Philipp Renner

Advancement of mesenchymal stem cell therapy in solid organ transplantation (MISOT).

There is evolving interest in the use of mesenchymal stem cells (MSC) in solid organ transplantation. Pre-clinical transplantation models show efficacy of MSC in prolonging graft survival and a number of clinical studies are planned or underway. At a recent meeting of the MISOT consortium (MSC In Solid Organ Transplantation) the advances of these studies were evaluated and mechanisms underlying the potential effects of MSC discussed. Continued discussion is required for definition of safety and eventually efficacy endpoints for MSC therapy in solid organ transplantation.

Toward MSC in Solid Organ Transplantation: 2008 Position Paper of the MISOT Study Group

The following position paper summarizes the recommendations for early clinical trials and ongoing basic research in the field of mesenchymal stem cell-induced solid organ graft acceptance—agreed upon on the first meeting of the Mesenchymal Stem Cells In Solid Organ Transplantation (MISOT) study group in late 2008.

Features of synergism between mesenchymal stem cells and immunosuppressive drugs in a murine heart transplantation model.

BACKGROUND Mesenchymal stem cells (MSCs) can be used for immunomodulation therapy after solid organ transplantation. Here, we focus on the immunoregulatory potential of combination therapies of MSCs and classic pharmacotherapy to mediate acceptance of solid organ grafts. METHODS To determine which drugs influence the immunosuppressive effect of MSCs, we assessed the interaction of MSCs and common clinical immunosuppresants (MMF, sirolimus [Srl], and ciclosporin A [CiA]) in a parent-into-F1 cell transfer model. In this model, the transfer of parental strain T cells into semi-allogeneic F1 recipients induces a graft-versus-host reaction (GvHR). Re-isolated CFSE-labelled T lymphocytes were analyzed by flow cytometry. These findings were compared to a fully allogeneic heart transplantation model. RESULTS We found that MSC treatment alone had no significant effect on allograft survival of heterotopic heart grafts. However, MSCs combined with short-term mycophenolate mofetil (MMF) significantly prolonged graft survival. Quantitative analysis of three different MSC - drug combinations in the F1 model revealed, that only the MSC-MMF combination led to a super-additive immunosuppressive effect. We also investigated the effect of MMF and CiA on IFNγ production of stimulated lymphocytes and found that MMF left the expression of IFNγ unaffected, whereas CiA completely abolished the production of IFNγ. CONCLUSION Our data show that the type of concurrent immunosuppression strongly influences the immunosuppressive effect of MSC, most likely through differential secretion of IFNγ. A regimen combining MSCs and MMF was most immunosuppressive.

Mesenchymal stem cells as immunomodulators after liver transplantation

Mesenchymal stem cells (MSCs) are promising candidate cells for immunomodulation therapy that are currently being tested in the preclinical and clinical setting. MSCs suppress the immune response in a variety of in vitro and disease models and may thus be of benefit for patients suffering from autoimmune disorders or transplant rejection. The mechanism by which MSCs modulate the immune response is still under thorough investigation, but it most likely involves expression of local factors such as indoleamine 2,3‐dioxygenase, inducible nitric oxide synthase, and others as well as interactions with dendritic or antigen‐presenting cells. Although MSCs have been evaluated in clinical phase I and II studies for graft‐versus‐host disease and heart, kidney, and bone disease, their introduction into solid organ transplantation is still eagerly awaited. In this short review, we summarize the current understanding of immunomodulation achieved by MSC therapies and introduce a possible outline for a clinical study that will use MSCs in the context of a calcineurin inhibitor–free induction protocol after liver transplantation. Liver Transpl 15:1192–1198, 2009.

Intestinal ischemia: current treatment concepts

PurposeMesenteric ischemia is a condition well-known among physicians treating patients with abdominal symptoms. Even so, mortality rates have not decreased significantly over the last decades. The purpose of this article is to review current treatment concepts of acute and chronic mesenteric ischemia.ResultsEarly diagnosis is one of the most important features that determine a patient’s prognosis. Conventional angiography and multidetector computed tomography are therefore appropriate to quickly diagnose mesenteric ischemia, the latter being commonly more available. Once a patient presents with signs of peritonitis, instant laparotomy is indicated, and infarcted bowel segments need to be resected, followed by a second-look operation if necessary. If bowel necrosis is clinically not suspected, different approaches should be applied according to source and nature of mesenteric ischemia. Besides established surgical treatment concepts, more and more interventional procedures are developed and evaluated. However, superiority of these new techniques could only be shown for selected patient groups so far. In chronic mesenteric ischemia, interventional approaches seem to be an attractive alternative in patients who are in a condition too bad to undergo surgery. Patients with colonic ischemia are treated best in a conservative manner and by resolving the underlying cause, if identified.ConclusionPatients with acute mesenteric ischemia are still at highest risk for a fatal course of disease. New diagnostic and therapeutic developments have not been tested in larger studies yet, neither has any of these methods led to an increased survival in studies published so far. Taken together, mesenteric ischemia requires high awareness, earliest possible diagnosis, and treatment by an experienced interdisciplinary team of gastroenterologists, radiologists, and surgeons.

Urinary Biomarkers TIMP-2 and IGFBP7 Early Predict Acute Kidney Injury after Major Surgery

Objective To assess the ability of the urinary biomarkers IGFBP7 (insulin-like growth factor-binding protein 7) and TIMP-2 (tissue inhibitor of metalloproteinase 2) to early predict acute kidney injury (AKI) in high-risk surgical patients. Introduction Postoperative AKI is associated with an increase in short and long-term mortality. Using IGFBP7 and TIMP-2 for early detection of cellular kidney injury, thus allowing the early initiation of renal protection measures, may represent a new concept of evaluating renal function. Methods In this prospective study, urinary [TIMP-2]×[IGFBP7] was measured in surgical patients at high risk for AKI. A predefined cut-off value of [TIMP-2]×[IGFBP7] >0.3 was used for assessing diagnostic accuracy. Perioperative characteristics were evaluated, and ROC analyses as well as logistic regression models of risk assessment were calculated with and without a [TIMP-2]×[IGFBP7] test. Results 107 patients were included in the study, of whom 45 (42%) developed AKI. The highest median values of biomarker were detected in septic, transplant and patients after hepatic surgery (1.24 vs 0.45 vs 0.47 ng/l2/1000). The area under receiving operating characteristic curve (AUC) for the risk of any AKI was 0.85, for early use of RRT 0.83 and for 28-day mortality 0.77. In a multivariable model with established perioperative risk factors, the [TIMP-2]×[IGFBP7] test was the strongest predictor of AKI and significantly improved the risk assessment (p<0.001). Conclusions Urinary [TIMP-2]×[IGFBP7] test sufficiently detect patients with risk of AKI after major non-cardiac surgery. Due to its rapid responsiveness it extends the time frame for intervention to prevent development of AKI.

Heart Grafts Tolerized Through Third-Party Multipotent Adult Progenitor Cells Can Be Retransplanted to Secondary Hosts With No Immunosuppression

Multipotent adult progenitor cells (MAPCs) are an adherent stem cell population that belongs to the mesenchymal‐type progenitor cell family. Although MAPCs are emerging as candidate agents for immunomodulation after solid organ transplantation, their value requires further validation in a clinically relevant cell therapy model using an organ donor‐ and organ recipient‐independent, third‐party cell product. We report that stable allograft survival can be achieved following third‐party MAPC infusion in a rat model of fully allogeneic, heterotopic heart transplantation. Furthermore, long‐term accepted heart grafts recovered from MAPC‐treated animals can be successfully retransplanted to naïve animals without additional immunosuppression. This prolongation of MAPC‐mediated allograft acceptance depends upon a myeloid cell population since depletion of macrophages by clodronate abrogates the tolerogenic MAPC effect. We also show that MAPC‐mediated allograft acceptance differs mechanistically from drug‐induced tolerance regarding marker gene expression, T regulatory cell induction, retransplantability, and macrophage dependence. MAPC‐based immunomodulation represents a promising pathway for clinical immunotherapy that has led us to initiate a phase I clinical trial for testing safety and feasibility of third‐party MAPC therapy after liver transplantation.

Hepatobiliary Procedures in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

BackgroundThe long-term prognosis of patients with peritoneal malignancies has greatly improved since the introduction of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Nevertheless, CRS can be associated with high postoperative morbidity. In this retrospective study, we analyzed the influence of hepatobiliary surgery as part of CRS on postoperative short-term patient outcome.MethodsBetween 2005 and 2008, a total of 63 (25%) of 252 patients with peritoneal surface malignancies undergoing CRS and HIPEC required hepatobiliary surgery. Liver resection was performed in 22, resection of Glisson capsule in 39, and bile duct resection in 2 patients. The mean age of the study population was 49.3 years. Thirty-four patients (54%) were women.ResultsComplete macroscopic cytoreduction (CC-0/1) was reached in 59 patients (93.7%). The median hospital stay was 18 days. Twenty-two patients developed minor complications (35%), such as moderate fever, pain, or secondary wound healing. In 21 patients (33%), severe complications occurred, most commonly pancreatitis and abdominal abscess. Three patients (4.8%) developed a biliary leakage. Of these, 2 had to be reoperated.ConclusionsIn our experience, hepatobiliary procedures have to be performed in up to one-third of patients and are associated with a low rate of specific complications, such as biliary leakages.

Mesenchymal stem cells can affect solid organ allograft survival.

It has recently been recognized that mesenchymal stem cells (MSCs) isolated from adult bone marrow are able to modify the alloimmune response in vitro and in vivo. MSCs can be expanded into large quantities in culture, thereby facilitating potential future applications in solid organ transplantation. To develop novel MSC-based antirejection treatments, the mechanism behind the immunomodulatory ability of MSCs has to be elucidated further. At present, a variety of possible in vitro effects of MSCs on immune system effector cells have been reported, but little is known about their in vivo properties. Here, we discuss recent findings regarding the influence of MSCs on different effector cell populations in vitro and summarize the available data describing their in vivo properties.

KLRG1+ NK Cells Protect T-bet–Deficient Mice from Pulmonary Metastatic Colorectal Carcinoma

We studied the developmental and functional mechanisms behind NK cell–mediated antitumor responses against metastatic colorectal carcinoma (CRC) in mice. In particular, we focused on investigating the significance of T-box transcription factors and the immunotherapeutic relevance of IL-15 in the development and function of tumor-reactive NK cells. Pulmonary CRC metastases were experimentally seeded via an adoptive i.v. transfer of luciferase-expressing CT26 CRC cells that form viewable masses via an in vivo imaging device; genetically deficient mice were used to dissect the antitumor effects of developmentally different NK cell subsets. IL-15 precomplexed to IL-15 receptor-α was used in immunotherapy experiments. We found that mice deficient for the T-box transcription factor T-bet lack terminally differentiated antitumor CD27lowKLRG1+ NK cells, leading to a terminal course of rapid-onset pulmonary CRC metastases. The importance of this NK cell subset for effective antitumor immunity was shown by adoptively transferring purified CD27lowKLRG1+ NK cells into T-bet–deficient mice and, thereby, restoring immunity against lung metastasis formation. Importantly, immunity to metastasis formation could also be restored in T-bet–deficient recipients by treating mice with IL-15 precomplexed to IL-15 receptor-α, which induced the development of eomesodermin+KLRG1+ NK cells from existing NK cell populations. Thus, contingent upon their T-bet–dependent development and activation status, NK cells can control metastatic CRC in mice, which is highly relevant for the development of immunotherapeutic approaches in the clinic.