Eine funktionale Charakterisierung der Transplantat-Akzeptanz-Induzierende Zelle

Clinical organ transplantation became the therapy of choice for endstage organ diseases. This development was closed related to the history of potent immunosuppressive drugs. Although major progress in the improvement of immunosuppressive therapy regimes was made, long-term graft survival is still limited and recipients are affected due to several adverse effects. For this reason numerous attempts were undertaken to induce operational tolerance. This thesis engaged in an attempt in which a subset of monocytes, named Transplant Acceptance Inducing Cells (TAIC), is given to patients in order to substitute conventional immunosuppressive therapy. The focus of the thesis was the detection of potential immunosuppressive effects to allogeneic lymphocytes induced by TAIC cells in in-vitro co-cultures. Further a case study was performed to demonstrate an interesting outcome of a renal transplant patient who received TAIC cells and to show the clinical feasibility of this treatment. First experiments indicated that TAIC cells are able to suppress the proliferation of allogeneic CD8+ T cells under co-culture conditions, provided that the T cells are existent in a mitogen activated state. Without the addition of mitogen to co-cultures, TAIC cells promoted the survival of allogeneic lymphocytes. Under changed conditions, which were closer related to previous undertaken clinical TAIC trials, TAIC cells suppressed both CD4+ and CD8+ mitogen stimulated allogeneic lymphocytes. In absence of mitogen stimulation TAIC cells were not able to rescue allogeneic lymphocytes from death by neglect. Although these results apparently demonstrate immunosuppressive properties of TAIC cells adverse activated allogeneic lymphocytes, it is obligatory to identify the exact mode of function of these cells in order to distinguish them clearly from other macrophage subsets with immunoregulatory features. The described renal transplant patient in the case study received TAIC cells afterwards the transplantation as an adjunct immunosuppressive therapy within an alternative healing attempt. The infusion of TAIC cells proceeded without any complications and the subsequent reduction of immunosuppressants up to a low grade tacrolimus monotherapy was well tolerated by the patient for the almost last five years. A biopsy, which was taken in the 17th week after transplantation, showed an unusual pattern of focal lymphocytic infiltration how it was already seen in spontaneously tolerant kidney transplant patients. Both the undertaken experiments and the described case study in this thesis demonstrate that TAIC cells have immunosuppressive characteristics which might have the potential to become a feasible immunosuppressive therapy approach in the clinic. But therefore it is necessary that further studies depict the specific mode of function of those cells and that meaningful clinical trials definitely prove the beneficial effect of TAIC cells in transplant patient. Furthermore it is needed that long-term experiments exclude potential adverse effects.Die Transplantation von Organen hat sich zur Therapie der Wahl von zahlreichen Organerkrankungen im Endstadium entwickelt. Insbesondere die Zunahme potenter immunsuppressiver Medikamente hat einen entscheidenden Beitrag zu dieser Entwicklung geleistet. Dennoch ist das langfristige Transplantatüberleben begrenzt und die Patienten müssen beträchtliche Nebenwirkung der immunsuppressiven Therapie in Kauf nehmen. Aus diesem Grund ist einer der zentralen Forschungsansätze der Transplantationsmedizin die Induktion peripherer Toleranz im Organempfänger. Diese Arbeit beschäftigt sich mit einer speziellen Form regulatorischer Makrophagen, so genannter Transplantat Akzeptanz-Induzierender Zellen (TAIZ), die Patienten verabreicht werden mit dem Ziel die konventionelle immunsuppressive Therapie zu ersetzen. Der Schwerpunkt dieser Arbeit liegt auf der Untersuchung möglicher immunsuppressiver Effekte humaner TAIZ Zellen gegenüber allogenen Lymphozyten in in-vitro Kokulturen. Weiterhin wurde ein Case Report erstellt, um das interessante klinische Ergebnis eines nierentransplantierten Patienten vorzustellen, der mit TAIZ Zellen behandelt wurde. Ziel dieses Berichtes ist es aufzuzeigen, dass die Therapie mit TAIZ Zellen ein potentiell klinisch anwendbares Verfahren darstellt. In den ersten Experimenten wird dargelegt, dass TAIZ Zellen in der Lage sind unter Kokultur-Bedingungen die Proliferation allogener CD8+ T-Zellen zu unterdrücken; vorausgesetzt, dass sich T-Zellen in einem Mitogen-aktivierten Zustand befinden. Ohne die Zugabe eines Mitogens zu den Kokulturen verlängerten TAIZ Zellen das Überleben allogener Lymphozyten. Unter ähnlichen Bedingungen wie in zuvor durchgeführten klinischen Studien mit TAIZ Zellen, unterdrückten TAIZ Zellen sowohl CD4+, als auch CD8+ Mitogen-stimulierte allogene Lymphozyten. Ohne die Zugabe eines Mitogens waren TAIZ Zellen nicht in der Lage allogene Lymphozyten vor dem "death by neglect" zu retten. Obwohl diese Resultate deutlich immunsuppressive Eigenschaften von TAIZ Zellen gegenüber aktivierten allogen Lymphozyten demonstrieren, ist es notwendig die exakte Funtkionsweise dieser Zellen zu identifizieren, um sie klar von anderen Makrophagen mit immunregulatorischen Eigenschaften zu unterscheiden. Der in dem Fallbericht beschriebene Patient hat TAIZ Zellen nach einer Nierentransplantation als eine ergänzende immunsuppressive Therapie im Rahmen eines alternativen Heilansatzes erhalten. Die Infusion der TAIZ Zellen verlief komplikationslos und die anschließende Reduktion der Immunsuppression bis hin zu einer geringgradigen Tacrolimus Monotherapie wurde von dem Patienten über einen Zeitraum von fünf Jahren gut vertragen. Eine Biopsie, die in der siebzehnten Woche nach der Transplantation durchgeführt wurde, zeigte ein ungewöhnliches Bild fokaler Lymphozyteninfiltrate wie es bereits in spontan toleranten nierentransplantierten Patienten gesehen wurde. Sowohl die durchgeführten Experimente, als auch der beschriebene Fallbericht in dieser Arbeit zeigen, dass TAIZ Zellen immunsuppressive Eigenschaften besitzen, die durchaus das Potential für eine klinisch praktikable immunsuppressive Therapie haben. Dafür ist es zunächst jedoch noch notwendig, dass die genaue Funktionsweise dieser Zellen dargestellt wird und dass aussagekräftige Studien die Wirksamkeit von TAIZ Zellen belegen. Weiterhin müssen langfristige Nebenwirkungen ausgeschlossen werden

Antibody-related movement disorders – a comprehensive review of phenotype-autoantibody correlations and a guide to testing

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

The spectrum of involuntary vocalizations in humans: A video atlas

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

Dynamic causal modeling revealed dysfunctional effective connectivity in both, the cortico-basal-ganglia and the cerebello-cortical motor network in writers' cramp

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. Keywords: Dynamic causal modeling, Focal hand dystonia, Writer's cramp, Network disorder, Cerebellu

Orthostatic myoclonus associated with Caspr2 antibodies

Orthostatic myoclonus (OM) is a clinical phenomenon in which myoclonus of the lower limbs appears or becomes worse upon standing.(1) OM usually affects patients older than 65 years and may be a frequent cause of unsteadiness upon standing in the elderly.(2) Although the underlying etiology remains unclear, OM has predominantly been described in association with neurodegenerative diseases.(1) We describe a patient with OM in association with antibodies against contactin-associated protein-2 (Caspr2) whose symptoms markedly improved with immunotherapy

Distinct movement disorders in contactin-associated-protein-like-2 antibody-associated autoimmune encephalitis

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

Distinct movement disorders in contactin-associated-protein-like-2 antibody-associated autoimmune encephalitis

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