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Abstract Flood simulations are important for flood (fatality) risk assessment. This article provides insight into the sensitivity of flood fatality risks to the model resolution of flood simulations and to several uncertain parameters in the loss of life model used. A case study is conducted for river flooding in a polder in the Netherlands (the Bommelerwaard) where the Dutch approach for loss of life estimation is applied. Flood models with resolutions of 100, 25, and 5 m are considered. Results show locally increased mortality rates in higher resolution simulations nearby structures including road embankments, dikes, and culverts. This causes a larger maximum individual risk value (annual probability of death for a person due to flooding) which has consequences for safety standards based on the individual risk criterion. Mortality rate in the breach zone is also affected by representations of buildings as solid objects versus as roughness elements. Furthermore, changes in the loss of life estimation approach via alternative ways of including people's behaviour, building characteristics, and age of the population, have a significant impact on flood fatality risk. Results from this study can be used to support future risk assessments and decision making with respect to safety standards.

Background: Head tremor is common in dystonia syndromes and difficult to treat. Deep brain stimulation (DBS) is a therapeutic option in medically-refractory cases. In most DBS-centers, the globus pallidus internus (GPi) is targeted in patients with predominant dystonia and the ventrointermediate nucleus of the thalamus (Vim) in predominant tremor. The aim of the study was to evaluate the effect of GPi- versus Vim-DBS in dystonic or essential head tremor., Methods: All patients with dystonia or essential tremor (ET) (n = 381) who underwent DBS surgery at our institution between 1999 and 2020 were screened for head tremor in our database according to predefined selection criteria. Of the 33 patients meeting inclusion criteria tremor and dystonia severity were assessed at baseline, short- (mean 10 months) and long-term follow-up (41 months) by two blinded video-raters., Results: Twenty-two patients with dystonic head tremor received either GPi- (n = 12) or Vim-stimulation (n = 10), according to the prevailing clinical phenotype. These two groups were compared with 11 patients with ET, treated with Vim-stimulation. The reduction in head tremor from baseline to short- and long-term follow-up was 60-70% and did not differ significantly between the three groups., Conclusions: GPi-DBS effectively and sustainably reduced head tremor in idiopathic dystonia. The effect was comparable to the effect of Vim-DBS on head tremor in dystonia patients with predominant limb tremor and to the effect of Vim-DBS on head tremor in ET., (© 2024 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Questionable signs of dystonia are a common finding in patients with essential tremor (ET). Brain structural alterations in ET patients plus dystonic soft signs (ET + ds) in comparison to ET patients without dystonic soft signs (ET-ds) or patients with tremor associated with manifest dystonia (TAWD) have not been examined yet. Therefore, our study aims to explore alterations of brain grey matter in patients with ET + ds., Methods: A total of 68 elderly patients with ET-ds (n = 32), ET + ds (n = 20) or idiopathic cervical dystonia with dystonia associated action tremor of the upper limbs (TAWD, n = 16) and 42 age-matched healthy controls underwent a clinical and electrophysiological assessment and 3T MRI. For grey matter alterations T1 MRI images were analysed by voxel-based morphometry. Additionally, regression analyses with clinical parameters (tremor frequency, severity and disease duration) were performed., Results: VBM showed a significant increase of grey matter in the right lentiform nucleus in ET + ds and TAWD compared to HC and ET-ds. Further, an increase of cortical grey matter in the middle frontal gyrus in ET + ds was shown. The hypertrophy of the lentiform nucleus in ET + ds was correlated with disease severity and duration., Conclusion: Patients with ET + ds showed grey matter brain structural alterations similar to TAWD. Our findings suggest an involvement of the basal ganglia-cortical loop in ET + ds which may indicate a pathophysiological similarity with TAWD rather than ET., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Autoimmune encephalitis can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory aetiologies. In the elderly, anti-LGI1 and contactin associated protein like 2 (CASPR2) antibody-associated diseases compose a relevant fraction of autoimmune encephalitis. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan's syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2 autoantibody-associated syndromes have caused substantial concern regarding necessity of autoantibody testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centres in Europe. Patients with ataxia and/or movement disorders were analysed in detail using questionnaires and video recordings. We recruited a comparator group with anti-LGI1 encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2 and 15 (9.1%) both CASPR2 and LGI1 autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6 versus 3.8%; P < 0.001). This was evident in all subgroups: ataxia 22.6 versus 0.0%, myoclonus 14.6 versus 0.0%, tremor 11.0 versus 1.9%, or combinations thereof 9.8 versus 0.0% (all P < 0.001). The small group of patients double-positive for LGI1/CASPR2 autoantibodies (15/164) significantly more frequently had myoclonus, tremor, 'mixed movement disorders', Morvan's syndrome and underlying tumours. We observed distinct movement disorders in CASPR2 autoimmunity (14.6%): episodic ataxia (6.7%), paroxysmal orthostatic segmental myoclonus of the legs (3.7%) and continuous segmental spinal myoclonus (4.3%). These occurred together with further associated symptoms or signs suggestive of CASPR2 autoimmunity. However, 2/164 patients (1.2%) had isolated segmental spinal myoclonus. Movement disorders and ataxia are highly prevalent in CASPR2 autoimmunity. Paroxysmal orthostatic segmental myoclonus of the legs is a novel albeit rare manifestation. Further distinct movement disorders include isolated and combined segmental spinal myoclonus and autoimmune episodic ataxia., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Dystonia occurring in the context of parkinsonism is well-known, e.g. as foot dystonia in young-onset Parkinson's disease (PD), anterocollis in multisystem atrophy (MSA) or blepharospasm (levator inhibition) in progressive supranuclear palsy. We have, however, encountered a series of patients whose phenotype differed from the above described entities., Methods: We describe a cohort of patients in whom typical idiopathic isolated (primary) late-onset focal or segmental (predominantly cervical) dystonia preceded the development of parkinsonism by several years, sometimes decades., Results: In a cohort of 450 patients followed in our botulinum toxin injections clinic, we identified 11 (2.4%; 7 women) who developed parkinsonism at a median of 14 years after the onset of dystonia. Median age at onset of parkinsonism was 70 years (range 59-87), usually manifesting with a new tremor or a change of tremor pattern, complaints of 'slowing down' or new walking difficulties. Parkinsonism resembled PD in 5 (one pathologically confirmed); the remainder had atypical parkinsonism of MSA (n = 3) or indeterminate phenotype (n = 3)., Conclusion: The relatively frequent occurrence of parkinsonism after long-standing dystonia would suggest a link between the two, in line with evidence from other clinical reports, imaging studies, animal models and genetics. It appears that in some cases of dystonia this could be an antecedent manifestation of a syndrome with parkinsonism developing later, or be a risk factor for parkinsonism. In practice, it is important for clinicians to be alert to new symptoms/signs in patients with long-standing dystonia. From a research point of view, longitudinal case-control studies would be required to further investigate the link between long-standing dystonia and subsequent parkinsonism., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: To describe findings on cerebral imaging in patients with COVID-19 and neurological symptoms at two German university hospitals., Materials and Methods: Patients with COVID-19 and neurological symptoms and cerebral imaging (CT or MRI) were included. A chart review regarding neurological symptoms, COVID-19 and imaging findings was conducted., Results: 12 patients (4 females, age 68 ± 12 years) could be included. Three patients had acute findings. Two patients had acute and subacute cerebral ischemia, one patient had additional intracranial hemorrhages and presumed central pontine myelinolysis. One patient had presumed COVID-19-associated pansinusitis., Conclusion: Findings on cerebral imaging in patients with COVID-19 are uncommon and nonspecific. However, cerebral ischemia is regularly encountered and patients should be evaluated for stroke symptoms., Key Points: · Approx. 20 % of patients with COVID-19 develop neurological symptoms.. · Findings on cerebral imaging in patients with COVID-19 are heterogeneous and nonspecific.. · The most common findings are cerebral ischemia and hemorrhages.., Citation Format: · Jensen-Kondering U, Neumann A, Margraf N et al. Cerebral Imaging in Patients with COVID-19 and Neurological Symptoms: First Experience from two University Hospitals in Northern Germany. Fortschr Röntgenstr 2021; 193: 667 - 671., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Patients with upper limb action tremor frequently exhibit additional neurological signs of uncertain significance. Clinicians vary in their interpretation, and interrater agreement on the final diagnosis is poor., Objectives: A new clinical tool for assessing the presence or absence of clinical signs that are important in axis-1 classification of tremor patients is introduced: the Standardized Tremor Elements Assessment (STEA). Interrater agreement is determined, and signs leading to disagreement in the final diagnosis are identified., Methods: Three tremor-focussed and one dystonia-focussed movement disorder specialists rated 59 videos of patients with upper limb action tremor syndromes using STEA. Interrater agreements for final diagnosis and STEA items were calculated., Results: Interrater agreement regarding the final diagnosis was higher within the group of tremor specialists and poor between dystonia and tremor specialists. Greater agreement was found for items characterizing tremor than for signs of dystonia., Conclusions: Clinical signs leading to diagnostic disagreement were identified with STEA, and STEA should therefore be useful in future studies of diagnostic disagreement. The thresholds for considering neurological signs as soft versus significant for ataxia, parkinsonism, dystonia, etc. are critically important in tremor classification and must be studied across movement disorder subspecialties, not simply within a pool of tremor specialists., (© 2021 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.)

Background: Over the past decade increasing scientific progress in the field of autoantibody-mediated neurological diseases was achieved. Movement disorders are a frequent and often prominent feature in such diseases which are potentially treatable., Main Body: Antibody-mediated movement disorders encompass a large clinical spectrum of diverse neurologic disorders occurring either in isolation or accompanying more complex autoimmune encephalopathic diseases. Since autoimmune movement disorders can easily be misdiagnosed as neurodegenerative or metabolic conditions, appropriate immunotherapy can be delayed or even missed. Recognition of typical clinical patterns is important to reach the correct diagnosis., Conclusion: There is a growing number of newly discovered antibodies which can cause movement disorders. Several antibodies can cause distinctive phenotypes of movement disorders which are important to be aware of. Early diagnosis is important because immunotherapy can result in major improvement.In this review article we summarize the current knowledge of autoimmune movement disorders from a point of view focused on clinical syndromes. We discuss associated clinical phenomenology and antineuronal antibodies together with alternative etiologies with the aim of providing a diagnostic framework for clinicians considering underlying autoimmunity in patients with movement disorders., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: Unilateral or very asymmetric upper limb tremors with a jerky appearance are poorly investigated. Their clinical classification is an unsolved problem because their classification as essential tremor versus dystonic tremor is uncertain. To avoid misclassification as essential tremor or premature classification as dystonic tremor, the term indeterminate tremor was suggested., Objectives: The aim of this study was to characterize this tremor subgroup electrophysiologically and evaluate whether diagnostically meaningful electrophysiological differences exist compared to patients with essential tremor and dystonic tremor., Methods: We enrolled 29 healthy subjects and 64 patients with tremor: 26 with dystonic tremor, 23 with essential tremor, and 15 patients with upper limb tremor resembling essential tremor but was unusually asymmetric and jerky (indeterminate tremor). We investigated the somatosensory temporal discrimination threshold, the short-interval intracortical inhibition, and the cortical plasticity by paired associative stimulation., Results: Somatosensory temporal discrimination threshold was significantly increased in patients with dystonic tremor and indeterminate tremor, but it was normal in the essential tremor patients and healthy controls. Significant differences in short-interval intracortical inhibition and paired associative stimulation were not found among the three patient groups and controls., Conclusion: These results indicate that indeterminate tremor, as defined in this study, shares electrophysiological similarities with dystonic tremor rather than essential tremor. Therefore, we propose that indeterminate tremor should be considered as a separate clinical entity from essential tremor and that it might be dystonic in nature. Somatosensory temporal discrimination appears to be a useful tool in tremor classification. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

In clinical practice, involuntary vocalizing behaviors are typically associated with Tourette syndrome and other tic disorders. However, they may also be encountered throughout the entire tenor of neuropsychiatry, movement disorders, and neurodevelopmental syndromes. Importantly, involuntary vocalizing behaviors may often constitute a predominant clinical sign, and, therefore, their early recognition and appropriate classification are necessary to guide diagnosis and treatment. Clinical literature and video-documented cases on the topic are surprisingly scarce. Here, we pooled data from 5 expert centers of movement disorders, with instructive video material to cover the entire range of involuntary vocalizations in humans. Medical literature was also reviewed to document the range of possible etiologies associated with the different types of vocalizing behaviors and to explore treatment options. We propose a phenomenological classification of involuntary vocalizations within different categorical domains, including (1) tics and tic-like vocalizations, (2) vocalizations as part of stereotypies, (3) vocalizations as part of dystonia or chorea, (4) continuous vocalizing behaviors such as groaning or grunting, (5) pathological laughter and crying, (6) vocalizations resembling physiological reflexes, and (7) other vocalizations, for example, those associated with exaggerated startle responses, as part of epilepsy and sleep-related phenomena. We provide comprehensive lists of their associated etiologies, including neurodevelopmental, neurodegenerative, neuroimmunological, and structural causes and clinical clues. We then expand on the pathophysiology of the different vocalizing behaviors and comment on available treatment options. Finally, we present an algorithmic approach that covers the wide range of involuntary vocalizations in humans, with the ultimate goal of improving diagnostic accuracy and guiding appropriate treatment. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Introduction: Late-onset essential tremor is characterised by shorter life expectancy and more advanced aging parameters and may therefore be an 'aging-related' tremor. Brainstem functions involved in pupillary responses are hypothesized to reflect such earlier aging. The pupillary light response (PLR) and a task evoked pupillary response (TEPR) were used to test this hypothesis in same-aged patients with early onset (EOET) and late onset (LOET) essential tremor and healthy controls., Subjects and Methods: Age related changes of the PLR and TEPR during the paced auditory serial addition test (PASAT) were tested in 57 normal subjects. Subsequently, 13 patients with LOET and 16 patients with EOET were compared with 15 age matched healthy controls. Standard parameters of PLR were recorded, amongst others the time to maximum acceleration of the PLR (T1) and the time to maximum velocity (T2). The TEPR was determined during the PASAT as the percentage change in pupil size (PCPS). Data were analysed with ANOVA and post-hoc testing., Results: In normal subjects the pupil diameter, latency, maximum acceleration/velocity and percentage amplitude were correlated with age. Latency of the pupillary light response was significantly longer in LOET compared to controls and EOET while no differences were found between EOET and controls. The TEPR showed no significant differences between the three groups., Conclusion: LOET showed a prolonged latency of the PLR compared to EOET possibly indicating premature aging or rather pathophysiological differences on brainstem level. This study further supports the hypothesis of abnormal aging in LOET., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Tremor is one of the most frequent movement disorders. The recently published new classification of the Movement Disorder Society separates the clinical description of tremor syndromes as so-called axis 1 symptom constellations from the etiologies of tremor (axis 2). The same tremor syndromes can therefore be combined with different causes and vice versa. The terminology used in this classification is precisely defined and thereby also the necessary language for medical communication. Frequent tremor syndromes, such as enhanced physiologic tremor, dystonic and parkinsonian tremor as well as focal tremors and task and position-specific tremors are discussed with respect to the phenomenology, and current therapy.

Writer's cramp (WC) is a focal task-specific dystonia characterized by sustained or intermittent muscle contractions while writing, particularly with the dominant hand. Since structural lesions rarely cause WC, it has been assumed that the disease might be caused by a functional maladaptation within the sensory-motor system. Therefore, our objective was to examine the differences between patients suffering from WC and a healthy control (HC) group with regard to the effective connectivity that describes causal influences one brain region exerts over another within the motor network. The effective connectivity within a network including contralateral motor cortex (M1), supplementary motor area (SMA), globus pallidus (GP), putamen (PU) and ipsilateral cerebellum (CB) was investigated using dynamic causal modeling (DCM) for fMRI. Eight connectivity models of functional motor systems were compared. Fifteen WC patients and 18 age-matched HC performed a sequential, five-element finger-tapping task with the non-dominant and non-affected left hand within a 3 T MRI-scanner as quickly and accurately as possible. The task was conducted in a fixed block design repeated 15 times and included 30 s of tapping followed by 30 s of rest. DCM identified the same model in WC and HC as superior for reflecting basal ganglia and cerebellar motor circuits of healthy subjects. The M1-PU, as well as M1-CB connectivity, was more strongly influenced by tapping in WC, but the intracortical M1-SMA connection was more facilitating in controls. Inhibiting influences originating from GP to M1 were stronger in controls compared to WC patients whereby facilitating influences the PU exerts over CB and CB exerts over M1 were not as strong. Although the same model structure explains the given data best, DCM confirms previous research demonstrating a malfunction in effective connectivity intracortically (M1-SMA) and in the cortico-basal ganglia circuitry in WC. In addition, DCM analysis demonstrates abnormal reciprocal excitatory connectivity in the cortico-cerebellar circuitry. These results highlight the dysfunctional cerebello-cortical as well as basalganglio-cortical interaction in WC.

Purpose of Review: This review focuses on important new findings in the field of tremor and illustrates the consequences for the current definition and classification of tremor., Recent Findings: Since 1998 when the consensus criteria for tremor were proposed, new variants of tremors and new diagnostic methods were discovered that have changed particularly the concepts of essential tremor and dystonic tremor. Accumulating evidence exists that essential tremor is not a single entity rather different conditions that share the common symptom action tremor without other major abnormalities. Tremor is a common feature in patients with adult-onset focal dystonia and may involve several different body parts and forms of tremor. Recent advances, in particular, in the field of genetics, suggest that dystonic tremor may even be present without overt dystonia. Monosymptomatic asymmetric rest and postural tremor has been further delineated, and apart from tremor-dominant Parkinson's disease, there are several rare conditions including rest and action tremor with normal dopamine transporter imaging (scans without evidence of dopaminergic deficit) and essential tremor with tremor at rest., Summary: Increasing knowledge in the last decades changed the view on tremors and highlights several caveats in the current tremor classification. Given the ambiguous assignment between tremor phenomenology and tremor etiology, a more cautious definition of tremors on the basis of clinical assessment data is needed.

Purpose of Review: The differential diagnosis of chorea syndromes may be complex and includes various genetic disorders such as Huntington's disease and mimicking disorders called Huntington's disease-like (HDL) phenotypes. To familiarize clinicians with these (in some cases very rare) conditions we will summarize the main characteristics., Recent Findings: HDL disorders are rare and account for about 1% of cases presenting with a Huntington's disease phenotype. They share overlapping clinical features, so making the diagnosis purely on clinical grounds may be challenging, however presence of certain characteristics may be a clue (e.g. prominent orofacial involvement in neuroferritinopathy etc.), Information of ethnic descent will also guide genetic work-up [HDL2 in Black Africans; dentatorubral-pallidoluysian atrophy (DRPLA) in Japanese etc.], Huntington's disease, the classical HDL disorders (except HDL3) and DRPLA are repeat disorders with anticipation effect and age-dependent phenotype in some, but genetic underpinnings may be more complicated in the other chorea syndromes., Summary: With advances in genetics more and more rare diseases are disentangled, allowing molecular diagnoses in a growing number of choreic patients. Hopefully, with better understanding of their pathophysiology we are moving towards mechanistic therapies.

The Transplant Acceptance-inducing Cell (TAIC) is a form of immunoregulatory macrophage which appears to be capable of establishing a state of alloantigen-specific partial tolerance of solid organ transplants in renal transplant recipients. This report establishes that human TAICs do not elicit a proliferative response from co-cultured allogeneic T cells. More significantly, it has been shown that TAICs are able to suppress proliferation of allogeneic CD4(+) and CD8(+) T cells after mitogenic stimulation. This suppressive activity can be attributed to the deletion of activated T cells by TAICs and to the secretion of a soluble inhibitor of T cell proliferation. It is further shown that the acquisition of T cell-suppressive properties by human TAICs depends upon an unidentified component of human serum.

There is very limited published information testifying to the safety and possible complications of cell-based therapies. Accurately assessing the potential risks of translating novel, cell-based immunosuppressive protocols into clinical trials is therefore extremely difficult. This report describes the use of a pulmonary allograft model in outbred miniature pigs as a preliminary step in the development of a safe, clinically feasible, cell-based immunosuppressive protocol. Single lung transplants were performed in 22 MHC Class I-mismatched donor-recipient pairs, which were randomized between four treatment groups. For the first 28 days postoperatively, all animals were immunosuppressed with methylprednisilone and tacrolimus, with or without preoperative irradiation; subsequently, pharmacological immunosuppression was stopped in all treatment groups. Animals in two groups also received a central venous infusion of donor-derived 'transplant acceptance-inducing cells' (TAICs) on the seventh and 14th days postoperatively. Allograft survival was monitored by sequential chest X-rays, bronchoscopies and transbronchial biopsy histologies. No acute adverse events were associated with the administration of TAICs and there was no evidence of accelerated graft rejection. The observations presented in this report represent an important first step towards the development of a clinically applicable protocol for the use of TAIC therapy in lung transplantation.

Under certain culture conditions human peripheral blood monocytes may be induced to express phenotypic markers of non-haematopoietic lineages, including hepatocyte-defining traits. One such example, the NeoHepatocyte, was previously shown to express a broad panel of hepatocyte-like marker antigens and metabolic activities, both in vitro and following engraftment in the liver of immunodeficient mice. In this report, a refined description of NeoHepatocytes, with regard to their expression of xenobiotic-metabolising enzymes, morphology, hepatocyte marker expression and cell surface phenotype, is presented in comparison with human macrophages in defined states of activation. Contrary to prior assertions, it would seem more likely that NeoHepatocytes express particular hepatocyte-defining genes during a normal programme of macrophage differentiation rather than undergoing a process of transdifferentiation to become hepatocyte-like cells.

Patient KW, a 36-yr-old male renal transplant recipient, received transplant acceptance-inducing cells (TAICs) as an adjunct immunosuppressive therapy. In the weeks post-transplantation, the patient's conventional immunosuppressive treatment was gradually minimized, such that, from the 21st wk post-transplantation onwards, the patient was stably maintained on tacrolimus monotherapy. Treatment with TAICs was without complication, both at the time of administration and in the four-yr follow-up period. It is concluded that the production and administration of TAICs to recipients of kidney transplants from deceased donors is technically feasible.

This report describes the case of patient FR, a 31-year-old recipient of a living-related kidney transplant from a donor against whom he was presensitized. Seventeen days prior to transplantation, a central venous infusion of transplant acceptance-inducing cells (TAICs) was administered to the patient. During the 27-month follow up, the patient experienced no acute rejection episodes under an immunosuppressive regime comprising anti-thymocyte globulin (ATG) induction, corticosteroids and tacrolimus. In a similar manner to the kidney transplant recipients treated preoperatively with TAICs in a previous study, patient FR achieved a state of donor-specific hypo-responsiveness. Most remarkably, the deliberate preoperative exposure of a sensitized patient to the sensitizing alloantigen did not heighten his response; on the contrary, after TAIC treatment and transplantation, HLA-specific antibodies were no longer detectable. The case of patient FR provides further evidence of the safety of pre-transplantation treatment with TAICs.

Five renal transplant recipients were preoperatively treated with transplant acceptance-inducing cells (TAICs) in a Phase-I safety study of TAICs as an adjunct immune-conditioning therapy in living-donor kidney transplantation. Initially, patients received anti-thymocyte globulin induction therapy in combination with tacrolimus and steroid immunosuppression. Over the course of 12 weeks, steroids were withdrawn and tacrolimus therapy was minimized. Three of the five patients were able to tolerate low-dose tacrolimus monotherapy and one patient was withdrawn from all immunosuppression for over 8 months. No acute or delayed adverse events were associated with the infusion of TAICs. Monitoring of the recipient anti-donor reactivity of TAIC-treated patients in mixed lymphocyte cultures demonstrated that, during periods of clinically stable graft function, recipient T-cell proliferation and cytokine secretion in response to stimulation with donor alloantigen was relatively suppressed. Therefore, although the TAIC-II trial did not provide conclusive evidence of a beneficial effect of preoperative TAIC treatment, the results were encouraging because they suggest that TAICs promote a state of alloantigen-specific unresponsiveness, which might allow safe minimization of pharmacological immunosuppression.