Remyelinating strategies for the treatment of multiple sclerosis

Demyelination is the pathological hallmark of multiple sclerosis (MS) lesions. The concept of remyelination has gained acceptance in recent years, but naturally occurring remyelination is incomplete. To improve repair processes, a number of strategies have been explored experimentally and clinical trials are being carried out. In principle, remyelination can be achieved by either promoting endogenous repair mechanisms or by providing an exogenous source of myelinating cells via transplantation. Both approaches have been successful in animal models of demyelination. Besides, many studies have elucidated principal mechanisms of oligodendrocyte biology and remyelination in the central nervous system (CNS). This progress in knowledge also allowed for more specific interventions. First clinical trials to enhance endogenous remyelination have been performed, unfortunately with disappointingly negative results. This illustrates that experimental data cannot be easily transferred to human disease, and more detailed knowledge on the regulatory mechanisms of remyelination in MS is required. Recently, the first MS patient received a transplant of autologous Schwann cells. Many other cell types are being studied experimentally, including stem cells. Despite the ethical problems associated with an embryonic cell source, new developments in stem cell biology indicate that adult stem cells or bone marrow-derived cells may substitute for embryonic cells in the future. In this review, we describe the current views on oligodendrocyte biology, myelination and remyelination, and focus on recent developments leading to reconstructing, remyelinating strategies in MS.     

Klarzelltumor der Lunge

Clear cell tumors of the lung are rare tumors composed of epithelioid HMB45 positive tumor cells. It has been proposed that clear cell tumors generate from perivascular epithelioid cells which are also found in renal angiomyolipoma. Due to its morphologic epithelioid features with clear cytoplasm the distinction from either primary or metastatic clear cell carcinoma is difficult. Usually clinical investigations do not lead to the final diagnosis so that only subsequent histological examination and immunophenotyping can establish the correct tumor classification. We describe the case of a 52 year old woman who underwent exploratory thoracotomy because of a lung mass in the right lower lobe. In frozen sections a solid trabecular tumor was diagnosed, paraffin histology and immunohistochemistry revealed a clear cell tumor of the lung. The difficulty of the correct diagnosis of the clear cell tumor of the lung in frozen sections is discussed as well as the differential diagnosis.     

Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis

 Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are chronic autoimmune-mediated diseases of the biliary tree, resulting in a loss of bile ducts. There are morphological features that clearly distinguish them from each other: in PBC, there is overt destruction of the bile ducts with disruption of the basement membrane; in PSC there is abundant periductular fibrosis with shrinkage and subsequent loss of the bile ducts. In order to see if the disparate histopathology is paralleled by different immunohistology we looked at a panel of epitopes on bile duct epithelia especially to see if biliary epithelial cells may present as targets for cell mediated immune respone. In PBC bile duct epithelial cells mostly expressed CD58 (lymphocyte function-associated antigen 3), CD80 (B7 BB1), and CD95 (Fas). In PSC, however, these epitopes were only expressed in a few examples to a lower degree. The respective effector T lymphocytes were positive for CD2 and CD28. Subtyping of the lymphocytes in the liver tissue further showed a predominance of CD4 positive T cells over CD8 cells up to 2-to-1 in both diseases. Determination of lymphocytes by cytokines to Th1 or Th2 subtype showed a majority of Th1 lymphocytes in PBC and PSC. We conclude that in PBC bile duct epithelial cells may display features of target cells of a T cell-mediated immune reaction with the Th1 cells predominating. In PSC other mechanisms of bile duct loss may play a role, since in this disease the majority of cells lack essential epitopes that constitute targets of cell mediated immunity. Received: 19 November 1996 / Accepted: 26 February 1997     

Selective breeding for extremes in open-field activity of mice entails a differentiation of hippocampal mossy fibers

The brains of mice selectively bred for differential locomotor activity in an open field (DeFrieset al., Behav. Genet. 8:3–13, 1978) were analyzed for selection-dependent changes in the size of synaptic fields at the midseptotemporal level of the hippocampus. Timm-stained areas of all hippocampal fields from both left and right hippocampi were measured on five horizontal sections from the midseptotemporal level. The sample included 25 mice from two replicate lines, each one consisting of a high (HI); a low (LO), and a control line (CTL). The main selection effect was an enlargement of the intrainfrapyramidal mossy fiber (IIP-MF) projection in both HI lines by about 70% compared to LO and CTL mice (p<.0001), while other mossy fiber fields did not show differences. These findings confirm that genetic variations of the IIP-MF projection influence hippocampal processes mediating exploratory activities. This article is part of a M.D. thesis submitted to the Medical Faculty of the University of Zürich by the first author. We are deeply saddened by her untimely death.     

Dissimilar background genes control susceptibility to autoimmune disease in the context of different MHC haplotypes: NOD.H-2(s) congenic mice are relatively resistant to both experimental autoimmune encephalomyelitis and type I diabetes

Nonobese diabetic (NOD) mice develop multi-organ autoimmune diseases, including type 1 diabetes. We hypothesized that backcrossing the MHC region from SJL (H-2(s)) mice, which have an endogenous PLP(139-151)-reactive repertoire, onto the background of autoimmune-prone NOD mice would result in a mouse strain that is highly susceptible to experimental autoimmune encephalomyelitis (EAE). Unexpectedly, although we detected an endogenous PLP(139-151) repertoire in the NOD.S mice, they did not develop spontaneous EAE and were relatively resistant to PLP(139-151)-induced EAE when compared to SJL mice. This resistance was associated with lower production of proinflammatory cytokines and a decreased expansion of PLP(139-151)-specific CD4(+) T cells after immunization and restimulation with PLP peptide in vitro. V(beta) chain usage among PLP(139-151)-reactive T cells differed between SJL and NOD.S mice. Furthermore, NOD.S mice were resistant to the development of insulitis and cyclophosphamide-induced diabetes, but not sialadenitis. Altogether, even though NOD mice develop spontaneous autoimmune diseases, they become relatively resistant to induction of EAE even when they express the EAE-permissive class II molecule I-A(s). Our data show that certain combinations of otherwise susceptibility-conferring MHC and non-MHC genes can mediate autoimmune-disease resistance when they are paired together. These findings do not support the "shared autoimmune gene" hypothesis.     

Endothelial and Hematopoietic Progenitor Cells (EPCs and HPCs): Hand in Hand Fate Determining Partners for Cancer Cells

Tumor growth and metastasis need new vessel formation by angiogenesis provided by mature endothelial cells and postnatal vasculogenesis provided by endothelial progenitor cells (EPCs). Emerging data suggest a coordinated interaction between EPCs and hematopoietic progenitor cells (HPCs) in these processes. The complexity of the mechanisms governing the new vessel formation by postnatal vasculogenesis has increased by new evidence that not only bone marrow derived EPCs and HPCs seem to be involved in this process but also local progenitors residing within the vascular wall are mobilized and activated to new vessel formation by tumor cells. This review attempts to bring these systemic and local players of postnatal vasculogenesis together and to highlight their role in tumor growth and mestastasis.     

Nuclear translocation of β‐catenin and decreased expression of epithelial cadherin in human papillomavirus‐positive tonsillar cancer: an early event in human papillomavirus‐related tumour progression?

Stenner M, Yosef B, Huebbers C U, Preuss S F, Dienes H‐P, Speel E‐J M, Odenthal M & Klussmann J P (2011) Histopathology 58 , 1117–1126 Nuclear translocation of β‐catenin and decreased expression of epithelial cadherin in human papillomavirus‐positive tonsillar cancer: an early event in human papillomavirus‐related tumour progression? Aims: High‐risk human papillomaviruses (HPVs) constitute an important risk factor for tonsillar cancer. This study describes changes in cell adhesion molecules during metastasis of HPV‐related and HPV‐unrelated tonsillar carcinomas. Methods and results: We examined 48 primary tonsillar carcinoma samples (25 HPV‐16 DNA‐positive, 23 HPV‐16 DNA‐negative) and their respective lymph node metastases for their HPV status and for the expression of p16, epithelial cadherin (E‐cadherin), β‐catenin, and vimentin. A positive HPV‐specific polymerase chain reaction finding correlated significantly with p16 overexpression in both primary tumours and their metastases (P < 0.0001 for both). In HPV‐unrelated carcinomas, the expression of E‐cadherin was significantly lower in metastases than in primary tumours (P < 0.001). In contrast, the expression of nuclear β‐catenin was significantly higher in metastases than in primary tumours (P = 0.016). In HPV‐related carcinomas, nuclear localization of β‐catenin expression was already apparent in primary tumours (P = 0.030). The expression of vimentin significantly correlated with the grading of the primary tumour (P = 0.021). Conclusions: Our data indicate that the down‐regulation of E‐cadherin and the up‐regulation of nuclear β‐catenin expression might be crucial steps during tumour progression of tonsillar carcinomas, being already present in primary tumours in HPV‐driven carcinomas, but becoming apparent in HPV‐unrelated tumours later in the process of metastasis.     

Combined measurement of event-related potentials (ERPs) and fMRI

The study investigates the possibility of combined recording event-related potentials (ERPs) and functional MRI (fMRI). Visual evoked potentials (VEPs) were elicited by an alternating black and white checkerboard, which was presented blockwise outside the static 1.5 T magnetic field and during an echo planar imaging (EPI). An fMRI sequence with a time window for interleaved EEG-measurement and a measurement protocol which reduces pulse artifacts and vibrations was used. Thus, during an EPI sequence, it was possible to detect VEPs which had the same structure and latencies as VEPs outside the magnetic field and which corresponded well with the observed activated areas of the visual cortex.     

Gene therapy in the transplantation of allogeneic organs and stem cells

Most of the current hematopoietic stem cell (HSC) -directed gene therapy applications have focused on the replacement of defective or deficient genes in an autologous setting. More recently HSC gene therapy applications have also included the enhancement or improvement of HSC features. Allogeneic HSCs have been used to facilitate and improve allogeneic transplantation and to achieve tolerance to transplanted cells, tissues or organs. Different gene transfer approaches addressing a variety of immunomodulatory mediators contributing to graft tolerance or immunological ignorance may have a critical role in improving long-term graft survival. Allogeneic tissues are frequently recognized by allospecific T cells as foreign and are rapidly rejected in the absence of immunosuppression. The higher susceptibility to cancer and infectious diseases of immunosuppressed patients led to investigation of new therapies to induce graft-specific tolerance. Peripheral tolerance to allogeneic grafts can be achieved by a variety of mechanisms including clonal deletion, suppression caused by regulatory T cells and anergy induction associated with microchimerism effect. In the last decades, potential candidates to confer allograft protection were identified. In this review, we summarize ongoing strategies and developments in genetic manipulation of cells, tissues and organs for allogeneic transplantation including modulating the effector arm of the immune response.