Serum 14­3­3η levels are increased and associated with a higher risk of osteoporosis in patients with rheumatoid arthritis: A meta­analysis.

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.

Altered intrinsic functional brain architecture in patients with functional constipation: a surface-based network study.

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.

Clinical characteristics of moderate or severe COVID-19 infection in patients with rheumatic diseases and analysis of risk factors leading to severe disease.

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.

Autoantibodies against DNA topoisomerase I promote renal allograft rejection by increasing alloreactive T cell responses.

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.

Aberrant intrinsic functional brain networks in patients with functional constipation.

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.

[The prognosis of neck dissection with sternocleidomastoid muscle preservation and resection in advanced oral squamous cell carcinoma: a retrospective cohort analysis].

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 Ⅲ and stage Ⅳ) 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 survival（OS）, 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.

Macrophage-inducible C-type lectin activates B cells to promote T cell reconstitution in heart allograft recipients.

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.

Early T cell infiltration is modulated by programed cell death-1 protein and its ligand (PD-1/PD-L1) interactions in murine kidney transplants.

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.

B cell-derived IL-1ß and IL-6 drive T cell reconstitution following lymphoablation.

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.

Anti-donor MHC Class II Alloantibody Induces Glomerular Injury in Mouse Renal Allografts Subjected to Prolonged Cold Ischemia.

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.

Interleukin-27 promotes CD8+ T cell reconstitution following antibody-mediated lymphoablation.

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.

Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia.

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.

CD4+ T lymphocytes produce adiponectin in response to transplants.

Adiponectin is a pleiotropic cytokine with diverse immunomodulatory effects on macrophages and lymphocytes. In the current paradigm, lymphocytes and macrophages respond to adiponectin that is produced by adipocytes and other parenchymal cells. Using a model of chronic arterial inflammation in cardiac transplants, we found that T cells derived from the recipient migrate to the heart and produce adiponectin locally. The evidence that T cells produce significant amounts of adiponectin is based on 3 experimental approaches. First, CD4+ T cells isolated from the blood and spleen after cardiac transplantation express mRNA for adiponectin. Second, reconstitution of T cell-deficient recipients with transgenic CD4+ T cells that express receptors for donor antigens results in arterial infiltrates containing T cells and increased mRNA expression for adiponectin in cardiac transplants. Third, CD4+ T cells isolated from the allograft secrete adiponectin in vitro. Taken together, these data indicate that adiponectin-competent cells originating in the recipient migrate into the transplant. Establishing T cells as a source of adiponectin provides a new dimension, to our knowledge, to the modulatory effects of adiponectin on immune responses.

Remote ischemic preconditioning improves post resuscitation cerebral function via overexpressing neuroglobin after cardiac arrest in rats.

In this study, we investigated the effects of remote ischemic preconditioning on post resuscitation cerebral function in a rat model of cardiac arrest and resuscitation. The animals were randomized into six groups: 1) sham operation, 2) lateral ventricle injection and sham operation, 3) cardiac arrest induced by ventricular fibrillation, 4) lateral ventricle injection and cardiac arrest, 5) remote ischemic preconditioning initiated 90min before induction of ventricular fibrillation, and 6) lateral ventricle injection and remote ischemic preconditioning before cardiac arrest. Reagent of Lateral ventricle injection is neuroglobin antisense oligodeoxynucleotides which initiated 24h before sham operation, cardiac arrest or remote ischemic preconditioning. Remote ischemic preconditioning was induced by four cycles of 5min of limb ischemia, followed by 5min of reperfusion. Ventricular fibrillation was induced by current and lasted for 6min. Defibrillation was attempted after 6min of cardiopulmonary resuscitation. The animals were then monitored for 2h and observed for an additionally maximum 70h. Post resuscitation cerebral function was evaluated by neurologic deficit score at 72h after return of spontaneous circulation. Results showed that remote ischemic preconditioning increased neurologic deficit scores. To investigate the neuroprotective effects of remote ischemic preconditioning, we observed neuronal injury at 48 and 72h after return of spontaneous circulation and found that remote ischemic preconditioning significantly decreased the occurrence of neuronal apoptosis and necrosis. To further comprehend mechanism of neuroprotection induced by remote ischemic preconditioning, we found expression of neuroglobin at 24h after return of spontaneous circulation was enhanced. Furthermore, administration of neuroglobin antisense oligodeoxynucleotides before induction of remote ischemic preconditioning showed that the level of neuroglobin was decreased then partly abrogated neuroprotection of remote ischemic preconditioning. These date suggested that neuroglobin involved in neuroprotective effect of remote ischemic preconditioning. In conclusion, remote ischemic preconditioning attenuated post resuscitation cerebral dysfunction and the neuroprotection was mediated partly by high level of neuroglobin in a rat model of cardiac arrest and resuscitation.

Memory CD4 T Cells Induce Antibody-Mediated Rejection of Renal Allografts.

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.

CD4 T Cell Help via B Cells Is Required for Lymphopenia-Induced CD8 T Cell Proliferation.

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.

Cellular Membrane Microparticles: Potential Targets of Combinational Therapy for Vascular Disease.

Vascular disease constitutes the leading health problem throughout the entire world. Current therapies for vascular disease mainly rely on comprehensive strategies including control of risk factors, vascular interventions and conventional supportive treatments. To improve the preventive and therapeutic efficacies of current approaches, novel combinational therapies are required. Microparticles (MPs) are small membrane vesicles derived from cells undergoing stress, activation or apoptosis. They carry the characteristics of their parent cells, enabling them to serve as potential biomarkers for various diseases. Of note, MPs also have been shown to mediate cell communications through transferring membrane proteins, phospholipids and RNAs from their parent cells to recipient cells. Recent novel approaches have started to reveal the functions of MPs. In this review, we summarize the general concepts and the latest research progress in MPs. And the potential of MPs as novel targets of combinational therapy for vascular disease will be discussed.

IFN-γ production by memory helper T cells is required for CD40-independent alloantibody responses.

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.

Platelets in early antibody-mediated rejection of renal transplants.

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.