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Reinhard Kiefer

Publications and source records attributed to Reinhard Kiefer.

17 recordsLinked to original sources
PubMed2006

Macrophage colony stimulating factor is a crucial factor for the intrinsic macrophage response in mice heterozygously deficient for the myelin protein P0.

Mouse mutants heterozygously deficient for the myelin protein P0 (P0+/-) resemble certain forms of human hereditary neuropathies. Endoneurial macrophages of intrinsic origin are intimately involved in the pathogenesis of the demyelinating neuropathy in these mutants. We have previously shown that deficiency for macrophage colony stimulating factor (M-CSF) prevents an increase of the number of endoneurial macrophages and alleviates the mutants' demyelinating phenotype. The aim of this study was to investigate which population of endoneurial macrophages - long-term resident macrophages or recently infiltrated macrophages - is affected by M-CSF deficiency. For this purpose, we generated bone marrow chimeric mice by transplanting GFP+ bone marrow into P0 mutants (P0+/-) and P0 mutants that lack M-CSF (P0+/- mcsf-op). This enabled us to discriminate recently infiltrated short-term resident GFP+ macrophages from long-term resident GFP- macrophages. Three months after bone marrow transplantation, P0+/- mice expressing M-CSF showed a substantial upregulation and activation of both GFP- and GFP+ macrophages in femoral nerves when compared to P0+/+ mice. In contrast, in P0+/- mcsf-op mutants, both GFP- and GFP+ macrophages did not substantially increase. Only small numbers of GFP+ but no GFP- macrophages were activated and phagocytosed myelin in chimeric P0+/- mcsf-op mutants, possibly reflecting recent activation outside the endoneurium before entering the nerve. Our findings demonstrate that M-CSF is crucial for the activation, in situ increase and myelin phagocytosis of both long-term and short-term resident endoneurial macrophages in P0+/- myelin mutants. M-CSF is, therefore, considered as a target candidate for therapeutic strategies to treat human demyelinating neuropathies.

Animals↗
PubMed2006

Contribution of resident endoneurial macrophages to the local cellular response in experimental autoimmune neuritis.

Macrophages are intimately involved in the pathogenesis of inflammatory neuropathies. The contribution of resident endoneurial macrophages is unknown since their differentiation from infiltrating macrophages is difficult due to missing cellular markers. Previous studies demonstrated the participation of resident macrophages in Wallerian degeneration and the pathogenesis of hereditary neuropathies. The question arises whether resident macrophages are involved in experimental autoimmune neuritis (EAN) where they could contribute to immunosurveillance and antigen presentation. To address this question we used bone marrow chimeric rats, allowing the differentiation between resident and hematogenous cells. Immunohistochemistry and in situ hybridization were applied on to identify and characterize resident macrophages in terms of morphological features, expression of activation markers, proliferation, phagocytosis, and MHC-II expression. Endoneurial macrophages of resident origin were detectable at all stages of disease with a contribution of at least 27% of the total macrophages. They appeared activated by morphological and immunohistochemical criteria and proliferated early. MHC-II-positive resident macrophages were observed that had phagocytosed myelin. These results demonstrate that the macrophage response in EAN is partly of intrinsic origin. The rapid activation and proliferation of resident endoneurial macrophages points toward an active role of these cells in inflammatory peripheral nerve disease, especially early in disease.

Animals↗
PubMed2005

Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice.

Activated microglia and hematogenous macrophages are known to be involved in infarct development after cerebral ischemia. Traditionally, hematogenic macrophages are thought to be the primary cells to remove the ischemic cell debris. However, phagocytosis is a well known property also of activated microglia. Due to a lack of discriminating cellular markers, the cellular origin of phagocytes and the temporal course of phagocytosis by these two cell types are largely unknown. In this study, we used green fluorescent protein (GFP) transgenic bone marrow chimeric mice and semithin serial sections after methyl methacrylate embedding of the brains to dissect in detail the proportion of identified activated resident microglial cells and infiltrating hematogenous macrophages in phagocytosing neuronal cell debris after 30 min of transient focal cerebral ischemia. Already at day one after reperfusion, we found a rapid decrease of neurons in the ischemic tissue reaching minimum numbers at day seven. Resident GFP-negative microglial cells rapidly became activated at day one and started to phagocytose neuronal material. By contrast, hematogenous macrophages incorporating neuronal cell debris were observed in the ischemic area not earlier than on day four. Quantitative analysis showed maximum numbers of phagocytes of local origin within 2 days and of blood-borne macrophages on day four. The majority of phagocytes in the infarct area were derived from local microglia, preceding and predominating over phagocytes of hematogenous origin. This recruitment reveals a remarkable predominance of local defense mechanisms for tissue clearance over immune cells arriving from the blood after ischemic damage.

Animals↗
PubMed2005

A CTLA4high genotype is associated with myasthenia gravis in thymoma patients.

Myasthenia gravis (MG) in thymoma patients depends critically on intratumorous generation and export of mature autoreactive CD4+ T cells. Why non-MG thymomas fail to produce CD4+ T cells is unknown. We studied three single-nucleotide polymorphisms of the cytotoxic T-lymphocyte-associated antigen 4(CTLA4) gene in thymoma patients, nonthymoma early-onset MG patients, and control subjects. Surprisingly, the CTLA4high genotype +49A/A, which is protective against several autoimmune diseases, exerted a prominent predisposing effect to paraneoplastic MG in thymoma patients. The unusual disease association with a CTLA4high genotype implies a unique pathogenesis of paraneoplastic MG, with high CTLA4 levels possibly supporting the nontolerogenic selection of CD4+ T cells in MG-associated thymomas.

Adolescent↗
PubMed2005

Neuroprotective effect of the immune system in a mouse model of severe dysmyelinating hereditary neuropathy: enhanced axonal degeneration following disruption of the RAG-1 gene.

In mouse models of later onset forms of human hereditary demyelinating neuropathies, the immune system plays a crucial pathogenic role. Here, we investigated the influence of immune cells on early onset dysmyelination in mice homozygously deficient of the myelin component P0. In peripheral nerves of P0(-/-) mice, CD8+ T-lymphocytes increased with age. Macrophages peaked at 3 months followed by a substantial decline. They were mainly of hematogenous origin. To evaluate the functional role of immune cells, we cross-bred P0(-/-) mutants with RAG-1-deficient mice. At 3 months, the number of endoneurial macrophages did not differ from the macrophage number of immunocompetent myelin mutants, but the later decline of macrophages was not observed. Quantitative electron microscopy revealed that in plantar nerves of 6-month-old double mutants, significantly more axons had degenerated than in immunocompetent littermates. These data suggest a neuroprotective net effect of T-lymphocytes on axon survival in inherited, early onset dysmyelination.

Age Factors↗
PubMed2004

Transient hemiplegia in posterior instrumentation of scoliosis.

STUDY DESIGN: A case of transient hemiplegia during posterior correction and instrumentation of scoliosis in an 18-year-old woman. OBJECTIVE: To present a case of transient hemiplegia most probably resulting from an arteriovenous fistula. SUMMARY OF BACKGROUND DATA: Neurologic impairment in spinal surgery is a feared complication. Common reasons are direct or indirect trauma to neural elements, intraoperative hypotension, ischemia, bleeding, metabolic dysbalances, or drug effects. Review of the literature did not reveal any case of transient hemiplegia similar to the presented one in which none of the mentioned pathologies could be found. CASE SUMMARY: An 18-year-old woman with a right long thoracic lordoscoliosis measuring 67 degrees Cobb angle and a marfanoid phenotype underwent posterior correction and transpedicular instrumentation from T3 to L2. After uneventful correction of the deformity through rod rotation, the wake-up test revealed a right-sided hemiplegia without facial asymmetry or other neurologic abnormalities affecting structures above the spinal cord. The rods were removed, the pedicle screws left in place, and the patient was turned on her back. Within 30 minutes after extubation, the neurologic deficits disappeared completely. Extensive diagnostic workup, including magnetic resonance angiography, did not show any pathologic findings explaining the transient hemiplegia. Two weeks later, the surgical correction was completed. After rod rotation again, right-sided hemiplegia was found in the wake-up test. Leaving the correction and after finalizing surgery, the patient was turned on her back and a 5 x 3-cm mass became apparent in her right sternocleidomastoid region. Color-coded duplex sonography revealed an arteriovenous fistula between the right external carotid artery and the right internal jugular vein. After extubation, the mass disappeared and within minutes all neurologic functions returned to normal again. CONCLUSIONS: Spine surgeons should be aware of arteriovenous malformations as a potential cause of neurologic disturbances.

Abnormalities, Multiple↗
PubMed2004

Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis.

PURPOSE: Thymic epithelial tumors (TET) are rare epithelial neoplasms of the thymus with considerable histologic heterogeneity. This retrospective study focused on the correlation of WHO-defined TET histotypes with survival and tumor recurrence in a large cohort of patients receiving different modes of treatment. PATIENTS AND METHODS: Two hundred twenty-eight patients were followed for up to 21 years (median, 60 months; range, 1 to 252 months) after primary surgery. Forty-two patients received adjuvant radiotherapy (mean dose, 53 Gy), and 33 patients received adjuvant chemotherapy. RESULTS: Seventy-six (88%) of 86 patients with WHO type A, AB, and B1 thymomas were treated by surgery alone, with three tumor relapses after 3 to 10 years (median, 3.4 years). Twelve of 67 patients with WHO type B2 and B3 thymomas in Masaoka stages I and II were treated by adjuvant radiotherapy without evidence of tumor recurrence after 1 to 12 years (median, 4 years). Among 75 patients with B2 and B3 thymomas with incomplete resection or a tumor stage III or higher, the recurrence rate was 34% (n = 23) after 0.5 to 17 years (median, 5 years) in patients receiving adjuvant radiochemotherapy, compared to 78% (seven of nine patients) in patients without adjuvant radiochemotherapy. Incomplete tumor resection was associated with a high recurrence rate (65%) and a poor prognosis (P <.01). CONCLUSION: The long-term outcome of TET patients is related to tumor stage, WHO histotype, completeness of surgical removal, and type of treatment. Prospective trials are warranted to formally address the efficacy of adjuvant therapy in the treatment of localized and advanced malignant TETs.

Carcinoma, Squamous Cell↗
PubMed2004

Selective loss of regulatory T cells in thymomas.

Myasthenia gravis (MG) is the prime autoimmune manifestation of thymomas. We investigated the generation of T cells with a regulatory phenotype (T(R)) in thymomas with and without associated MG. In patients with MG(+) thymomas, maturation and export of T(R) cells but not of other T-cell subsets was significantly reduced. We conclude that imbalance between effector and regulatory T cells in thymomas may be involved in modulation of onset and/or severity of MG.

Adolescent↗
PubMed2004

Advances in understanding and treatment of immune-mediated disorders of the peripheral nervous system.

During recent years, novel insights in basic immunology and advances in biotechnology have contributed to an increased understanding of the pathogenetic mechanisms of immune-mediated disorders of the peripheral nervous system. This increased knowledge has an impact on the management of patients with this class of disorders. Current advances are outlined and their implication for therapeutic approaches addressed. As a prototypic immune-mediated neuropathy, special emphasis is placed on the pathogenesis and treatment of the Guillain-Barré syndrome and its variants. Moreover, neuropathies of the chronic inflammatory demyelinating, multifocal motor, and nonsystemic vasculitic types are discussed. This review summarizes recent progress with currently available therapies and--on the basis of present immunopathogenetic concepts--outlines future treatment strategies.

Animals↗
PubMed2003

Side effects of intravenous immunoglobulins in neurological autoimmune disorders--a prospective study.

The increased use of intravenous immunoglobulins (IVIg) in the treatment of neurological autoimmune diseases has led to more awareness of adverse reactions. We studied prospectively the side effects of IVIg during 84 treatment courses with a total of 341 infusions under routine clinical conditions. Mild reactions were common. Headache was noted most often, occurring during 30% of treatment courses. There were three severe adverse events (3.6% of all treatment courses) that led to discontinuation of the treatment, namely thrombosis of the jugular vein, allergic reaction and retrosternal pressure. Significant changes in laboratory findings were seen for leucocytes, erythrocytes, haematocrit, haemoglobin, ALAT and ASAT. None of these changes were clinically relevant. The elevation of liver enzymes was dependent on the IVIg preparation used, while there was no association with the underlying disease, age, or gender of the patient. In conclusion, this prospective study confirms the high frequency of mild, self-limited side effects of IVIg. Elevation of liver enzymes may possibly be associated with certain IVIg preparations. Bearing these complications in mind, this prospective study supports the notion that IVIg can generally be regarded as safe, leading to severe adverse events during only 3 (0.9%) of 341 infusions (or 3 of 84 treatment courses, 3.6 %). However, careful monitoring for severe side effects remains mandatory, and we propose that laboratory findings like full blood count, renal and liver function should be monitored routinely.

Adolescent↗
PubMed2003

Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice.

Resident microglia and hematogenous macrophages play crucial roles in the pathogenetic cascade following cerebral ischemia but may functionally differ regarding neuroprotective and cytotoxic properties. Distinction between these cells has not been possible due to a lack of discriminating cellular markers. We generated bone marrow chimeric mice by transplanting bone marrow from green fluorescent protein (GFP) transgenic mice into irradiated wild-type recipients. Transient focal cerebral ischemia was induced by transient middle cerebral artery occlusion (MCAO) for 30 min. Resident microglia and infiltrating macrophages were identified by immunohistochemistry and GFP fluorescence after 1-28 days. The first blood-derived cells infiltrating the infarct area were seen on Day 1 and identified as granulocytes. Hematogenous GFP(+) macrophages were rarely observed on Day 2, reached peak numbers on Day 7, and decreased thereafter. In contrast, resident GFP(-) microglial cells rapidly became activated already on Day 1 after MCAO. Even on Days 4 and 7, most macrophage-like cells remained GFP(-), indicating their derivation from resident microglia. Hematogenous macrophages were able to acquire a ramified morphology indistinguishable from resident microglia while microglial cells could develop into a phagocytic phenotype indistinguishable from infiltrating macrophages. The vast majority of macrophages in the infarct area are derived from local microglia, revealing a remarkable predominance of local defense mechanisms over immune cells arriving from the blood. GFP bone marrow chimeric mice are a powerful tool to further differentiate the function of resident microglia and hematogenous macrophages following cerebral ischemia.

Animals↗
PubMed2003

A novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia.

Autosomal dominant progressive external ophthalmoplegia is a common neurological presentation of mitochondrial disease and is characterised by multiple deletions of mitochondrial DNA in muscle. We describe a family with autosomal dominant progressive external ophthalmoplegia caused by a novel heterozygous A to C transversion at nucleotide 956 of the Twinkle gene. The deltoid muscle biopsy of the index case revealed sparse respiratory deficient cells. Multiple mitochondrial DNA deletions were clearly evident in the index case by both long-range and real-time polymerase chain reaction assays but not by Southern blotting, highlighting the diagnostic difficulties associated with characterising patients with multiple mitochondrial DNA deletions.

Adult↗
PubMed2003

Origin of pathogenic macrophages and endoneurial fibroblast-like cells in an animal model of inherited neuropathy.

Macrophages have recently been shown to be critically involved in the pathogenesis of genetically determined demyelination in mice heterozygously deficient for P0 (P0(+-)). Since little is known about the origin of these cells, we created chimeric P0(+-) mice by transplanting bone marrow from green fluorescent protein (GFP)-transgenic mice into irradiated P0(+-) mice. When analyzing chimeric P0(+-) mice, we could determine two populations (GFP(+) and GFP(-)) of endoneurial macrophages that became phagocytic for myelin and increased in number. We found that both GFP(-) resident macrophages and GFP(+) macrophages proliferated in peripheral nerves of P0(+-) mice but not in nerves of chimeric or nonchimeric P0(++) mice. These findings demonstrate a so far poorly recognized role of resident endoneurial macrophages in demyelinating neuropathies. Surprisingly, we also found GFP(+) cells that unequivocally showed the morphological characteristics of fibroblasts. These blood-borne fibroblast-like cells express the common hematopoetic stem cell marker CD34 and might comprise another cell type of potential importance for immune regulation in hereditary demyelinating neuropathies.

Animals↗
PubMed2003

Macrophage response to peripheral nerve injury: the quantitative contribution of resident and hematogenous macrophages.

Whereas local microglial cells of the CNS rapidly respond to injury, little is known about the functional role of resident macrophages of the peripheral nervous system in nerve pathology. Using bone marrow chimeric rats, we recently identified individual resident endoneurial macrophages that rapidly became activated after nerve injury. However, the extent of local macrophage activation and its quantitative contribution to the total macrophage response is unknown. We now have created chimeric mice by transplanting bone marrow from green fluorescent protein (GFP)-transgenic mice into irradiated wild-type mice, allowing easy differentiation and quantification of hematogenous and resident endoneurial macrophages. After sciatic nerve crush injury, both GFP(-) and GFP(+) resident macrophages, the latter having undergone physiological turnover from the blood before injury, rapidly underwent morphological alterations and increased in number. Proliferating GFP(-) and GFP(+) resident macrophages were abundant and peaked 3 days after injury. A major lesion-induced influx of hematogenous macrophages with a disproportionate increase of GFP(+) macrophages was not observed until Day 4. Throughout all time points examined, GFP(-) resident macrophages were strikingly frequent, reaching maximum numbers 9.5-fold above baseline. There was also a notable proportion of GFP(-) resident endoneurial macrophages phagocytosing myelin and expressing major histocompatibility complex class II. Our results demonstrate for the first time that the rapid response of resident endoneurial macrophages to nerve injury is quantitatively important and that local macrophages contribute significantly to the total endoneurial macrophage pool during Wallerian degeneration.

Animals↗
PubMed2003

Autoimmunity in the peripheral nervous system.

Autoimmune disorders of the peripheral nervous system (PNS) comprise a heterogeneous group of diseases that result from an aberrant immune response. Most of these disorders present severe morbidity and, in some cases, mortality. Even those conditions that are self-limited may display severe disability and necessitate hospitalization. Although their etiology remains elusive, there is increasing knowledge of the pathophysiological mechanisms causing tissue dysfunction and structural damage. The discovery of several mediators that constitute the molecular mechanisms of cell-cell and cell-extracellular-matrix interactions has revealed insight into various aspects of the neuroimmune interaction. Classic animal models associated with new genetic approaches have further increased our comprehension of the molecular pathways that regulate inflammatory disorders of the nervous system. The aim of this review is to describe various types and functions of the principal molecular components of the neuroimmune interaction and their importance in the principal autoimmune disorders of the PNS. We also provide an extensive description of clinical and pathological features of autoimmune disorders of the PNS, along with diagnostic and therapeutic implications.

Animals↗
PubMed2002

Lesion response of long-term and recently immigrated resident endoneurial macrophages in peripheral nerve explant cultures from bone marrow chimeric mice.

Resident macrophages of the peripheral nervous system have recently been shown to respond rapidly to Wallerian degeneration before the influx of blood-derived macrophages. Because resident endoneurial macrophages are slowly but incompletely exchanged from the blood within 3 months, they could potentially comprise a heterogenous cell population consisting of long-term resident cells and more mobile cells undergoing turnover. We used bone marrow chimeric mice created by transplanting bone marrow from green fluorescent protein-transgenic mice into irradiated wildtype recipients to selectively analyse the response of these two resident macrophage populations to Wallerian degeneration in sciatic nerve explant cultures. In such nerves, recently immigrated macrophages exhibit green fluorescence whereas long-term resident macrophages do not. Studies in cultures from wildtype controls revealed rapid morphological changes of resident macrophages towards a bloated phenotype, a proliferative response resulting in a 3.7-fold increase of macrophage numbers over 2 weeks, and phagocytosis of myelin basic protein-immunoreactive myelin debris. When chimeric mice were analysed, both populations of resident endoneurial macrophages participated in morphological transformation, proliferation and phagocytosis. Quantitative studies revealed a stronger proliferative and phagocytic response in long-term resident endoneurial macrophages compared with recently immigrated macrophages. Our results point towards subtle, but not principal, differences between the two macrophage populations, which might indicate different stages of macrophage differentiation rather than the existence of entirely distinct endoneurial macrophage populations. The results further underline the versatility of resident endoneurial macrophages following peripheral nerve injury, which is reminiscent of the lesion response of microglial cells within the brain.

Animals↗