Transplantation research最新文献

{"title":"Phospho-specific flow cytometry for pharmacodynamic monitoring of immunosuppressive therapy in transplantation.","authors":"Carla Baan,&nbsp;Anne Bouvy,&nbsp;Ramin Vafadari,&nbsp;Willem Weimar","doi":"10.1186/2047-1440-1-20","DOIUrl":"https://doi.org/10.1186/2047-1440-1-20","url":null,"abstract":"<p><p> Organ transplant recipients frequently suffer from toxicity or from lack of efficacy of immunosuppressive drugs, which can be attributed to individual variations in drug sensitivity. This problem can be resolved by applying pharmacodynamic monitoring that focuses on measuring the biological effects of drugs. Here we discuss the new technique called phospho-specific flow cytometry to monitor the activity of intracellular immune signaling pathways at the single-cell level in whole blood samples. Through this tool the efficacy of immunosuppressive medication can be assessed, novel targets can be identified, and differences in drug sensitivity between cells and patients can be clarified.</p>","PeriodicalId":89864,"journal":{"name":"Transplantation research","volume":"1 1","pages":"20"},"PeriodicalIF":0.0,"publicationDate":"2012-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2047-1440-1-20","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31203453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Male human papillomavirus infection post-kidney transplant: an overlooked disease.","authors":"Oksana Genzer,&nbsp;Suzanne E El-Sayegh,&nbsp;Morton J Kleiner,&nbsp;Mario R Castellanos","doi":"10.1186/2047-1440-1-21","DOIUrl":"https://doi.org/10.1186/2047-1440-1-21","url":null,"abstract":"<p><p> While immunosuppressive regimens improve the overall survival of renal transplant recipients, they also contribute to the long-term complications of post-transplant malignancies. Chronic immune suppression in renal transplant recipients (RTR) increases the risk of viral-associated cancers. In male RTR, human papillomavirus (HPV) is implicated in the development of penile, anal, oropharyngeal, and non-melanoma skin carcinomas. Despite the significance of this virus in RTR, there is an overall deficiency in the understanding of the natural history of HPV infection in male RTR. In the next 20 years, it is believed that cancers will be the leading cause of death in kidney transplant recipients. HPV-associated carcinomas are of particular interest since they are sexually transmitted and in theory may be preventable diseases. This commentary highlights some of the progress made in understanding how HPV is transmitted amongst couples in the general population. It also summarizes the current knowledge of HPV infection in male RTR and describes the deficiencies in published medical literature.</p>","PeriodicalId":89864,"journal":{"name":"Transplantation research","volume":"1 1","pages":"21"},"PeriodicalIF":0.0,"publicationDate":"2012-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2047-1440-1-21","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31204737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PDX1-engineered embryonic stem cell-derived insulin producing cells regulate hyperglycemia in diabetic mice.","authors":"Sudhanshu P Raikwar,&nbsp;Nicholas Zavazava","doi":"10.1186/2047-1440-1-19","DOIUrl":"https://doi.org/10.1186/2047-1440-1-19","url":null,"abstract":"<p><strong>Unlabelled: </strong></p><p><strong>Background: </strong>Type 1 diabetes can be treated by the transplantation of cadaveric whole pancreata or isolated pancreatic islets. However, this form of treatment is hampered by the chronic shortage of cadaveric donors. Embryonic stem (ES) cell-derived insulin producing cells (IPCs) offer a potentially novel source of unlimited cells for transplantation to treat type 1 and possibly type 2 diabetes. However, thus far, the lack of a reliable protocol for efficient differentiation of ES cells into IPCs has hindered the clinical exploitation of these cells.</p><p><strong>Methods: </strong>To efficiently generate IPCs using ES cells, we have developed a double transgenic ES cell line R1Pdx1AcGFP/RIP-Luc that constitutively expresses pancreatic β-cell-specific transcription factor pancreatic and duodenal homeobox gene 1 (Pdx1) as well as rat insulin promoter (RIP) driven luciferase reporter. We have established several protocols for the reproducible differentiation of ES cells into IPCs. The differentiation of ES cells into IPCs was monitored by immunostaining as well as real-time quantitative RT-PCR for pancreatic β-cell-specific markers. Pancreatic β-cell specific RIP became transcriptionally active following the differentiation of ES cells into IPCs and induced the expression of the luciferase reporter. Glucose stimulated insulin secretion by the ES cell-derived IPCs was measured by ELISA. Further, we have investigated the therapeutic efficacy of ES cell-derived IPCs to correct hyperglycemia in syngeneic streptozotocin (STZ)-treated diabetic mice. The long term fate of the transplanted IPCs co-expressing luciferase in syngeneic STZ-induced diabetic mice was monitored by real time noninvasive in vivo bioluminescence imaging (BLI).</p><p><strong>Results: </strong>We have recently demonstrated that spontaneous in vivo differentiation of R1Pdx1AcGFP/RIP-Luc ES cell-derived pancreatic endoderm-like cells (PELCs) into IPCs corrects hyperglycemia in diabetic mice. Here, we investigated whether R1Pdx1AcGFP/RIP-Luc ES cells can be efficiently differentiated in vitro into IPCs. Our new data suggest that R1Pdx1AcGFP/RIP-Luc ES cells efficiently differentiate into glucose responsive IPCs. The ES cell differentiation led to pancreatic lineage commitment and expression of pancreatic β cell-specific genes, including Pax4, Pax6, Ngn3, Isl1, insulin 1, insulin 2 and PC2/3. Transplantation of the IPCs under the kidney capsule led to sustained long-term correction of hyperglycemia in diabetic mice. Although these newly generated IPCs effectively rescued hyperglycemic mice, an unexpected result was teratoma formation in 1 out of 12 mice. We attribute the development of the teratoma to the presence of either non-differentiated or partially differentiated stem cells.</p><p><strong>Conclusions: </strong>Our data show the potential of Pdx1-engineered ES cells to enhance pancreatic lineage commitment and to robustly drive t","PeriodicalId":89864,"journal":{"name":"Transplantation research","volume":"1 1","pages":"19"},"PeriodicalIF":0.0,"publicationDate":"2012-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2047-1440-1-19","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31294736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The influence of perfusion solution on renal graft viability assessment.","authors":"Colin H Wilson,&nbsp;Hugh Wyrley-Birch,&nbsp;Dhakshinarmoorthy Vijayanand,&nbsp;Anabelle Leea,&nbsp;Noel M Carter,&nbsp;Malcolm Haswell,&nbsp;Anne C Cunningham,&nbsp;David Talbot","doi":"10.1186/2047-1440-1-18","DOIUrl":"https://doi.org/10.1186/2047-1440-1-18","url":null,"abstract":"<p><strong>Background: </strong>Kidneys from donors after cardiac or circulatory death are exposed to extended periods of both warm ischemia and intra-arterial cooling before organ recovery. Marshall's hypertonic citrate (HOC) and Bretschneider's histidine-tryptophan-ketoglutarate (HTK) preservation solutions are cheap, low viscosity preservation solutions used clinically for organ flushing. The aim of the present study was to evaluate the effects of these two solutions both on parameters used in clinical practice to assess organ viability prior to transplantation and histological evidence of ischemic injury after reperfusion.</p><p><strong>Methods: </strong>Rodent kidneys were exposed to post-mortem warm ischemia, extended intra-arterial cooling (IAC) (up to 2 h) with preservation solution and reperfusion with either Krebs-Hensleit or whole blood in a transplant model. Control kidneys were either reperfused directly after retrieval or stored in 0.9% saline. Biochemical, immunological and histological parameters were assessed using glutathione-S-transferase (GST) enzymatic assays, polymerase chain reaction and mitochondrial electron microscopy respectively. Vascular function was assessed by supplementing the Krebs-Hensleit perfusion solution with phenylephrine to stimulate smooth muscle contraction followed by acetylcholine to trigger endothelial dependent relaxation.</p><p><strong>Results: </strong>When compared with kidneys reperfused directly post mortem, 2 h of IAC significantly reduced smooth muscle contractile function, endothelial function and upregulated vascular cellular adhesion molecule type 1 (VCAM-1) independent of the preservation solution. However, GST release, vascular resistance, weight gain and histological mitochondrial injury were dependent on the preservation solution used.</p><p><strong>Conclusions: </strong>We conclude that initial machine perfusion viability tests, including ischemic vascular resistance and GST, are dependent on the perfusion solution used during in situ cooling. HTK-perfused kidneys will be heavier, have higher GST readings and yet reduced mitochondrial ischemic injury when compared with HOC-perfused kidneys. Clinicians should be aware of this when deciding which kidneys to transplant or discard.</p>","PeriodicalId":89864,"journal":{"name":"Transplantation research","volume":"1 1","pages":"18"},"PeriodicalIF":0.0,"publicationDate":"2012-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2047-1440-1-18","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31204783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human tolerogenic DC-10: perspectives for clinical applications.","authors":"Giada Amodio,&nbsp;Silvia Gregori","doi":"10.1186/2047-1440-1-14","DOIUrl":"https://doi.org/10.1186/2047-1440-1-14","url":null,"abstract":"<p><p> Dendritic cells (DCs) are critically involved in inducing either immunity or tolerance. During the last decades efforts have been devoted to the development of ad hoc methods to manipulate DCs in vitro to enhance or stabilize their tolerogenic properties. Addition of IL-10 during monocyte-derived DC differentiation allows the induction of DC-10, a subset of human tolerogenic DCs characterized by high IL-10/IL-12 ratio and co-expression of high levels of the tolerogenic molecules HLA-G and immunoglobulin-like transcript 4. DC-10 are potent inducers of adaptive type 1 regulatory T cells, well known to promote and maintain peripheral tolerance. In this review we provide an in-depth comparison of the phenotype and mechanisms of suppression mediated by DC-10 and other known regulatory antigen-presenting cells currently under clinical development. We discuss the clinical therapeutic application of DC-10 as inducers of type 1 regulatory T cells for tailoring regulatory T-cell-based cell therapy, and the use of DC-10 as adoptive cell therapy for promoting and restoring tolerance in T-cell-mediated diseases.</p>","PeriodicalId":89864,"journal":{"name":"Transplantation research","volume":"1 1","pages":"14"},"PeriodicalIF":0.0,"publicationDate":"2012-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2047-1440-1-14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31204078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternative approaches to myeloid suppressor cell therapy in transplantation: comparing regulatory macrophages to tolerogenic DCs and MDSCs.","authors":"Paloma Riquelme,&nbsp;Edward K Geissler,&nbsp;James A Hutchinson","doi":"10.1186/2047-1440-1-17","DOIUrl":"https://doi.org/10.1186/2047-1440-1-17","url":null,"abstract":"<p><p> Several types of myeloid suppressor cell are currently being developed as cell-based immunosuppressive agents. Despite detailed knowledge about the molecular and cellular functions of these cell types, expert opinions differ on how to best implement such therapies in solid organ transplantation. Efforts in our laboratory to develop a cell-based medicinal product for promoting tolerance in renal transplant patients have focused on a type of suppressor macrophage, which we call the regulatory macrophage (M reg). Our favoured clinical strategy is to administer donor-derived M regs to recipients one week prior to transplantation. In contrast, many groups working with tolerogenic dendritic cells (DCs) advocate post-transplant administration of recipient-derived cells. A third alternative, using myeloid-derived suppressor cells, presumably demands that cells are given around the time of transplantation, so that they can infiltrate the graft to create a suppressive environment. On present evidence, it is not possible to say which cell type and treatment strategy might be clinically superior. This review seeks to position our basic scientific and early-stage clinical studies of human regulatory macrophages within the broader context of myeloid suppressor cell therapy in transplantation.</p>","PeriodicalId":89864,"journal":{"name":"Transplantation research","volume":"1 1","pages":"17"},"PeriodicalIF":0.0,"publicationDate":"2012-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2047-1440-1-17","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31204908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell therapy using tolerogenic dendritic cells in transplantation.","authors":"Aurélie Moreau,&nbsp;Emilie Varey,&nbsp;Laurence Bouchet-Delbos,&nbsp;Maria-Cristina Cuturi","doi":"10.1186/2047-1440-1-13","DOIUrl":"https://doi.org/10.1186/2047-1440-1-13","url":null,"abstract":"<p><p> Organ transplantation is the main alternative to the loss of vital organ function from various diseases. However, to avoid graft rejection, transplant patients are treated with immunosuppressive drugs that have adverse side effects. A new emerging approach to reduce the administration of immunosuppressive drugs is to co-treat patients with cell therapy using regulatory cells. In our laboratory, as part of a European project, we plan to test the safety of tolerogenic dendritic cell (TolDC) therapy in kidney transplant patients. In this mini-review, we provide a brief summary of the major protocols used to derive human TolDC, and then focus on the granulocyte macrophage-TolDC generated by our own team. Proof of safety of TolDC therapy in the clinic has already been demonstrated in patients with diabetes. However, in transplantation, DC therapy will be associated with the administration of immunosuppressive drugs, and interactions between drugs and DC are possible. Finally, we will discuss the issue of DC origin, as we believe that administration of autologous TolDC is more appropriate, as demonstrated by our experiments in animal models.</p>","PeriodicalId":89864,"journal":{"name":"Transplantation research","volume":"1 1","pages":"13"},"PeriodicalIF":0.0,"publicationDate":"2012-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2047-1440-1-13","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31295348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ONE Study compares cell therapy products in organ transplantation: introduction to a review series on suppressive monocyte-derived cells.","authors":"Edward K Geissler","doi":"10.1186/2047-1440-1-11","DOIUrl":"https://doi.org/10.1186/2047-1440-1-11","url":null,"abstract":"","PeriodicalId":89864,"journal":{"name":"Transplantation research","volume":"1 1","pages":"11"},"PeriodicalIF":0.0,"publicationDate":"2012-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2047-1440-1-11","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31204073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generation of myeloid-derived suppressor cells using prostaglandin E2.","authors":"Nataša Obermajer,&nbsp;Pawel Kalinski","doi":"10.1186/2047-1440-1-15","DOIUrl":"https://doi.org/10.1186/2047-1440-1-15","url":null,"abstract":"<p><p> Myeloid-derived suppressor cells (MDSCs) are natural immunosuppressive cells and endogenous inhibitors of the immune system. We describe a simple and clinically compatible method of generating large numbers of MDSCs using the cultures of peripheral blood-isolated monocytes supplemented with prostaglandin E2 (PGE2). We observed that PGE2 induces endogenous cyclooxygenase (COX)2 expression in cultured monocytes, blocking their differentiation into CD1a+ dendritic cells (DCs) and inducing the expression of indoleamine 2,3-dioxygenase 1, IL-4Rα, nitric oxide synthase 2 and IL-10 - typical MDSC-associated suppressive factors. The establishment of a positive feedback loop between PGE2 and COX2, the key regulator of PGE2 synthesis, is both necessary and sufficient to promote the development of CD1a+ DCs to CD14+CD33+CD34+ monocytic MDSCs in granulocyte macrophage colony stimulating factor/IL-4-supplemented monocyte cultures, their stability, production of multiple immunosuppressive mediators and cytotoxic T lymphocyte-suppressive function. In addition to PGE2, selective E-prostanoid receptor (EP)2- and EP4-agonists, but not EP3/1 agonists, also induce the MDSCs development, suggesting that other activators of the EP2/4- and EP2/4-driven signaling pathway (adenylate cyclase/cAMP/PKA/CREB) may be used to promote the development of suppressive cells. Our observations provide a simple method for generating large numbers of MDSCs for the immunotherapy of autoimmune diseases, chronic inflammatory disorders and transplant rejection.</p>","PeriodicalId":89864,"journal":{"name":"Transplantation research","volume":"1 1","pages":"15"},"PeriodicalIF":0.0,"publicationDate":"2012-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2047-1440-1-15","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31204298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal stem cell-educated macrophages.","authors":"Elke Eggenhofer,&nbsp;Martin J Hoogduijn","doi":"10.1186/2047-1440-1-12","DOIUrl":"https://doi.org/10.1186/2047-1440-1-12","url":null,"abstract":"<p><p> Mesenchymal stem cells (MSC) mediate their immunosuppressive effects via a variety of mechanisms. One of these mechanisms involves the induction of macrophages with immunomodulatory capacities. This effect of MSC may be exploited when MSC are used as a cell therapeutic product. Furthermore, MSC are resident in tissues where they may locally target infiltrating macrophages to adapt more regulatory properties. The present review discusses the interaction between MSC and macrophages, the induction of MSC-educated macrophages, how these cells position between other immune regulatory cells, and how they may be used in the clinic.</p>","PeriodicalId":89864,"journal":{"name":"Transplantation research","volume":"1 1","pages":"12"},"PeriodicalIF":0.0,"publicationDate":"2012-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2047-1440-1-12","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31204286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}