German Primate Center Research Articles

Histomorphological analysis of the superficial musculoaponeurotic system in Macaca mulatta species

IntroductionThe superficial musculoaponeurotic system (SMAS) is a well described facial functional unit in humans. SMAS connects mimic musculature to the skin having many implication in facial mimic expression. One of the various morphological and physiological analogies in human and Macaca mulatta species is the facial mimic. The present study analyzed Macaca mulatta species SMAS morphology and its facial topographical differences and compared this with human SMAS tissue morphology. Material and methodsMacaca mulatta full-graft tissue blocks of skin, subcutaneous tissue and mimic muscles from five topographical different facial regions (Regio Temporalis, Regio Buccalis, Regio Infraorbitalis, Regio Angulus Oris and Regio Mandibularis) were collected postmortem from eight individuals (n = 8) at the German Primate Center, Leibniz Institute for Primate Research in Göttingen (DPZ) and studied histologically. Haematoxylin-eosin and azan stained histological serial sections of full-graft tissue blocks were analyzed and SMAS topographical differences evaluated. ResultsSMAS typical tissue morphology was recognized in all Macaca mulatta histological serial sections (n = 780). Regio Infraorbitalis Macaca mulatta SMAS (MmSMAS) morphology was similar to human infraorbital SMAS morphology (type I SMAS). Suborbicularis oculi fat pad was recognized in Macaca mulatta samples. Human type I similar SMAS morphology was demonstrated over Macaca mulatta Regio Temporalis and Regio Buccalis. Regio Angulus Oris and the cranial area of the Regio Mandibularis presented human type II similar SMAS morphology. Type IV MmSMAS was closely related to the parotid gland tissue presence. The cervical area of the Regio Mandibularis presented human type V similar SMAS morphology. ConclusionsSMAS is a complex fibro-musculo-adipose tissue network and probably an important pivot in Macaca mulatta facial system supporting mimic expression. This study provided insights into MmSMAS typology and similarity with human SMAS tissue morphology.

A Touchscreen-Based, Multiple-Choice Approach to Cognitive Enrichment of Captive Rhesus Macaques (Macaca mulatta).

Research on the psychological and physiological well-being of captive animals has focused on investigating different types of social and structural enrichment. Consequently, cognitive enrichment has been understudied, despite the promising external validity, comparability, and applicability. As we aim to fill this gap, we developed an interactive, multiple-choice interface for cage-mounted touchscreen devices that rhesus monkeys (Macaca mulatta) can freely interact with, from within their home enclosure at the Cognitive Neuroscience Laboratory of the German Primate Center. The multiple-choice interface offers interchangeable activities that animals can choose and switch between. We found that all 16 captive rhesus macaques tested consistently engaged with the multiple-choice interface across 6 weekly sessions, with 11 of them exhibiting clear task preferences, and displaying proficiency in performing the selected tasks. Our approach does not require social separation or dietary restriction and is intended to increase animals' sense of competence and agency by providing them with more control over their environment. Thanks to the high level of automation, our multiple-choice interface can be easily incorporated as a standard cognitive enrichment practice across different facilities and institutes working with captive animals, particularly non-human primates. We believe that the multiple-choice interface is a sustainable, scalable, and pragmatic protocol for enhancing cognitive well-being and animal welfare in captivity.

The German Primate Center, Göttingen

No abstract

Is there an unmet medical need for improved hearing restoration?

Hearing impairment, the most prevalent sensory deficit, affects more than 466 million people worldwide (WHO). We presently lack causative treatment for the most common form, sensorineural hearing impairment; hearing aids and cochlear implants (CI) remain the only means of hearing restoration. We engaged with CI users to learn about their expectations and their willingness to collaborate with health care professionals on establishing novel therapies. We summarize upcoming CI innovations, gene therapies, and regenerative approaches and evaluate the chances for clinical translation of these novel strategies. We conclude that there remains an unmet medical need for improving hearing restoration and that we are likely to witness the clinical translation of gene therapy and major CI innovations within this decade.

Camostat Mesylate but Not Hydroxychloroquine May Reduce Severity of Organ Failure in COVID-19 Sepsis: A Case-Control Study

Background: The pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). COVID-19 may take a severe course, resulting in sepsis, and antivirals are urgently needed to combat the disease. However, at present, only drugs developed against other diseases are available including the Malaria drug hydroxychloroquine but their therapeutic efficacy is unclear. Camostat mesylate, a clinically-proven protease inhibitor for treatment of pancreatitis, was shown to block SARS-CoV-2 entry into lung cells. Whether camostat mesylate dampens COVID-19 induced sepsis and the associated organ failure is unknown. Here we compare clinical courses of critically ill COVID-19 patients treated with either camostat mesylate or hydroxychloroquine. Methods: Eleven COVID-19 patients with organ failure were treated in intensive care unit (ICU) at our institution. Five patients (group 1) received hydroxychloroquine and six patients (group 2) camostat mesylate. Clinical disease status was assessed by Simplified Acute Physiology Score (SAPS) II and Sequential/ Sepsis-related Organ Failure Assessment (SOFA) score at day 1, 3 and 8. Viral load was determined from nasopharyngeal swabs. Findings: Patient age ranged from 45 to 76 years, all but one had histories of chronic disease and cardiovascular risk factors. Median symptomatic period was 2-10 days before being transferred to ICU. No differences in SAPS II scores or SOFA scores were observed upon ICU admission. In group 1, SOFA and SAPS II scores remained elevated (2 patients died) while in group 2 SOFA and SAPS II score decreased from 9 to 4 points (1 patient died). The decline in disease severity for group 2 was paralleled by a decline in inflammatory markers, which was not observed in group 1. The virus load in the nasopharynx was variable between patients, did not correlate with organ failure and no marked differences were observed between groups 1 and 2. Interpretation: The severity of COVID-19 sepsis markedly decreased upon camostat mesylate treatment within a period of 8 days and a similar effect was not observed upon hydroxychloroquine treatment. Camostat mesylate thus warrants further evaluation within randomized clinical studies. Funding Statement: Authors were employed at the University of Gottingen or at the Infection Biology Unit of the German Primate Center (Leibniz Institute for Primate Research). All expenses were covered by publicly funded institutions. Stefan Pohlmann received funding from the German Federal Ministry of Education and Research (BMBF), RAPID Fund (#01KI1723D). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Compassionate use was approved by our local ethical committee at the University of Gottingen.

COVID 19: Camostat and The Role of Serine Protease Entry Inhibitor TMPRSS2

According to the latest research, the novel coronavirus uses the protein angiotensin-converting enzyme 2 (ACE-2) as a receptor for docking to the host cell. Essential for entry is the priming of the spike (S) protein of the virus by host cell proteases. A broadly based team led by infection biologists from the German Primate Centre and with the participation of the Charité Hospital in Berlin, the Hanover Veterinary University Foundation, the BG-UnfallklinikMurnau, the LMU Munich, the Robert Koch Institute and the German Centre for Infection Research wanted to find out how SARS-CoV-2 enters host cells and how this process can be blocked [1]. They have published their findings in the journal "Cell" [1]. The team of scientists was initially able to confirm that SARS-CoV-2 docks to the host cell via the ACE-2 receptor. They also identified Transmembrane serine protease 2 (TMPRSS2) as the cellular protein responsible for entry into the cell [1-3].

Preface: Franz-Josef Kaup and the development of the Pathology Unit at the German Primate Center.

This special issue about selected diseases of nonhuman primates was created in honor of Franz-Josef Kaup, who worked as a primate pathologist at the German Primate Center (DPZ) for 25 years. In 1992, Franz-Josef Kaup started his career at the DPZ as head of the working group Experimental Pathology. Prior to that he worked as a research assistant in the division Electron Microscopy at the Institute of Pathology of the University of Veterinary Medicine in Hanover. He was very experienced in the field of electron microscopy and used this expertise to establish a central electron microscopy laboratory at the DPZ. In the beginning, research of the working group Experimental Pathology was focused on gastrointestinal and respiratory infections and was closely related to projects of the Department of Virology. At that time, experimental infections of rhesus macaques with simian immunodeficiency virus (SIV) and associated opportunistic infections became the main subject of his research. The contribution of Christiane Stahl-Hennig and coauthors about SIV-induced cardiovascular diseases reflects the still ongoing collaboration in this research field. After merging the Experimental Pathology and Primate Husbandry in 1996, Franz-Josef Kaup headed the newly created Department of Veterinary Medicine and Primate Husbandry. This department became the central service unit of the DPZ in 1999 and offered a broad spectrum of services in veterinary diagnostics, primate husbandry, and animal welfare, which was intensively used by many internal and external scientists. In 2001, Walter Bodemer joined the group and the scientific contents expanded with a new focus on the pathogenesis of prion diseases. Some important aspects of this era are summarized in the work of Walter Bodemer.

Revisiting a quarter of a century of simian immunodeficiency virus (SIV)-associated cardiovascular diseases at the German Primate Center.

Human immunodeficiency virus (HIV) comorbidities have become clinically more important due to antiretroviral therapy. Although therapy increases life expectancy, it does not completely suppress immune activation and its associated complications. The simian immunodeficiency virus (SIV)-infected rhesus macaque (Macaca mulatta) represents a valuable model for the investigation of SIV-associated diseases. Although cardiovascular (CV) changes are common in HIV-infected patients, there are only a few reports on the incidence of CV findings in SIV-infected animals. In addition, potential associations between pathohistological findings and hematological parameters are still unclear.We therefore conducted a retrospective analysis of 195 SIV-infected rhesus macaques that were euthanized with AIDS-related symptoms at the German Primate Center, Goettingen, over a 25-year period. Pathological findings were correlated with hematological data.The main findings included myocarditis (12.8 %), endocarditis (9.7 %), and arteriopathy (10.3 %) in various organs. Thrombocytopenia occurred more frequently in macaques with endocarditis or arteriopathy than in macaques without CV disease (80 % in animals with endocarditis, 60 % in animals with arteriopathy, and , respectively).Further investigations of the interaction between coagulation markers, proinflammatory cytokines, and biomarkers associated with endothelial dysfunction (e.g., D-dimers) and histological data (vascular wall structure) may unravel the mechanisms underlying HIV/SIV-associated CV comorbidities.

Morphological and immunohistochemical characterization of spontaneous endometriosis in rhesus macaques (Macaca mulatta).

Several cases of spontaneous endometriosis in middle-aged to old rhesus macaques (Macaca mulatta) from the breeding colony of the German Primate Center were thoroughly characterized with regards to anatomical distribution and macroscopic appearance, histological differentiation and immunohistochemical profile including somatic markers, hormonal receptors, and proliferation indices. More than half of the examined animals (five of nine) were directly related to one breeding male, supporting a strong genetic predisposition. Histologically, four different types of endometriotic lesions, depending on the degree of ectopic endometrial gland and stromal differentiation (well differentiated, purely stromal, mixed differentiation, poorly differentiated), could be constantly identified within all animals. Immunohistochemistry (IHC) of cytokeratin (CK), vimentin, smooth muscle actin (SMA), desmin, estrogen (ER), and progesterone (PR) receptors as well as of the nuclear proteins Ki67 and p53 revealed varying staining patterns in the four different types of endometriosis differentiation and compared to normal endometrium. Purely stromal, mixed, or poorly differentiated lesions, especially, showed additional cytokeratin-positive stromal cells, whereas epithelial cells of endometriosis with mixed or poor differentiation increasingly expressed mesenchymal markers (vimentin, SMA). Hormonal receptor and Ki67 expression in well-differentiated endometriotic lesions mostly reflected that of normal endometrial tissue according to the cyclic phase of the animal, while the expression gradually diminished with decreasing grade of differentiation. However, increased nuclear accumulations of p53 antigen could only be continuously detected in epithelial cells of mixed or poorly differentiated endometriosis. Altogether, these findings support the pathogenetic theory of coelomic metaplasia, since the expression profiles of somatic markers in less differentiated forms closely resembled that of mesothelial cells. Thus, the four different histological types of endometriosis might display subsequent grades of differentiation in the course of time, with poorly differentiated types representing newly formed, immature lesions and well-differentiated types being older, fully differentiated forms, rather than being the outcome of dedifferentiation processes.

Spontaneous lung pathology in a captive common marmoset colony (Callithrix jacchus).

Data on spontaneous pathology are substantially scarce for common marmosets, compared to other laboratory animals, but is essential for the interpretation of histological findings in the context of toxicological and experimental studies. Especially if common marmosets are used as experimental animals in respiratory research, detailed knowledge on the spectrum, occurrence, and incidence of spontaneous histopathological pulmonary lesions in this non-human primate species is required. In this study, lung tissue of 638 common marmosets from the marmoset colony of the German Primate Center was examined histologically. The analysis revealed a high incidence of predominantly mild and multifocal interstitial pneumonia (32.99 %) of unknown etiology in most cases. Only few marmosets exhibited lobar pneumonia (1.41 %) and bronchopneumonia (0.94), which were mainly caused by bacterial pathogens such as Bordetella bronchiseptica and Klebsiella pneumoniae. Lung immaturity and atelectasis were common histological findings in newborn marmosets. Typical background lesions included anthracosis (8.15 %), hemosiderosis (1.72 %), extramedullary hematopoiesis (11.6 %), mineralization (10.97 %), and inflammatory cell foci (10.34 %). In addition, three cases of pulmonary arteriopathy (0.47 %) and 1 case of foreign-body granuloma (0.16 %) were detected in the marmoset study cohort. The high prevalence of circulatory disturbances (congestion, edema, hemorrhage) and changes in air content (secondary atelectasis, alveolar emphysema) could partly be explained by euthanasia-related artifacts or agonal changes. The present study provides a comprehensive overview of the range and incidence of spontaneous pulmonary histopathology in common marmosets, serving as valuable reference data for the interpretation of lung lesions in toxicological and experimental marmoset studies.

Lymphocryptovirus-dependent occurrence of lymphoma in SIV-infected rhesus macaques with particular consideration to two uncommon cases of non-Hodgkin's lymphoma

Abstract. Despite combination antiretroviral therapy, high-grade malignant non-Hodgkin's lymphoma (NHL) is still one of the most frequently acquired immunodeficiency syndrome (AIDS)-defining disorders in the end stage of infection with human immunodeficiency virus (HIV). NHL can also be observed in rhesus macaques infected with the simian immunodeficiency virus (SIV). Thus, they represent a useful model to study morphological characteristics and oncogenetic mechanisms of NHL in humans.When reviewing the occurrence of lymphoma at the German Primate Center over the past 25 years within the context of pathogenic SIV infection we noticed a strikingly high incidence (four out of seven animals) of these tumors in rhesus macaques infected with ex vivo derived SIVmac251/32H/spleen in AIDS-defining end-stage disease. Polymerase chain reaction analysis of this virus stock revealed the co-presence of rhesus lymphocryptovirus (rhLCV), which represents the monkey homologue to human Epstein–Barr virus (EBV), suggesting an association between co-application of SIV and rhLCV and increased tumorigenesis.In addition, we present two cases of NHL in rhesus macaques infected with a SIVmac239 nef-mutant variant because one exhibited an unusual immunophenotype and the other an uncommon organ manifestation. Histological and immunohistochemical examinations of tumors of the first animal revealed metastatic diffuse large B-cell lymphomas (DLBCL) affecting the stomach and the pancreaticoduodenal lymph nodes, of which the one in the stomach presented the rare dual expression of CD20 and CD3. Necropsy of the second animal revealed an obstructive DLBCL around the urinary bladder neck that led to urine backflow and eventually death due to acute uremia without any further AIDS-like manifestations. In the tumors of both animals, abundant Epstein–Barr nuclear antigen-2 expression was demonstrated, thus verifying concurrent rhLCV infection. Flow cytometric analyses revealed a high percentage of activation as well as proliferation in B cells from peripheral lymph nodes in both animals. Moreover, CD4+ T cells were depleted in blood, colon and lymphoid tissue. Concomitantly, CD8+ T cells showed an exhausted phenotype. The two case reports and the increased incidence of NHL following co-application of SIV and rhLCV underline the role of rhLCV in lymphomagenesis.

Prions

Abstract. Prions gained widespread public and scientific interest in the year 2000. At that time, the human neurological Creutzfeldt–Jakob disease (CJD) was known. However, new CJD cases were diagnosed but they could not be ascribed to one of the classical CJD categories i.e. sporadic (sCJD), hereditary or acquired. Hence, they were classified as variant CJD (vCJD). Later on, experimental evidence suggested that vCJD was caused by prions postulated as unique novel infectious agents and, for example, responsible for bovine spongiform encephalopathy (BSE) also known as mad cow disease. The infection of humans by transmission of BSE prions also defined vCJD as a zoonotic disease. Prions, especially those associated with scrapie in sheep had been known for quite some time and misleadingly discussed as a slow virus. Therefore, this enigmatic pathogen and the transmission of this unusual infectious agent was a matter of a controversial scientific debate. An agent without nucleic acid did not follow the current dogma postulating DNA or RNA as inheritable information encoding molecules. Although numerous experimental results clearly demonstrated the infectious capacity of prions in several animal species, a model close to human was not readily available. Therefore, the use of rhesus monkeys (Macaca mulatta) served as a non-human primate model to elucidate prion infection under controlled experimental conditions. Not the least, transmission of BSE, human vCJD, and sCJD prions could be confirmed in our study. Any prion infection concomitant with progression of disease in humans, especially vCJD, could be analyzed only retrospectively and at late stages of disease. In contrast, the prion-infected rhesus monkeys were accessible before and after infection; the progression from early stage to late clinical stages – and eventually death of the animal – could be traced. Because of the phylogenetic proximity to humans, the rhesus monkey was superior to any rodent or other animal model. For these reasons an experimental approach had been conceived by J. Collinge in London and A. Aguzzi in Zurich and performed in a cooperative study with both research groups in the pathology unit of the German Primate Center (DPZ). The study in the DPZ lasted from 2001 until 2012. Our research in the pathology unit provided a temporal monitoring of how an initial prion infection develops eventually into disease; an approach that would have never been possible in humans since the time point of infection with prions from, for example, BSE is always unknown. Telemetry revealed a shift in sleep–wake cycles early on, long before behavioral changes or clinical symptoms appeared. Pathology confirmed non-neuronal tissue as hidden places where prions exist. The rhesus model also allowed first comparative studies of epigenetic modifications on RNA in peripheral blood and brain tissue collected from uninfected and prion-infected animals. To conclude, our studies clearly demonstrated that this model is valid since progression to disease is almost identical to human CJD.

Tree shrews at the German Primate Center

Abstract. For many years, Tupaia (family Tupaiidae), most commonly known as tree shrews, have been studied almost exclusively by zoologists resulting in a controversial debate on their taxonomic status among mammals. Today, tree shrews are placed in the order Scandentia; they are valuable, widely accepted and increasingly used model animals as an alternative to rodents and non-human primates in biomedical research. After a brief description on how tree shrews entered science and their taxonomic odyssey, the present article describes the history of the tree shrew (Tupaia belangeri) colony at the German Primate Center and selected aspects of our work with special emphasis on the psychosocial stress model in these animals.

The Department of Pathology at the German Primate Center from 1973 to 1999

Abstract. The Department of Pathology was the first scientific unit established at the German Primate Center (DPZ) already in its planning phase. At that early time the planning of administrative duties was also necessary, including the financial framework of the laboratory equipment of the then-envisioned three departments of pathology, virology and physiology, in order to get the DPZ off the ground. Otherwise the functions of the Department of Pathology were both service duties and scientific evaluations. The service functions after the establishment of the DPZ included pathological, bacteriological and parasitological examinations/surveys and the veterinary care of nonhuman primates at the DPZ and other primate colonies. On an international level its service functions were reflected by the collaboration within the Office International de Epizooties (OIE, Paris) (Dollinger et al., 1996) and the Infectious Diseases Working Group of the European Association of Zoo and Wildlife Veterinarians, and the establishment of a bacteriological laboratory in Iquitos, Peru, at the request of the Pan American Health Organization. Parallel to those administrative and service duties to the DPZ and to international communities, the different scientific activities started, which in a pathology department always are a combination of service and research. They are documented by a total of almost 120 publications, including 3 doctoral theses and 116 publications by the author from 1973 to 1999; the most important ones are summarized in the following examples.

History of primate behavioural and ecological field research at the German Primate Center

Abstract. This paper describes the background of the first behavioural and ecological field studies on primates conducted by German primatologists in the late 1960s and early 1970s. Field research by scientists from DPZ started in the middle 1980s at a time when this was not yet considered a major task for DPZ. Establishment of field research became possible due to recommendations from institutional and departmental evaluations and the formation of a working group "Ethology and Ecology", which was later transformed into a department in the 1990s. Since then, field research has gained momentum, and has become part of the research program of other DPZ departments. The DPZ is now unique, as it runs field sites in all major areas of primate distribution. The foresight and support of Hans-Jürg Kuhn during his period as scientific director was seminal and essential for the evolution of primate field research at DPZ.

Preface: Hans-Jürg Kuhn and the German Primate Center

Preface: Hans-Jürg Kuhn and the German Primate Center

From the working group "Experimental Pathology" to the department "Pathology Unit" – historical development in retrospect

Abstract. The Pathology Unit of the German Primate Center started as the working group of Experimental Pathology in 1992. This small group with one veterinary pathologist and a technician was founded based on an idea of Prof. Dr. Kuhn, who wanted to strengthen the pathology research activities and to establish a centralized electron microscopy laboratory. Later on, experimental pathology, veterinary services and primate husbandry were integrated as the Department of Veterinary Medicine and Primate Husbandry but subsequently again separated. Prof. Dr. Franz-Josef Kaup, the head of the previously integrated department, remained in his capacity as the leader of the different units. Over the years, the research activities have changed from SIV-associated pathology to other infectious diseases. Today, the main research focus is on the pathogenesis of orthopoxvirus infection, primate pathology, neglected tropical diseases and nonhuman primates as models for chronic respiratory diseases. This paper gives an overview of the historical development and aspects of research activities.

Evaluating noninvasive markers of nonhuman primate immune activation and inflammation.

Health, disease, and immune function are key areas of research in studies of ecology and evolution, but work on free-ranging primates has been inhibited by a lack of direct noninvasive measures of condition. Here, we evaluate the potential usefulness of noninvasive measurement of three biomarkers, the acute-phase proteins C-reactive protein (CRP) and haptoglobin, and neopterin, a by-product of macrophage activity. We took advantage of veterinary checks on captive rhesus (24) and long-tailed (3) macaques at the German Primate Center (DPZ) to analyze serum marker measures, before measuring concentrations in feces and urine, and evaluating relationships between matched serum, urine, and fecal concentrations. In a second study, we monitored excretion of these markers in response to simian immunodeficiency virus (SIV) infection and surgical tissue trauma, undertaken for a separate study. We found that each biomarker could be measured in each matrix. Serum and urinary concentrations of neopterin were strongly and significantly correlated, but neither haptoglobin nor CRP concentrations in excreta proxied circulating serum concentrations. Our infection study confirmed that urinary neopterin, in particular, is a reliable marker of viral infection in macaques, but also indicated the potential of urinary and fecal CRP and haptoglobin as indicators of inflammation. We highlight the potential of noninvasive markers of immune function, especially of urinary neopterin, which correlates strongly with serum neopterin, and is highly responsive to infection.

The German Primate Center – planning and realization of the institute

Abstract. It took almost 20 years from the first proposal for the foundation of a German primate centre to the final establishment of an institute for research on primates. Since 1964, the German science community had considered the idea of founding a national primate centre in the Federal Republic of Germany (West Germany) following existing models in the USA. In 1967, the project received a significant boost from the outbreak of the lethal Marburg virus infections, which was transmitted from African green monkeys to humans. However, a memorandum from Hans-Jürg Kuhn, at that time at the University of Frankfurt, facilitated a breakthrough in 1970. He conceived an interdisciplinary institute that would both conduct its own scientific research and be a service institute for other German institutions. After highly charged debates on a suitable location, the federal government decided on Göttingen, and in 1972 the University of Göttingen provided the necessary ground. With the certificate of incorporation in 1977, the federal government and the German state Lower Saxony appointed Professor Kuhn as the first scientific director. Based on his memorandum, a research and service institute was developed with several scientific departments associated with primate husbandry, and full operation began in 1984.

Xenotransplantation of porcine islet cells as a potential option for the treatment of type 1 diabetes in the future.

Solid organ and cell transplantation, including pancreatic islets constitute the treatment of choice for chronic terminal diseases. However, the clinical use of allogeneic transplantation is limited by the growing shortage of human organs. This has prompted us to initiate a unique multi-center and multi-team effort to promote translational research in xenotransplantation to bring xenotransplantation to the clinical setting. Supported by the German Research Foundation, an interdisciplinary group of surgeons, internal medicine doctors, diabetologists, material sciences experts, immunologists, cell biologists, virologists, veterinarians, and geneticists have established a collaborative research center (CRC) focusing on the biology of xenogeneic cell, tissue, and organ transplantation. A major strength of this consortium is the inclusion of members of the regulatory bodies, including the Paul-Ehrlich Institute (PEI), infection specialists from the Robert Koch Institute and PEI, veterinarians from the German Primate Center, and representatives of influential ethical and religious institutions. A major goal of this consortium is to promote islet xenotransplantation, based on the extensive expertise and experience of the existing clinical islet transplantation program. Besides comprehensive approaches to understand and prevent inflammation-mediated islet xenotransplant dysfunction [immediate blood-mediated inflammatory reaction (IBMIR)], we also take advantage of the availability of and experience with islet macroencapsulation, with the goal to improve graft survival and function. This consortium harbors a unique group of scientists with complementary expertise under a cohesive program aiming at developing new therapeutic approaches for islet replacement and solid organ xenotransplantation.