMD): 1.34; 95% confidence interval (CI): 1.01-1.66; P<0.001]. In addition, the serum levels of 14-3-3η were also significantly higher in patients with RA with osteoporosis and osteopenia compared with those with normal bone mass (SMD: 1.96; 95% CI: 0.01-3.92; P=0.049 and SMD: 0.80; 95% CI: 0.09-1.52; P=0.028, respectively). Begg's and Egger's tests demonstrated that the publication bias for each evaluated indicator was low (all P>0.05). However, sensitivity analyses revealed that the findings were not very robust, which may be due to the omission of several individual studies. Overall, the present meta-analysis suggested that the serum levels of 14-3-3η were elevated and were associated with a higher risk of osteoporosis in patients with RA, thus supporting its potency as a circulating biomarker in the management of RA.
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In multi-regional clinical trials, planning the sample size for participating regions is essential for the evaluation of the treatment effect consistency across regions. Based on the MRCT design and sample size allocation to regions, consistency probability is usually used to predict the consistent trend between regions and the overall population, while preserving a certain proportion of the overall treatment effect. Specific enrollment characteristics in a region of interest should also be considered during the time of the sample size planning. To facilitate efficient and harmonized regional sample size planning, we have developed RegionSizeR, a comprehensive and user-friendly interactive web-based R shiny application that can be obtained from https://github.com/rsr-ss/RegionSizeR . This simulation-based app can serve as an initial point for discussions on sample size allocation plans, following preservation of treatment effect method in ICH E17. The app accommodates various types of endpoints and designs, including continuous, binary, and time-to-event endpoints, for superiority, non-inferiority, and MCP-Mod designs. To ensure the validity of this app, independent testing is conducted allowing a discrepancy of no more than 1% across all results considering various scenarios.
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CD40/CD154 interactions are essential for productive antibody responses to T-dependent antigens. Memory CD4 T cells express accelerated helper functions and are less dependent on costimulation when compared with naïve T cells. Here, we report that donor-reactive memory CD4 T cells can deliver help to CD40-deficient B cells and induce high titers of IgG alloantibodies that contribute to heart allograft rejection in CD40-/- heart recipients. While cognate interactions between memory helper T and B cells are crucial for CD40-independent help, this process is not accompanied by germinal center formation and occurs despite inducible costimulatory blockade. Consistent with the extrafollicular nature of T/B cell interactions, CD40-independent help fails to maintain stable levels of serum alloantibody and induce differentiation of long-lived plasma cells and memory B cells. In summary, our data suggest that while CD40-independent help by memory CD4 T cells is sufficient to induce high levels of pathogenic alloantibody, it does not sustain long-lasting anti-donor humoral immunity and B cell memory responses. This information may guide the future use of CD40/CD154 targeting therapies in transplant recipients containing donor-reactive memory T cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígenos CD40/imunologia , Rejeição de Enxerto/imunologia , Transplante de Coração , Imunidade Humoral/imunologia , Memória Imunológica/imunologia , Isoanticorpos/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/transplante , Ligante de CD40/imunologia , Feminino , Imunofluorescência , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Doadores de TecidosRESUMO
OBJECTIVE: To explore the clinical characteristics of rheumatic disease (RD) patients who suffered from moderate or severe coronavirus disease 2019 (COVID-19) infection and to evaluate risk factors of COVID-19 infection in RD patients. METHODS: A retrospective analysis was conducted on 148 moderate or severe COVID-19 patients admitted to the First People's Hospital of Suqian Affiliated to Nanjing Medical University, including 74 RD patients and 74 non-RD patients. Clinical data were collected including clinical characteristics and laboratory tests. RESULTS: The RD group showed a higher proportion of females with a higher incidence of interstitial lung disease and kidney disease than the non-RD group. Also, the incidence of fatigue, olfactory dysfunction and musculoskeletal pain was higher in the RD group, but the incidence of cough, wheezing, and fever was lower compared with non-RD patients. The hospitalized course of the RD group (12.7 days ± 6.55) was significantly longer than that in the non-RD group (8.07 days ± 3.40). Also, patients in the RD group had higher levels of erythrocyte sedimentation rate, interleukin (IL)-2, and IL-4 than the non-RD group. The logistic regression analysis showed that dizziness and headache, C-reactive protein (CRP) > 8 mg/L and lactate dehydrogenase (LDH) > 248 µ/L were independent risk factors for severe COVID-19 infections of RD patients. CONCLUSION: RD patients who suffered from moderate or severe COVID-19 infections have a higher risk of comorbidities, higher levels of inflammation, and longer hospitalized course. Dizziness and headache, CRP > 8 mg/L and LDH > 248 µ/L are risk factors for severe COVID-19 infections in RD patients.
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Background: Functional constipation (FCon) is a common functional gastrointestinal disorder (FGID). Studies have indicated a higher likelihood of psychiatric disorders, such as anxiety, depression, sleep disturbances, and impaired concentration, among patients with FCon. However, the underlying pathophysiological mechanisms responsible for these symptoms in FCon patients remain to be fully elucidated. The human brain is a complex network architecture with several fundamental organizational properties. Neurological interactions between gut symptoms and psychiatric issues may be closely associated with these complex networks. Methods: In the present study, a total of 35 patients with FCon and 40 healthy controls (HC) were recruited for a series of clinical examinations and resting-state functional magnetic imaging (RS-fMRI). We employed the surface-based analysis (SBA) approach, utilizing the Schaefer cortical parcellation template and Tikhonov regularization. Graph theoretical analysis (GTA) and functional connectivity (FC) analysis of RS-fMRI were conducted to investigate the aberrant network alterations between the two groups. Additionally, correlation analyses were performed between the network indices and clinical variables in patients with FCon. Results: At the global level, we found altered topological properties and networks in patients with FCon, mainly including the significantly increased clustering coefficient (CP), local efficiency (Eloc), and shortest path length (LP), whereas the decreased global efficiency (Eglob) compared to HC. At the regional level, patients with FCon exhibited increased nodal efficiency in the frontoparietal network (FPN). Furthermore, FC analysis demonstrated several functional alterations within and between the Yeo 7 networks, particularly including visual network (VN), limbic network (LN), default mode network (DMN), and somatosensory-motor network (SMN) in sub-network and large-scale network analysis. Correlation analysis revealed that there were no significant associations between the network metrics and clinical variables in the present study. Conclusion: These results highlight the altered topological architecture of functional brain networks associated with visual perception abilities, emotion regulation, sensorimotor processing, and attentional control, which may contribute to effectively targeted treatment modalities for patients with FCon.
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PURPOSE: To investigate the prognosis of advanced oral squamous cell carcinoma (AOSCC) patients undergoing neck dissection with sternocleidomastoid muscle (SCM) preservation and resection. METHODS: From January 2013 to June 2017, a total of 235 AOSCC patients(stage â ¢ and stage â £) who were diagnosed and underwent neck dissection at the Department of Oral and Maxillofacial Surgery, College and Hospital of Stomatology, Guangxi Medical University, were collected and followed-up. The differences in overall survivalï¼OSï¼, local recurrence-free survival (LRFS) and regional recurrence-free survival (RRFS) were compared between different surgical procedures. SPSS 25.0 software package was used for statistical analysis. RESULTS: Among 235 patients with postoperative follow-up, 101 patients retained the SCM during operation, and 134 patients had SCM removed. There was no significant difference in 5-year survival rate and 5-year regional recurrence rate between the SCM preservation group and the SCM resection group. Kaplan-Meier method of univariate analysis showed that SCM preservation or resection had no significant difference in OS, LRFS and RRFS. Cox multivariate regression analysis results showed that there was no significant difference between different surgical procedures in OS, LRFS and RRFS, while N stage and postoperative chemoradiotherapy were independent influencing factors for OS, LRFS and RRFS in AOSCC patients. CONCLUSIONS: Neck dissection with SCM preservation in AOSCC patients has no effect on survival and recurrence (including local recurrence and regional recurrence). It is feasible for AOSCC patients to undergo SCM-preserving neck dissection when metastatic cervical lymph nodes do not invade SCM. N stage and postoperative chemoradiotherapy affect the prognosis of AOSCC patients.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Esvaziamento Cervical/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/cirurgia , Neoplasias Bucais/patologia , Estudos Retrospectivos , China , Prognóstico , Estudos de Coortes , Neoplasias de Cabeça e Pescoço/cirurgia , Neoplasias de Cabeça e Pescoço/patologia , Músculos/patologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de NeoplasiasRESUMO
Acute cellular rejection of organ transplants is executed by donor-reactive T cells, which are dominated by interferon-gamma-producing cells. As interferon-gamma is dispensable for graft destruction, we evaluated the contribution of interleukin-17A (IL-17) to intragraft inflammation in major histocompatibility complex-mismatched heart transplants. A/J (H-2(a)) cardiac allografts placed into wild-type BALB/c (H-2(d)) mice induced intragraft IL-17 production on day 2 after transplant. Allografts placed into BALB/c IL-17(-/-) recipients demonstrated diminished production of the chemokines CXCL1 and CXCL2 and delayed neutrophil and T cell recruitment. However, by day 7 after transplant, allografts from IL-17(-/-) and wild-type recipients had comparable levels of cellular infiltration. The priming of donor-specific T cells was not affected by the absence of IL-17, and the kinetics of cardiac allograft rejection were similar in wild-type and IL-17(-/-) recipients. In contrast, IL-17(-/-) mice depleted of CD8 T cells rejected A/J allografts in a delayed fashion compared with CD8-depleted wild-type recipients. Although donor-reactive CD4 T cells were efficiently activated in both groups, the infiltration of effector T cells into allografts was impaired in IL-17(-/-) recipients. Our data indicate that locally produced IL-17 amplifies intragraft inflammation early after transplantation and promotes tissue injury by facilitating T cell recruitment into the graft. Targeting the IL-17 signaling network in conjunction with other graft-prolonging therapies may decrease this injury and improve the survival of transplanted organs.
Assuntos
Rejeição de Enxerto/imunologia , Transplante de Coração/imunologia , Inflamação/imunologia , Interleucina-17/imunologia , Infiltração de Neutrófilos/imunologia , Linfócitos T/imunologia , Animais , Feminino , Citometria de Fluxo , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Transplante de Coração/patologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-17/metabolismo , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas , Linfócitos T/metabolismoRESUMO
Antibody-mediated lymphoablation is used in solid organ and stem cell transplantation and autoimmunity. Using murine anti-thymocyte globulin (mATG) in a mouse model of heart transplantation, we previously reported that the homeostatic recovery of CD8+ T cells requires help from depletion-resistant memory CD4+ T cells delivered through CD40-expressing B cells. This study investigated the mechanisms by which B cells mediate CD8+ T cell proliferation in lymphopenic hosts. While CD8+ T cell recovery required MHC class I expression in the host, the reconstitution occurred independently of MHC class I, MHC class II, or CD80/CD86 expression on B cells. mATG lymphoablation upregulated the B cell expression of several cytokine genes, including IL-15 and IL-27, in a CD4-dependent manner. Neither treatment with anti-CD122 mAb nor the use of IL-15Rα-/- recipients altered CD8+ T cell recovery after mATG treatment, indicating that IL-15 may be dispensable for T cell proliferation in our model. Instead, IL-27 neutralization or the use of IL-27Rα-/- CD8+ T cells inhibited CD8+ T cell proliferation and altered the phenotype and cytokine profile of reconstituted CD8+ T cells. Our findings uncover what we believe is a novel role of IL-27 in lymphopenia-induced CD8+ T cell proliferation and suggest that targeting B cell-derived cytokines may increase the efficacy of lymphoablation and improve transplant outcomes.