CD4(+) T-cell subsets in transplantation.

The identification of T-helper 9 (Th9), Th17, Th22 cells as distinct subsets of CD4(+) T cells has extended the Th1/Th2 paradigm in the adaptive immunity. In the past decade, many studies in animal models and clinical transplantation have demonstrated that interleukin-17 (IL-17) is involved in allograft rejection. It appears that Th17 cells together with Th1 and Th2 cells play an important role in mediating allograft rejection. Here, we summarize our current knowledge on the contribution of Th1, Th2, Th9, Th17, Th22, and follicular T-helper (Tfh) cells in allograft rejection. We also discuss the regulation of CD4(+) T-cell subsets by CD4(+) Foxp3(+) regulatory T cells (Tregs) in the context of transplantation tolerance.

Regulatory T cell therapy for the induction of clinical organ transplantation tolerance.

The pursuit of transplantation tolerance is the holygrail in clinical organ transplantation. It has been established that regulatory T cells (Tregs) can confer donor-specific tolerance in mouse models of transplantation. However, this is crucially dependent on the strain combination, the organ transplanted and most importantly, the ratio of Tregs to alloreactive effector T cells. The ex vivo expansion of Tregs is one solution to increase the number of alloantigen specific cells capable of suppressing the alloresponse. Indeed, ex vivo expanded, alloantigen specific murine Tregs are shown to preferentially migrate to, and proliferate in, the graft and draining lymph node. In human transplantation it has been proposed that depletion of the majority of direct pathway alloreactive T cells will be required to tip the balance in favour of regulation. Ex vivo expansion of alloantigen specific, indirect pathway human Tregs, which can cross regulate the residual direct pathway has been established. Rapid expansion of these cells is possible, whilst they retain antigen specificity, suppressive properties and favourable homing markers. Furthermore, considerable progress has been made to define which immunosuppressive drugs favour the expansion and function of Tregs. Currently a series of clinical trials of adoptive Treg therapy in combination with depletion of alloreactive T cells and short term immunosuppression are underway for human transplantation with the aim of minimizing immunosuppressive drugs and completely withdrawal.

A nomogram based on clinicopathological and ultrasound characteristics to predict central neck lymph node metastases in papillary thyroid cancer.

Purpose: Papillary thyroid cancer (PTC) has grown rapidly in prevalence over the past few decades, and central neck lymph node metastasis (CNLNM) is associated with poor prognoses. However, whether to carry out preventive central neck lymph node dissection (CNLND) is still controversial. We aimed to construct a prediction model of CNLNM to facilitate making clinical surgical regimens. Methods: A total of 691 patients with PTC between November 2018 and December 2021 were included in our study. Univariate and multivariate analyses were performed on basic information and clinicopathological characteristics, as well as ultrasound characteristics (American College of Radiology (ACR) scores). The prediction model was constructed and performed using a nomogram, and then discriminability, calibrations, and clinical applicability were evaluated. Results: Five variables, namely, male, age >55 years, clinical lymph node positivity, tumor size ≥1 cm, and ACR scores ≥6, were independent predictors of CNLNM in the multivariate analysis, which were eventually included to construct a nomogram model. The area under the curve (AUC) of the model was 0.717, demonstrating great discriminability. A calibration curve was developed to validate the calibration of the present model by bootstrap resampling, which indicated that the predicted and actual values were in good agreement and had no differentiation from the ideal model. The decision curve analysis (DCA) indicated that the prediction model has good clinical applicability. Conclusions: Our non-invasive prediction model combines ACR scores with clinicopathological features presented through nomogram and has shown good performance and application prospects for the prediction of CNLNM in PTCs.

Association of the Coronavirus Disease 2019 Outbreak on the Diabetes Self-Management in Chinese Patients: An Analytical Cross-Sectional Study.

Background: The coronavirus disease 2019 (COVID-19) outbreak has seriously affected people's lives, especially those with chronic diseases. Diabetes self-management, which plays an important role in glycaemic control and reducing the risk of acute and long-term complications, may be discouraged by social distancing. Purpose: To evaluate the level of self-management activities in Chinese patients with type 2 diabetes mellitus (T2DM) during the COVID-19 pandemic. Patients and Methods: A survey of with 872 patients with T2DM in the inpatient and outpatient departments through face-to-face interviews was conducted from 1 July, 2020 to 30 September, 2020. The main outcome measures were glycaemic control status and level of self-management activities during the pandemic. Results: In terms of glycaemic control, the data showed that patients with fasting plasma glucose (FPG) < 7.0 mmol/L (36.4%), postprandial plasma glucose (PPG) < 10.0 mmol/L (26.3%), or glycosylated haemoglobin (HbA1c) < 7.0% (18.6%) in our investigation has well-controlled blood glucose level, and 11.9% of patients experienced blood glucose <3.9 mmol/L during the outbreak. The diabetes self-management of Chinese patients decreased and the final diabetes self-management score of the Chinese patients was 3.4 ± 1.45. Patients with higher education, diabetes education, comorbidities, and online consultations had higher diabetes self-management scores (P <0.05). Adherence to diabetes self-management in the normal glycaemic control group was higher than that in the substandard glycaemic control group (P<0.05). Among all participants, 72.1% of the patients reduced the frequency of hospital visits, and 44.8% considered that they had diabetes-related stress during the pandemic. The mean anxiety level score rated by 286 patients was 5.3±2.8. Conclusion: The COVID-19 pandemic has affected diabetes self-management, including substandard glycemic control, increased diabetes-related stress, limited exercise range and medical visits. Therefore, future interventions should focus on the online management of chronic diseases and support online consultation' development and promotion, which can overcome physical distance and provide personalized services conveniently.

Conferring indirect allospecificity on CD4+CD25+ Tregs by TCR gene transfer favors transplantation tolerance in mice.

T cell responses to MHC-mismatched transplants can be mediated via direct recognition of allogeneic MHC molecules on the cells of the transplant or via recognition of allogeneic peptides presented on the surface of recipient APCs in recipient MHC molecules - a process known as indirect recognition. As CD4(+)CD25(+) Tregs play an important role in regulating alloresponses, we investigated whether mouse Tregs specific for allogeneic MHC molecules could be generated in vitro and could promote transplantation tolerance in immunocompetent recipient mice. Tregs able to directly recognize allogeneic MHC class II molecules (dTregs) were obtained by stimulating CD4(+)CD25(+) cells from C57BL/6 mice (H-2(b)) with allogeneic DCs from BALB/c mice (H-2(d)). To generate Tregs that indirectly recognized allogeneic MHC class II molecules, dTregs were retrovirally transduced with TCR genes conferring specificity for H-2K(d) presented by H-2A(b) MHC class II molecules. The dual direct and indirect allospecificity of the TCR-transduced Tregs was confirmed in vitro. In mice, TCR-transduced Tregs, but not dTregs, induced long-term survival of partially MHC-mismatched heart grafts when combined with short-term adjunctive immunosuppression. Further, although dTregs were only slightly less effective than TCR-transduced Tregs at inducing long-term survival of fully MHC-mismatched heart grafts, histologic analysis of long-surviving hearts demonstrated marked superiority of the TCR-transduced Tregs. Thus, Tregs specific for allogeneic MHC class II molecules are effective in promoting transplantation tolerance in mice, which suggests that such cells have clinical potential.

New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance.

It has long been appreciated that MHC alloantigens can be recognized via two pathways; direct and indirect. The relative contributions of these two pathways to transplant rejection are partially understood. In studies of transplantation tolerance it appears that regulatory T cells (Trs) with indirect allospecificity, particularly the CD4+CD25+ population, play a key role and can regulate responder cells with direct allospecificity for the same alloantigens. One of the conundrums that remains is how helper T and Tr cells with indirect allospecificity regulate T cells with direct allospecificity. At face value, this appears to break the rules of linkage that require interacting T cells to make contact with the same antigen-presenting cell. A third, 'semi-direct' pathway involving MHC exchange may help to resolve this conundrum. Insights into how these pathways interact in transplant immunity and tolerance will assist the pursuit of clinical tolerance.

Generation and expansion of human CD4+ CD25+ regulatory T cells with indirect allospecificity: Potential reagents to promote donor-specific transplantation tolerance.

BACKGROUND: Harnessing naturally arising CD4+ CD25+ regulatory T cells (Tregs) for potential adoptive cell therapy is hampered by their innate autoreactivity and their limited number. METHODS: CD4+ CD25+ Tregs were purified from peripheral blood of human leukocyte antigen (HLA) DR1*0101+ A2- individuals, and stimulated with autologous monocyte-derived dendritic cells (DCs). RESULTS: Here we show that CD4+ CD25+ Tregs specific for an HLA A2 (103-120) peptide can be selected from the peripheral blood CD4+ CD25+ T cell population of a healthy individual and detected using a tetramer comprised of HLA DRB1*0101 and the A2 peptide. The selected cells can be expanded substantially (i.e., a 1600-fold increase over a two-week period) by T-cell receptor (TCR) stimulation and high-doses of interleukin-2 (IL-2). The CD4+ CD25+Tregs with indirect allospecificity for the A2 peptide showed more potent antigen-specific suppression than polyclonal CD4+ CD25+ Tregs. CONCLUSIONS: These data may pave the way for clinical studies using CD4+ CD25+ Tregs with indirect allospecificity as therapeutic reagents for the induction of donor-specific transplantation tolerance.

Regulatory T cells and transplantation tolerance.

In the past decade, several types of regulatory T cells (Tregs) have been identified to play a pivotal role in the control of autoimmunity and transplantation tolerance in rodents and in human beings, including innate regulatory NKT cells and gammadelta T cells, naturally occurring FoxP3 expressing CD4(+)CD25(+) T cells, and in-vitro induced Tregs including interleuking-10 (IL-10)-secreting Tr1 CD4(+) T cells, TGF-beta-producing Th3 CD4(+) T cells, anergic CD4(+) T cells, CD8(+)CD28(-) and CD3(+)CD4(-)CD8(-) T cells. Recent studies have shown that innate and adaptive Tregs may be linked and act in concert to mediate immunosuppression. As our understanding of regulatory T cell populations has substantially advanced, compelling evidence support the prospect that in-vitro expanded, patient-tailored Tregs with indirect anti-donor allospecificity could be potential reagents as adoptive cell therapy for individualized medicine to promote clinical transplantation tolerance.

New trends in immunosuppression and immunotherapy.

In the past years, research on immune regulation has exploded thanks to the re-emergence of T suppressor cells (Ts), now coined as regulatory T cells (Tregs). It has been established that different populations of Tregs exist in the immune system, and the generation, mechanism of suppression and the cellular and molecular targets of Tregs are being unraveled. This will lead to new opportunities for immune intervention to treat autoimmune disease and to achieve clinical transplantation tolerance. The scientific progress in the field of translational medicine was presented at the 7th International Conference on New Trends in Immunosuppression and Immunotherapy in Berlin in February 2006. In this special issue of International Immunopharmacology, several papers submitted to this congress will highlight some of the advances in this burgeoning field of translational medicine.

In vitro expanded alloantigen-specific CD4+CD25+ regulatory T cell treatment for the induction of donor-specific transplantation tolerance.

The key goal in clinical transplantation is the induction of donor-specific transplantation tolerance to minimise the morbidity and mortality associated with long-term immunosuppression. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) expressing forkhead transcript factor FoxP3 play a crucial role in the prevention of autoimmunity, and appear to mediate transplantation tolerance, and these cells can have indirect allospecificity for donor antigens. Here we show that self-reactive human CD4(+)CD25(+) Tregs can be subverted into allopeptide-specific cells in vitro and be expanded to large cell numbers, and that similar in vitro expanded murine CD4(+)CD25(+) Tregs with indirect allospecificity were capable of inducing donor-specific experimental transplantation tolerance. These data provide a platform for clinical studies using CD4(+)CD25(+) Tregs with indirect allospecificity as potential reagents for the induction of donor-specific transplantation tolerance.

In-vitro generation and characterisation of murine CD4+CD25+ regulatory T cells with indirect allospecificity.

Naturally arising CD4(+)CD25(+) regulatory T cells play a pivotal role in the prevention of autoimmunity and in the induction of donor-specific transplantation tolerance. Harnessing regulatory cells for potential adoptive cell therapy is hampered by their lack of antigen-specificity and their limited numbers. Here we describe the generation and expansion of murine CD4(+)CD25(+) T cells with antigen-specificity for an K(d) peptide as potential reagents for adoptive cell therapy in promoting donor-specific transplantation tolerance. Using bone marrow-derived autologous dendritic cells pulsed with the K(d) peptide, we generated T cell lines from purified CD4(+)CD25(+) T cells from C56BL/6 mice. The T cell lines expressed high level of CD25 and low level of CD45RB and CD69. They maintained the expression of CD62L, GITR, CTLA-4 and more importantly FoxP3. The CD4(+)CD25(+) T cell lines were anergic after TCR stimulation and produced little cytokine such as IL-2 and IFN-gamma. Importantly, they were more potent than freshly isolated CD4(+)CD25(+) T cells in suppressing proliferation and cytokine secretion by effector CD4(+) T cells. Furthermore, the CD4(+)CD25(+) T cell lines could be expanded to large cell numbers and maintained in culture up to 1 year. The K(d)-specific CD4(+)CD25(+) T cell lines will be invaluable in devising a strategy for the induction of cardiac transplantation tolerance in wild-type B6 mice carrying a full mismatch BALB/c heart.

T cell signaling targets for enhancing regulatory or effector function.

To respond to infection, resting or naïve T cells must undergo activation, clonal expansion, and differentiation into specialized functional subsets of effector T cells. However, to prevent excessive or self-destructive immune responses, regulatory T cells (T(regs)) are instrumental in suppressing the activation and function of effector cells, including effector T cells. The transcription factor Forkhead box P3 (Foxp3) regulates the expression of genes involved in the development and function of T(regs). Foxp3 interacts with other transcription factors and with epigenetic elements such as histone deacetylases (HDACs) and histone acetyltransferases. T(reg) suppressive function can be increased by exposure to HDAC inhibitors. The individual contributions of different HDAC family members to T(reg) function and their respective mechanisms of action, however, remain unclear. A study showed that HDAC6, HDAC9, and Sirtuin-1 had distinct effects on Foxp3 expression and function, suggesting that selectively targeting HDACs individually or in combination may enhance T(reg) stability and suppressive function. Another study showed that the receptor programmed death 1 (PD-1), a well-known inhibitor of T cell activation, halted cell cycle progression in effector T cells by inhibiting the transcription of the gene encoding the substrate-recognition component (Skp2) of the ubiquitin ligase SCF(Skp2). Together, these findings reveal new signaling targets for enhancing T(reg) or effector T cell function that may be helpful in designing future therapies, either to increase T(reg) suppressive function in transplantation and autoimmune diseases or to block PD-1 function, thus increasing the magnitude of antiviral or antitumor immune responses of effector T cells.

Regulatory T cells: customizing for the clinic.

Immune-suppressive cellular immunotherapy requires large numbers of antigen-specific regulatory T cells (T(reg) cells), lymphocytes that suppress certain immune responses. Together, three papers in this issue of Science Translational Medicine describe protocols for the ex vivo expansion of human T(reg) cells and assess the immune-suppressive function of ex vivo-manipulated T(reg) cells after transfer into humanized mouse disease models. Along with recent phase I clinical trial results, these new data provide a platform for clinical use of T(reg) cells as personalized therapeutic agents for the treatment of autoimmune diseases, graft-versus-host disease, and transplant rejection.

Th17 and regulatory T cell subsets in diseases and clinical application.

In the past decade it has been established that regulatory T cells (Tregs) control all immune responses. As the induction and effector mechanisms used by Tregs are being unraveled, it is emerging that a reciprocal population of CD4(+) T lymphocytes exists in the immune system that produces inflammatory cytokine IL-17, and coined "Th17 cells". Th17 cells have been implicated in the pathogenesis of many forms of human disease. The development, function, mechanism of action, and homeostasis of Tregs and Th17 cells, and the reciprocal control between Tregs and Th17 cells were presented at the Second International Conference on Regulatory T Cells and Th17 Cells and Clinical Application in Human Diseases in Shanghai on 17-20 July 2010 (China Tregs/Th17 2010). In this Special Issue of International Immunopharmacology, several paper submitted to the conference will highlight the biology of Tregs and Th17 cells, and their clinical application in human disease.

The yin and yang of signaling in Tregs and TH17 cells.

Substantial advances in our understanding of the developmental and functional relationship between regulatory T cells (T(regs)) and T helper 17 (T(H)17) cells and their potential clinical applications have been made. In response to these breakthroughs, the second international conference entitled "China Tregs/Th17 2010 Shanghai Conference," held in Shanghai, China, was dedicated to this topic. Various types of T(regs) and T(H)17 cells, as well as their relevant cytokines, were discussed. Here, we summarize some of the findings shared at the conference, specifically focusing on the biology of T(H)17 cells, including interleukin-17 (IL-17)-producing innate cells, T(regs), and the factors that control the critical balance between T(regs) and cells of the T(H)17 lineage.

Regulatory T cell immunotherapy for transplantation tolerance: step into clinic.

Recent studies in animal models have demonstrated that adoptive transfer of antigen-specific CD4+CD25+ regulatory T cells (Tregs) can prevent or even cure autoimmune diseases, and appear to induce transplantation tolerance. Thus, adoptive cell therapy using ex vivo induced and expanded patient-specific CD4+CD25+Tregs has emerged as a promising individualized medicine for the treatment of inflammatory disease. Here we discuss our current efforts on the pursuit of regulatory T cell therapy for the induction of transplantation tolerance.

Regulatory T cells: from bench to bedside.

Regulatory T cells (Tregs) are subsets of T cells that are specifically dedicated to controlling immune responses. It has been established that Tregs play a key role in regulating autoimmune disease, allergy, cancer, infectious disease, and in the induction of transplantation tolerance. The latest progress in the development, function, mechanism of action, and homeostasis of regulatory T cells, and their translation to the clinic were presented at the International Conference on Regulatory T Cells and Clinical Application in Human Diseases in Beijing on 25-27 October 2008 (China Tregs 2008). In this Special Issue of International Immunopharmacology, several papers submitted to the China Tregs 2008 will highlight some of the recent advances in the biology of regulatory T cells and current strategies to translate regulatory T cells into the clinic.