Chemotherapy has direct toxic effects on cancer cells; however, long-term cancer control and complete remission are likely to involve CD8+ T cell immune responses. To study the role of CD8+ T cell infiltration in the success of chemotherapy, we examined patients with muscle invasive bladder cancer (MIBC) who were categorized on the basis of the response to neoadjuvant chemotherapy (NAC). We identified the intratumoral CXCR3 chemokine system (ligands and receptor splice variants) as a critical component for tumor eradication upon NAC in MIBC. Through characterization of CD8+ T cells, we found that stem-like T cell subpopulations with abundant CXCR3alt, a variant form of the CXCL11 receptor, responded to CXCL11 in culture as demonstrated by migration and enhanced effector function. In tumor biopsies of patients with MIBC accessed before treatment, CXCL11 abundance correlated with high numbers of tumor-infiltrating T cells and response to NAC. The presence of CXCR3alt and CXCL11 was associated with improved overall survival in MIBC. Evaluation of both CXCR3alt and CXCL11 enabled discrimination between responder and nonresponder patients with MIBC before treatment. We validated the prognostic role of the CXCR3-CXCL11 chemokine system in an independent cohort of chemotherapy-treated and chemotherapy-naïve patients with MIBC from data in TCGA. In summary, our data revealed stimulatory activity of the CXCR3alt-CXCL11 chemokine system on CD8+ T cells that is predictive of chemotherapy responsiveness in MIBC. This may offer immunotherapeutic options for targeted activation of intratumoral stem-like T cells in solid tumors.

The worldwide epidemic of overweight and obesity has led to an increase in associated metabolic comorbidities. Obesity induces chronic low-grade inflammation in white adipose tissue (WAT). However, the function and regulation of both innate and adaptive immune cells in human WAT under conditions of obesity and calorie restriction (CR) is not fully understood yet. Using a randomized interventional design, we investigated postmenopausal overweight or obese female subjects who either underwent CR for 3 mo followed by a 4-wk phase of weight maintenance or had to maintain a stable weight over the whole study period. A comprehensive immune phenotyping protocol was conducted using validated multiparameter flow cytometry analysis in blood and s.c. WAT (SAT). The TCR repertoire was analyzed by next-generation sequencing and cytokine levels were determined in SAT. Metabolic parameters were determined by hyperinsulinemic-euglycemic clamp. We found that insulin resistance correlates significantly with a shift toward the memory T cell compartment in SAT. TCR analysis revealed a diverse repertoire in SAT of overweight or obese individuals. Additionally, whereas weight loss improved systemic insulin sensitivity in the intervention group, SAT displayed no significant improvement of inflammatory parameters (cytokine levels and leukocyte subpopulations) compared with the control group. Our data demonstrate the accumulation of effector memory T cells in obese SAT and an association between systemic glucose homeostasis and inflammatory parameters in obese females. The long-standing effect of obesity-induced changes in SAT was demonstrated by preserved immune cell composition after short-term CR-induced weight loss.

Viral infections have a major impact on morbidity and mortality of immunosuppressed solid organ transplant (SOT) patients because of missing or failure of adequate pharmacologic antiviral treatment. Adoptive antiviral T-cell therapy (AVTT), regenerating disturbed endogenous T-cell immunity, emerged as an attractive alternative approach to combat severe viral complications in immunocompromised patients. AVTT is successful in patients after hematopoietic stem cell transplantation where T-cell products (TCPs) are manufactured from healthy donors. In contrast, in the SOT setting TCPs are derived from/applied back to immunosuppressed patients. We and others demonstrated feasibility of TCP generation from SOT patients and first clinical proof-of-concept trials revealing promising data. However, the initial efficacy is frequently lost long-term, because of limited survival of transferred short-lived T-cells indicating a need for next-generation TCPs. Our recent data suggest that Rapamycin treatment during TCP manufacture, conferring partial inhibition of mTOR, might improve its composition. The aim of this study was to confirm these promising observations in a setting closer to clinical challenges and to deeply characterize the next-generation TCPs. Using cytomegalovirus (CMV) as model, our next-generation Rapamycin-treated (Rapa-)TCP showed consistently increased proportions of CD4+ T-cells as well as CD4+ and CD8+ central-memory T-cells (TCM). In addition, Rapamycin sustained T-cell function despite withdrawal of Rapamycin, showed superior T-cell viability and resistance to apoptosis, stable metabolism upon activation, preferential expansion of TCM, partial conversion of other memory T-cell subsets to TCM and increased clonal diversity. On transcriptome level, we observed a gene expression profile denoting long-lived early memory T-cells with potent effector functions. Furthermore, we successfully applied the novel protocol for the generation of Rapa-TCPs to 19/19 SOT patients in a comparative study, irrespective of their history of CMV reactivation. Moreover, comparison of paired TCPs generated before/after transplantation did not reveal inferiority of the latter despite exposition to maintenance immunosuppression post-SOT. Our data imply that the Rapa-TCPs, exhibiting longevity and sustained T-cell memory, are a reasonable treatment option for SOT patients. Based on our success to manufacture Rapa-TCPs from SOT patients under maintenance immunosuppression, now, we seek ultimate clinical proof of efficacy in a clinical study.

Obesity is a growing global health problem due to its association with chronic low-grade inflammation contributing to metabolic complications. Multiple studies indicate that white adipose tissue (WAT) inflammation can promote type 2 diabetes. However, the function and regulation of both innate and adaptive immune cells in human WAT under conditions of obesity and calorie restriction (CR) is not fully understood yet. Using a randomized interventional design, we investigated postmenopausal obese women who either underwent CR for three months followed by a 4 weeks phase of weight maintenance or had to maintain a stable weight over the whole study period. A comprehensive immune phenotyping protocol was conducted using validated multiparameter flow cytometry analysis in blood and subcutaneous WAT (SAT) (n=21). The T cell receptor repertoire was analyzed by next generation sequencing (n=20) and cytokine levels were determined in SAT (n=22). Metabolic parameters were determined by hyperinsulinemic-euglycemic clamp and then correlated to immune cell subsets. We found that insulin resistance (IR) correlates significantly with a shift towards the memory T cell compartment in SAT. Among various T cell subsets, predominantly CD8+ effector memory T cells were associated with obesity-related IR. Interestingly, T cell receptor analysis revealed a diverse repertoire in SAT arguing against an antigen-driven intra-SAT expansion of effector memory T cells. Surprisingly, neither inflammatory cytokine levels nor leucocyte subpopulations were significantly altered upon CR. Our findings demonstrate the accumulation of effector memory T cells in obese SAT contributing to chronic inflammation. The long-standing effect of obesity-induced changes in SAT was demonstrated by preserved immune cell composition after short-term CR induced weight loss. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT01105143 ### Funding Statement JS was supported by the DZHK (German Center for Cardiovascular Research), JS, KM and J-SK were supported by a clinical research group of the DFG (KFO218 and KFO192). This study was supported by grants from the Clinical Research Unit of the Berlin Institute of Health (BIH), the “BCRT-grant” by the German Federal Ministry of Education and Research and the Einstein Foundation. JSK and RJvonS were supported by the Charité Clinical Scientist Program. ### Author Declarations All relevant ethical guidelines have been followed and any necessary IRB and/or ethics committee approvals have been obtained. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes Any clinical trials involved have been registered with an ICMJE-approved registry such as ClinicalTrials.gov and the trial ID is included in the manuscript. Yes I have followed all appropriate research reporting guidelines and uploaded the relevant Equator, ICMJE or other checklist(s) as supplementary files, if applicable. Yes The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher

Mesenchymal stromal cells (MSCs) support endogenous regeneration and present therefore promising opportunities for in situ tissue engineering. They can be isolated and expanded from various tissues, for example, bone marrow, adipose tissue, or placenta. The minimal consensus definition criteria of ex vivo expanded MSCs requires them to be positive for CD73, CD90, and CD105 expression, while being negative for CD34, CD45, CD14, CD19, and HLA-DR. This study aimed to compare the in situ phenotype of MSCs with that of their culture-expanded progeny. We report for the first time in situ detection of cells expressing this marker combination in human placenta cryosections as well as in bone marrow aspirates using multiplex-immunohistology (Chipcytometry), a technique that allows staining of more than 100 biomarkers consecutively on the same cell. © 2018 International Society for Advancement of Cytometry.

BACKGROUND:The pathology and diagnosis of acute and chronic rejection in intestinal transplantation (ITX) are far from being completely understood. We established models of acute and chronic intestinal graft rejection and analyzed peripheral and intragraft immune responses.METHODS:We performed ITX from Dark Agouti into Lewis rats applying single-dose tacrolimus (TAC) at varying concentrations. Graft histology and immunohistology were assessed on postoperative day (POD)7, 14, and 45. Intragraft and peripheral gene expressions of inflammatory and anti-inflammatory markers and lipopolysaccharide binding protein (LBP) plasma as well as alloantibodies were measured simultaneously.RESULTS:A 1-mg TAC resulted in acute rejection and recipient death; 3 mg and 5 mg prolonged survival and led to severe or moderate chronic rejection, respectively, with 50% of the 5-mg TAC recipients surviving the observation period. Consequently, we observed severe infiltration on POD7 in untreated and 1-mg TAC recipients compared with minor histological alterations in 3 and 5 mg TAC groups. Only 5-mg TAC treatment prevented accumulation of CD4+ T cells and ED1+ macrophages over the entire observation period. Peripheral and intragraft expressions of T cell activation inhibitor-mitochondrial were stable in long-term surviving 5-mg TAC recipients but declined before acute or chronic rejection in 1 and 3 mg TAC recipients. In contrast, LBP levels increased during acute and chronic rejections.CONCLUSIONS:We studied acute and chronic rejections in a preclinical model of ITX, which recapitulates clinical findings and highlights the importance of monitoring peripheral T cell activation inhibitor-mitochondrial expression, LBP levels, and antidonor antibodies for revealing rejection.

Memory T cells expressing stem cell-like properties have been described recently. The capacity of self-renewal and differentiation into various memory/effector subsets make them attractive for adoptive T cell therapy to combat severe virus infections and tumors. The very few reports on human memory stem T cells (T(SCM)) are restricted to analyses on polyclonal T cells, but extensive data on Ag-specific T(SCM )are missing. This might be due to their very low frequency limiting their enrichment and characterization. In this article, we provide functional and phenotypic data on human viral-specific T(SCM), defined as CD8(+)CD45RA(+)CCR7(+)CD127(+)CD95(+). Whereas <1% of total T cells express the T(SCM) phenotype, human CMV-specific T(SCM) can be detected at frequencies similar to those seen in other subsets, resulting in ∼ 1 /10,000 human CMV-specific T(SCM). A new virus-specific expansion protocol of sort-purified T(SCM) reveals both upregulation of various T cell subset markers and preservation of their stem cell phenotype in a significant proportion, indicating both self-renewal and differentiation potency of virus-specific T cells sharing their TCR repertoire. Furthermore, we describe a simplified culture protocol that allows fast expansion of virus-specific T(SCM) starting from a mixed naive T/T(SCM) pool of PBLs. Due to the clinical-grade compatibility, this might be the basis for novel cell therapeutic options in life-threatening courses of viral and tumor disease.

CD8+ T cells play a cardinal feature in response to alloantigens and are able to generate effector/memory T cells independently from CD4+ T cells. To investigate the impact of aging on CD8 T cells, we used a fully mismatched mouse skin transplant model. Our findings showed a prolonged allograft survival in older recipients associated with a significant increase of CD4+ and CD8+ CD44high CD62Llow effector/memory T cells and a reduced systemic IFNγ production. When reconstituting young CBA Rag-1 mice that lack mature T and B cells with old CD8+ T cells expressing clonal anti-H2K T cell receptor (TCR) alloreactive for MHC I, graft survival was significantly prolonged and comparable to those receiving young CD8+ T cells. Moreover, our data showed that reduced systemic IFNγ levels observed in old recipients had been linked to a compromised expression of the IL-2R β subunit (CD122) by old CD8+ T cells. In addition, we observed an impaired IFNγ production on IL-2 receptor activation. At the same time, gene profiling analysis of old CD8 T cells demonstrated reduced chemokine ligand-3 and CD40L expression that resulted in compromised CD8+ T cell/dendritic cell communication, leading to impaired migratory and phagocytic activity of CD11c cells.Collectively, our study demonstrated that aging delays allograft rejection. CD8 T cells play a critical role in this process linked to a compromised production of IFNγ, in addition to a defective IL-2 receptor signaling machinery and a defective communication between CD8 T cells and dendritic cells.

Background Tumor necrosis factor (TNF)- inhibition was shown to reduce ischemia/reperfusion injury (IRI) after intestinal transplantation (ITX). We studied the effects of different TNF inhibitors on acute IRI and long-term inflammatory responses in experimental ITX.Methods Orthotopic ITX was performed in an isogenic ischemia/reperfusion model in Lewis rats. The TNF inhibition groups received infliximab post-reperfusion; etanercept pre-reperfusion and at postoperative days (POD) 1, 3, 5, and 7; or pentoxifylline pre-reperfusion and at POD 1 to 5. Tissue samples were taken from proximal and distal graft sections and mesenteric lymph nodes at 20 min, 12 hr, 7 day, and 6 months post-reperfusion for histopathology, immunohistology, terminal deoxyribosyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, and real-time RT-PCR. Lung sections were stained for the myeloperoxidase assay.Results TNF inhibitors decreased inflammatory changes after IRI in all treatment groups. Infliximab significantly improved 7-day survival and reduced the histological and immunohistochemical signs of IRI, the numbers of graft-infiltrating T cells and ED1(+) monocytes and macrophages, and pulmonary neutrophil infiltration, and also enhanced the accumulation of cytoprotective markers. Graft injury was more prominent in the distal graft than in the proximal graft in all groups, regardless of TNF inhibition.Conclusion Infliximab significantly reduced both acute IRI and, as with other TNF inhibitors, long-term inflammatory responses after rat ITX. TNF inhibition may help diminish chronic inflammatory long-term effects and avoid chronic allograft enteropathy.

Background. Organs from DCD (donation after cardiac death) donors are increasingly used for transplantation. The impact of advanced donor age and warm ischemia on the immune response of the recipient has not been studied. We developed a novel and clinically relevant model of DCD kidney transplantation and investigated the effects of donor age and prolonged warm ischemia on the recipient immune response after following DCD kidney transplantation.Methods. DCD grafts from young and old F-344 donor rats were engrafted into LEW recipients who were nephrectomized bilaterally after a short (20 minutes) or prolonged (45 minutes) warm ischemia time.Results. Analysis of the recipient's immune response early after transplantation showed an enhanced innate and adaptive immune response when old DCD kidneys were engrafted. Next, we studied DCD recipients with a supportive, contralateral native kidney in place, which allowed the recovery of the transplanted DCD kidney. Old DCD kidneys, demonstrated an impaired renal function associated with pronounced histomorphologic graft deterioration and an enhanced immune response by day 100 after transplantation. Interestingly, young DCD kidneys with a long warm ischemic time recovered from acute tubular necrosis and did not stimulate the long-term immune response.Conclusion. Our observations emphasize that prolonged warm ischemic time and advanced donor age augment the immune response after transplantation of DCD grafts. These results provide an experimental model and a mechanistic framework of clinically relevant aspects in DCD donation. (Surgery 2013;153:249-61.)

With an increasing demand, organs from elderly donors are more frequently utilized for transplantation. Herein, we analyzed the impact of donor age on CD4+ T-cell responses with regard to regulatory and effector mechanisms. Young (3 months) BM12 recipients were engrafted with young or old (18 months) B6 cardiac allografts. Systemic CD4+ T-cell responses and intragraft changes were monitored and compared to age-matched syngenic transplant controls. While elderly, nonmanipulated hearts contained significantly elevated frequencies of donor-derived leukocytes prior to transplantation, allograft survival was age-independent. T-cell activation, however, was delayed and associated with a compromised immune response in mixed lymphocyte cultures (MLR; P = 0.0002) early after transplantation (day 14). During the time course after transplantation, recipients of old grafts demonstrated an augmented immune response as shown by significantly higher frequencies of activated CD4+ T-cells and a stronger in vitro alloreactivity (MLR; ELISPOT; P < 0.01). In parallel, frequencies of regulatory T-cells had increased systemically and overall fewer CD4+ T-cells were detected intragraft. Interestingly, changes in the CD4+ T-cell response were not reflected by graft morphology. Of note, transplantation of young and old syngenic hearts did not show age-related differences of the CD4+ T-cells response suggesting that old grafts can recover from a period of short cold ischemia time. Our data suggest that donor age is associated with an augmented CD4+ T-cells response which did not affect graft survival in our model. These findings contribute to a better understanding of the immune response following the engraftment of older donor organs.

Aim: Ischemia/reperfusion (I/R) injury is one of the major problems in intestinal transplantation (ITx). Polimorphnuclear neutrophils (PMNs) mediate lung injury as a consequence of the systemic inflammatory response induced after IRI of the small bowel graft. The aim of the present study was to evaluate the effects of different TNF-α inhibition concepts on PMN infiltration of recipient lung and expression level of graft cytoprotective markers as well. Methods: Orthotopic small bowel transplantation was performed in an isogenic model in male Lewis (LEW) rats. Grafts were flushed with UW solution and stored for 6hrs at 4°C before implantation. The TNF-α inhibitor groups received either infliximab (I) (8 mg/kg b.w. i.v. immediately after reperfusion), etanercept (E) (1 mg/kg b.w. s.c.; pre reperfusion, PODs 1,3,5,7) or pentoxifylline (P) (50 mg/kg b.w. i.p pre reperfusion; 25 mg/kg b.w. i.p PODs 1-5). Controls (C) received no further treatment. Tissue samples of proximal and distal graft were taken 20 min, 12h, 7d and 6 mths after reperfusion (each n=6 per time point and group) for immunohistology (HSP70). Lung sections (12h, 7d and 6 mths after reperfusion) were stained for Myeloperoxidase (MPO, specific staining of neutrophil granulocytes). Significant differences were evaluated by multifactorial analysis using two-way ANOVA and Bonferroni post test. Results: Seven day survival was significantly improved following TNF-α inhibition with infliximab (I 100% vs. C 60%: p< 0.05). Beyond POD 7 survival was 100% in all groups. TNF-α inhibition with infliximab correlated with significantly enhanced accumulation of cytoprotective markers (HSP-70) in small bowel grafts. Moreover, MPO stain revealed a significant reduction of neutrophil infiltration of the lung following TNF-α inhibition with all three treatment modalities. Discussion: PMN infiltration of recipient lung was significantly reduced after short-term TNF-α inhibition. Single shot treatment with infliximab correlated with a significant increase in HSP-70 expression in intestinal grafts. These findings may help to: 1. improve injury of distant organs after ITx and 2. ameliorate initial graft injury after I/R, which is believed to exert long-term effects on graft outcome by activating innate immunity, thus contributing to chronic allograft enteropathy.

Introduction: CD8+ T cells play a cardinal feature in response to alloantigen following transplantation and are able to generate effector and memory T cells independently from CD4+ T cells. Methods: Using a fully allogeneic mouse skin transplant model, we investigated the role of CD8+ T cells and allograft survival in an age-dependent manner. Results: Our findings showed that allograft survival was significantly prolonged in older recipients (mean survival time 12 days compared to 9 days in younger recipients; p< 0.0001) when compared to young recipients.[Figure 1: Prolonged skin allograft survival in age]Flow cytometry analysis revealed a significant increase of CD4+ and CD8+CD44highCD62Llow effector/memory T cells in older recipients. However, MLR and ELISpot results demonstrated a reduced systemic inflammation of older recipients with decreased T cell proliferation and diminished IFNγ-production. Upon specific TCR activation, isolated CD8+ T cells from old recipients produced lower levels of IFNγ and higher levels of IL-2 when compared to young recipients.[Fig. 2: Altered TCR activation of aged CD8+ T cells]Moreover, expression of CD25, CD132 and Blimp-1 by old and young CD8+ T cells stimulated with anti-CD3 and anti-CD28 were comparable. However, older CD8+ T cells showed a lower expression of CD122.[Fig. 3: Downregulation of CD122 expression]Of note, age related changes in CD8+ T cells were impressively displayed in vivo. CBA Rag-1−/− mice reconstituted with CD8+tgTCR+ T cells from old BM3.3 mice demonstrated significantly prolonged graft survival over mice adoptively transferred with CD8+ T cells from young BM3.3 animals (45.8 days vs 18.7 days; p< 0.005). Conclusion: Older CD8+ T cells play a key role in organ transplant rejection and demonstrate a compromised functional capacity with reduced systemic inflammation and delayed allograft rejection.

Background: Brain death impairs donor organ quality and accelerates immune responses after transplantation. Detailed aspects of immune activation following brain death remain unclear. We have established a mouse model and investigated the immediate consequences of brain death and anesthesia on immune responses.Methods: C57JBI/6 mice (n = 6/group) were anesthetized with isoflurane (ISF) or ketamine/xylazine (KX); subsequently, animals underwent brain death induction and were followed for 3 h under continuous ventilation. Blood pressure was monitored continuously and animals were resuscitated with normal saline to achieve normotension. Immune activation in brain dead animals was analyzed by IFN-gamma-ELispot, MLR, and flow-cytometry. Sham-operated and naive animals served as controls.Results: Blood pressure remained stable in both BD/KX and BD/ISF animals during the 3 h observation time. Brain death was linked to systemic immune activation: IFN gamma-expression of splenocytes and lymphocyte proliferation rates was significantly elevated subsequent to brain death (p<0.02, <0.01); T-cell activation markers CD28 and CD69 had increased in brain dead animals (p<0.03, <0.02). Isoflurane treatment in sham controls throughout the observation period (3.5 h) revealed anesthesia associated IFN gamma-expression and lymphocyte activation which were not observed when animals were treated with ketamine/xylazine (p<0.04, <0.009).Conclusions: This study reports on a reproducible and hemodynamically stable brain death mouse model. Hemodynamic stability was not impacted through either isoflurane or ketamine/xylazine induction. Of clinical relevance, prolonged anesthesia with isoflurane had been linked to pro-inflammatory cytokine activation. Brain death caused systemic immune activation in organ donors. (C) 2012 Elsevier B.V. All rights reserved.

BACKGROUND: Donor brain death (BD) triggers inflammatory graft activation that leads to impaired graft quality and outcome. We used a mouse BD model to investigate graft inflammation in cardiac transplants from immune-competent and immune-deficient donor animals. Effects of donor T-cell depletion were tested in an additional group of cardiac transplant recipients.METHODS: We analyzed systemic and graft-specific inflammatory activation after BD in donors and in syngeneic recipients of hearts retrieved from BD donors. To dissect the role of donor-specific immune cells in communicating BD-triggered inflammation, immune-deficient T-cell-, B-cell-, and natural killer cell-deficient Rag2/double knockout mice and naive C57BL6 treated with anti-thymocyte globulin (Thymoglobulin; Genzyme Transplant, Cambridge, MA) were observed.RESULTS: Donor BD boosted lymphocyte activation in donors and recipients of syngeneic BD grafts. Lymphocyte activation was mitigated in recipients of immune-deficient and Thymoglobulin-treated BD donor grafts. Likewise, systemic and intra-graft levels of inflammatory cytokines interleukin -1, interleukin-6, interferon-gamma, and tumor necrosis factor-a were significantly reduced in immune-deficient and anti-thymocyte globulin-treated recipients. Dense lymphocyte infiltrates were detected in the hearts from untreated BD donors; in contrast, the hearts from donors treated with Thymoglobulin demonstrated a preserved structure with minimal infiltrates comparable with naive controls.CONCLUSION: BD triggers inflammatory graft activation communicated through ultra-graft immune cells. Donor treatment with Thymoglobulin prevented inflammatory immune activation and improved graft quality to levels comparable to living donor organs. J Heart Lung Transplant 2012; 31: 1293-300 (C) 2012 International Society for Heart and Lung Transplantation. All rights reserved.

Wnt-modulator in surface ectoderm (WISE) is a secreted modulator of Wnt signaling expressed in the adult kidney. Activation of Wnt signaling has been observed in renal transplants developing interstitial fibrosis and tubular atrophy; however, whether WISE contributes to chronic changes is not well understood. Here, we found moderate to high expression of WISE mRNA in a rat model of renal transplantation and in kidneys from normal rats. Treatment with a neutralizing antibody against WISE improved proteinuria and graft function, which correlated with higher levels of β-catenin protein in kidney allografts. In addition, treatment with the anti-WISE antibody reduced infiltration of CD68(+) macrophages and CD8(+) T cells, attenuated glomerular and interstitial injury, and decreased biomarkers of renal injury. This treatment reduced expression of genes involved in immune responses and in fibrogenic pathways. In summary, WISE contributes to renal dysfunction by promoting tubular atrophy and interstitial fibrosis.

Le modèle de transplantation rénale chez le rat est une méthode classique d’investigation dans le domaine de la transplantation rénale. De nombreuses variantes ont été rapportées sans qu’il n’existe de procédé standard. Nous décrivons une technique institutionnelle simple, utilisée avec succès dans plus de 500 interventions et enseignée à de nombreux étudiants en médecine, internes ou chirurgiens dépourvus d’expérience microchirurgicale antérieure. Notre description illustrée étape par étape devrait permettre une diffusion aisée de cette méthode auprès des étudiants et chercheurs francophones.

Kidney transplantation in rats is a classic experimental model used in transplant research. As several methods have been previously reported without definition of a gold standard, we describe herein a simple institutional technique that has been used in more than 500 procedures and taught to medical students or surgeons without previous microsurgical experience. Our step-by-step illustrated report would allow French-speaking trainees to learn how to perform kidney transplantation in rats in a reproducible manner and add this valuable tool to their research protocols. (c) 2010 Elsevier Masson SAS. All rights reserved.