Glial grafting for demyelinating disease

Remyelination of demyelinated central nervous system (CNS) axons is considered as a potential treatment for multiple sclerosis, and it has been achieved in experimental models of demyelination by transplantation of pro-myelinating cells. However, the experiments undertaken have not addressed the need for tissue-type matching in order to achieve graft-mediated remyelination since they were performed in conditions in which the chance for graft rejection was minimized. This article focuses on the factors determining survival of allogeneic oligodendrocyte lineage cells and their contribution to the remyelination of demyelinating CNS lesions. The immune status of the CNS as well as the suitability of different models of demyelination for graft rejection studies are discussed, and ways of enhancing allogeneic oligodendrocyte-mediated remyelination are presented. Finally, the effects of glial graft rejection on host remyelination are described, highlighting the potential benefits of the acute CNS inflammatory response for myelin repair.     

Characterization of chemokines and their receptors in the central nervous system: physiopathological implications

Chemokines represent key factors in the outburst of the immune response, by activating and directing the leukocyte traffic, both in lymphopoiesis and in immune surveillance. Neurobiologists took little interest in chemokines for many years, until their link to acquired immune deficiency syndrome-associated dementia became established, and thus their importance in this field has been neglected. Nevertheless, the body of data on their expression and role in the CNS has grown in the past few years, along with a new vision of brain as an immunologically competent and active organ. A large number of chemokines and chemokine receptors are expressed in neurons, astrocytes, microglia and oligodendrocytes, either constitutively or induced by inflammatory mediators. They are involved in many neuropathological processes in which an inflammatory state persists, as well as in brain tumor progression and metastasis. Moreover, there is evidence for a crucial role of CNS chemokines under physiological conditions, similar to well known functions in the immune system, such as proliferation and developmental patterning, but also peculiar to the CNS, such as regulation of neural transmission, plasticity and survival.     

胚胎海马伞移植物对成年大鼠海马胆碱能纤维生长的引导效应

在胚胎和新生的中枢神经系统(CNS)内,发育中的纤维束通道能引导轴突的生长。为了了解发育中的纤维束通道能否引导成年CNS轴突的生长,将胚胎海马伞移植到成年大鼠的海马,两周后,用AChE组织化学方法检查移植物内的胆碱能纤维。结果如下:在胚胎的海马伞移植物内出现大量的胆碱能纤维,但在成年的海马伞移植物内没有宿主的胆碱能纤维长入;如果在移植胚胎海马伞的同时,切断宿主的海马伞-穹窿通路,则在胚胎移植物和宿主海马内均无胆碱能纤维;将胚胎海马伞作成悬浮液进行移植,在移植部位,仅能看到少数长的胆碱能纤维;但是若把胚胎海马伞的组织碎片粘附在硝化纤维素滤纸条周围,再移植到成年大鼠海马内,来自宿主海马的大量胆碱能纤维被吸引围绕着滤纸条并沿其表面生长。结果似乎表明:胚胎海马伞或胚胎海马伞碎片都能有效引导宿主海马胆碱能纤维的生长。因此,胚胎海马伞和其它发育中的CNS纤维束通道可能是引导成年CNS轴突生长的良好天然基质。     

Alternatively Activated Macrophages in Spinal Cord Injury and Remission: Another Mechanism for Repair?

Tissues within the central nervous system (CNS) have generally been regarded as immunologically privileged. However, in recent decades, it has been shown that immune reactions in the CNS continuously occur via various types of inflammation following autoimmune diseases and mechanical insults such as spinal cord injury (SCI). Among the various inflammatory cells associated with CNS disease, activated macrophages are classically known to induce detrimental consequences that are mediated by the secretion of pro-inflammatory molecules. Alternatively activated macrophages have recently been shown to modulate various types of CNS inflammation, including SCI. This review summarizes the potential roles of alternatively activated macrophages in the course of CNS inflammation in rodent SCI models.     

The blood-brain barrier, chemokines and multiple sclerosis

The infiltration of leukocytes into the central nervous system (CNS) is an essential step in the neuropathogenesis of multiple sclerosis (MS). Leukocyte extravasation from the bloodstream is a multistep process that depends on several factors including fluid dynamics within the vasculature and molecular interactions between circulating leukocytes and the vascular endothelium. An important step in this cascade is the presence of chemokines on the vascular endothelial cell surface. Chemokines displayed along the endothelial lumen bind chemokine receptors on circulating leukocytes, initiating intracellular signaling that culminates in integrin activation, leukocyte arrest, and extravasation. The presence of chemokines at the endothelial lumen can help guide the movement of leukocytes through peripheral tissues during normal immune surveillance, host defense or inflammation. The expression and display of homeostatic or inflammatory chemokines therefore critically determine which leukocyte subsets extravasate and enter the peripheral tissues. Within the CNS, however, infiltrating leukocytes that cross the endothelium face additional boundaries to parenchymal entry, including the abluminal presence of localizing cues that prevent egress from perivascular spaces. This review focuses on the differential display of chemokines along endothelial surfaces and how they impact leukocyte extravasation into parenchymal tissues, especially within the CNS. In particular, the display of chemokines by endothelial cells of the blood brain barrier may be altered during CNS autoimmune disease, promoting leukocyte entry into this immunologically distinct site. Recent advances in microscopic techniques, including two-photon and intravital imaging have provided new insights into the mechanisms of chemokine-mediated capture of leukocytes within the CNS.     

The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus

Inflammation is an integral part of the body's physiological repair mechanism, unless it remains unresolved and becomes pathological, as evident in the progressive nature of neurodegeneration. Based on studies from outside the central nervous system (CNS), it is now understood that the resolution of inflammation is an active process, which is dependent on well‐orchestrated innate and adaptive immune responses. Due to the immunologically privileged status of the CNS, such resolution mechanism has been mostly ignored. Here, we discuss resolution of neuroinflammation as a process that depends on a network of immune cells operating in a tightly regulated sequence, involving the brain's choroid plexus (CP), a unique neuro‐immunological interface, positioned to integrate signals it receives from the CNS parenchyma with signals coming from circulating immune cells, and to function as an on‐alert gate for selective recruitment of inflammation‐resolving leukocytes to the inflamed CNS parenchyma. Finally, we propose that functional dysregulation of the CP reflects a common underlying mechanism in the pathophysiology of neurodegenerative diseases, and can thus serve as a potential novel target for therapy.     

Vascular tissue engineering: the next generation

It is the ultimate goal of tissue engineering: an autologous tissue engineered vascular graft (TEVG) that is immunologically compatible, nonthrombogenic, and can grow and remodel. Currently, native vessels are the preferred vascular conduit for procedures such as coronary artery bypass (CABG) or peripheral bypass surgery. However, in many cases these are damaged, have already been harvested, or are simply unusable. The use of synthetic conduits is severely limited in smaller diameter vessels due to increased incidence of thrombosis, infection, and graft failure. Current research has therefore energetically pursued the development of a TEVG that can incorporate into a patient's circulatory system, mimic the vasoreactivity and biomechanics of the native vasculature, and maintain long-term patency.     

The blood cerebrospinal fluid barrier orchestrates immunosurveillance,immunoprotection, and immunopathology in the central nervous system

Once characterized as an immune privileged area, recent scientific advances have demonstrated that the central nervous system (CNS) is both immunologically active and a specialized site. The anatomical and cellular features of the brain barriers, the glia limitans, and other superficial coverings of the CNS endow the brain with specificity for immune cell entry and other macro- and micro-elements to the brain. Cellular trafficking via barriers comprised of tightly junctioned non-fenestrated endothelium or tightly regulated fenestrated epithelium results in different phenotypic and cellular changes in the brain, that is, inflammatory versus regulatory changes. Based on emerging evidence, we described the unique ability of the blood cerebrospinal fluid barrier (BCSFB) to recruit, skew, and suppress immune cells. Additionally, we sum up the current knowledge on both cellular and molecular mechanisms governed by the choroid plexus and the cerebrospinal fluid at the BCSFB for immunosurveillance, immunoprotection, and immunopathology.     

Impaired recall of CD8 memory T cells in immunologically privileged tissue

Foreign Ags that enter immunologically privileged sites such as the eye, brain, and testis persist for an extended period of time, whereas the same Ags are rapidly eliminated at conventional sites. Immune privilege, therefore, provides unwanted refuge for pathogens and tumor cells but is beneficial for the survival of allogeneic grafts. In this study, we asked whether memory T cells can eliminate foreign Ags deposited at an immunologically privileged site by studying CD8 memory T cell-mediated rejection of pancreatic islet allografts placed either in the testis (a privileged organ) or under the kidney capsule (a nonprivileged site) of diabetic mice. We found that CD8 memory T cells reject intratesticular grafts at a significantly slower rate than the rejection of intrarenal grafts. Delayed graft rejection in the testis was not due to reduced homing or proliferation of memory T cells but due to their increased apoptosis at that site. Apoptosis was mediated by the combined actions of two TNFR family members that are up-regulated on activated memory T cells, Fas, and CD30. Therefore, memory T cells survey immunologically privileged tissues but are subject to the immunosuppressive mechanisms present at these sites.     

Immunity or tolerance: opposite outcomes of microchimerism from skin grafts

Solid organ transplants contain small numbers of leukocytes that can migrate into the host and establish long-lasting microchimerism. Although such microchimerism is often associated with graft acceptance and tolerance, it has been difficult to demonstrate a true causal link. Using skin from mutant mice deficient for leukocyte subsets, we found that donor T-cell chimerism is a 'double-edged sword' that can result in very different outcomes depending on the host's immunological maturity and the antigenic disparities involved. In immunologically mature hosts, chimerism resulted in immunity and stronger graft rejection. In immature hosts, it resulted in tolerance to the chimeric T cells, but not to graft antigens not expressed by the chimeric cells. Clinical efforts aimed at augmenting chimerism to induce tolerance must take into account the maturation state of host T cells, the type of chimerism produced by each organ and the antigenic disparities involved, lest the result be increased rejection rather than tolerance.     

Connecting cytokines and brain: a review of current issues

Cytokines have been a multi-disciplinary research focus for over 2 decades. To date, there have been more than 15,000 articles published concerning the relationship between cytokines and the central nervous system (CNS). Over half of these articles have been published in the last 5 years. From such vast number of studies, two major topics emerge as the critical issues: 1) how do cytokines modulate the functions of the CNS? 2) what is the role of cytokines in the pathogenesis of neurological diseases? Thus far, it has been clearly established that cytokines can alter the functions of the CNS in specific manners, invoking CNS-controlled autonomic, neuroendocrine, and behavioral responses. Induced expression of cytokines has also been found in the CNS during brain injury and infection, contributing to the immunological processes at this "immunologically privileged" site. Furthermore, increasing evidence points to the potential involvement of cytokines in the induction and modulation of an array of neurological diseases ranging from Alzheimer's disease to chronic fatigue syndrome. Despite such progress, however, substantial obstacles remain for both the basic understanding and the potential clinical exploitation of how cytokines interact with CNS. In this review, we will attempt to synopsize the current theories and evidence regarding the answers to the above-mentioned critical questions. These issues will be reviewed not only in isolation, as most of the original reports focused on only one of the questions, but also in parallel such that inter-issue insights may be gained.     

脐带血来源干细胞神经分化的研究进展

中枢神经系统损伤后的自身修复能力有限,因而研究者致力于寻找一种合适的细胞进行移植以代替受损的神经细胞修复神经损伤。近年来的研究表明,脐带血干细胞能够在体外诱导条件下向神经样细胞分化,并在动物体内实验中促进神经损伤的恢复,有可能作为一种有效的细胞资源,应用于人类中枢神经系统疾病的细胞替代治疗以及神经保护与支持。     

Intra-peritoneal Injection of Polyclonal Anti-Interferon Alpha Antibodies Cross the Blood Brain Barrier and Neutralize Interferon Alpha

The central nervous system (CNS) is known to be an immunologically privileged organ in the body largely because the blood brain barrier (BBB) prevents the flow of large molecules, proteins, and cells from crossing into the CNS from the periphery. These restrictive properties of the BBB have made it difficult to treat CNS diseases. In this study, mice were infected intracranially (i.c.) with Sindbis virus (SV) and then treated either i.c. or intraperitoneally (i.p.) with neutralizing antibodies against interferon alpha (IFNα). SV infected control mice received i.p. saline. Antibodies against mouse IFNα were detected in the brain tissue of mice that received i.p. and i.c. injections of the antibody. ELISA analysis showed that both i.c. and i.p. antibody treated mice had significantly decreased levels of IFNα in the brain tissue. Also, mice that received IFNα neutralizing antibodies showed decreased presence of protein kinase R (PKR) measured by immunohistochemical densitometry, indicating the antibody successfully inhibited IFNα. The data shows that antibodies are capable of crossing the BBB and inhibiting IFNα, indicating that it is possible to target molecules of interest in the CNS with peripheral antibody treatment.     

Rejection of fetal neocortical neural transplants by H-2 incompatible mice

In order to examine questions concerning immunologic privilege of the central nervous system, we placed neocortical transplants into cerebral ventricles of mice. We compared the fates of transplants between fully H-2 compatible (isografts) and H-2 incompatible (allografts) animals. Histologic evaluation comparing animals from iso- and allograft groups revealed significant differences in the number of inflammatory cells and in the degree of necrosis within the grafts. Response to allografted tissue within the brain mimics that seen in several immune-mediated diseases of the nervous system in that neurons appear to be selectively spared. Only upon subsequent stimulation of the host's immune system with an orthotopic skin graft bearing the major histocompatibility complex antigens of the neural graft are neurons destroyed. Immunohistochemical evaluation revealed that the inflammatory cell infiltrates in and around the allografts were composed of Lyt-2+, L3T4+, and Mac-1+ cells. In addition, Ia+ endothelial cells as well as Ia+ parenchymal CNS cells were found in both donor and host tissue of allografted animals. Hence, H-2 incompatible neural tissue transplanted to the CNS is recognized and rejected by the immune system of the recipient animal. The cellular infiltrates seen within the first weeks to months following transplantation of allogeneic CNS tissue resemble those seen in other allografts undergoing rejection. We conclude that the CNS is not unconditionally privileged as either a transplant site or as a source of transplanted tissue.     

Foxp3+ regulatory T cells control persistence of viral CNS infection

We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified) mice and recombinant measles virus (MV). Using this model infection we investigated the role of regulatory T cells (Tregs) as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4(+) CD25(+) Foxp3(+) Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8(+) T cells predominantly recognising the H-2D(b)-presented viral hemagglutinin epitope MV-H(22-30) (RIVINREHL) were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p.) application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT) in DEREG (depletion of regulatory T cells)-mice induced an increase of virus-specific CD8(+) effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.     

T cell subsets in allograft rejection. In situ characterization of T cell subsets in human skin allografts by the use of monoclonal antibodies

We have provided evidence that both major T cell subsets, T4-positive (helper/inducer) and T8-positive (cytotoxic/suppressor), infiltrate human skin allografts. Overall, and in the graft dermis and graft bed, T4-positive cells were predominant (1.5 to 3 times more numerous than T8-positive cells). In contrast, T8-positive cells were relatively more numerous in the epidermis and hair follicles. Rejection probably proceeded by two apparently independent pathways: 1) direct contact killing of graft epithelial cells, presumably by immunologically specific T8-positive cytotoxic cells, and 2) injury of microvascular endothelium of both the graft and graft bed with secondary graft infarction. Although important in first set skin allograft rejection, the mechanism of the second type of killing is uncertain. T4-positive cells were probably involved, as evidenced by their greater numbers; furthermore, studies in mice have shown that transfused helper/inducer cells are able to effect first-set skin graft rejection. It remains to be determined whether T4-positive cells act alone or cooperate with other cells to destroy vessels and bring about graft rejection. Langerhans cells were recognized in epithelial and dermal compartments of both allografts and autografts by their reactivity with anti-T6 and anti-Ia antibodies. We could not determine whether such cells in allografts were of host or donor origin.     

Cellular immune competence in the human fetus

Thymocytes from eight human fetuses of gestational ages 13–28 weeks were studied in mixed lymphocyte cultures. Seven of the eight thymocyte preparations recognized and responded to foreign histocompatibility loci on normal adult peripheral blood lymphocytes. Thymocytes from human fetuses as young as 13 weeks' gestation appear to be capable of initiating this immunologic response. These fetal cells are to be considered immunologically mature and potentially capable of initiating a graft vs host reaction if transplanted into immunoincompetent recipients.     

A Xenograft Mantle Transplantation Technique for Producing a Novel Pearl in an Akoya Oyster Host

The brightness and color of pearls varies among different pearl-producing shellfish and have been a source of human fascination since ancient times. When produced through cultivation, the characteristics and quality of a pearl depend on the kind of shellfish used and also the transplanted mantle graft. This suggests that the Akoya pearl oyster, which is generally used in Japan for pearl culturing, can produce different kinds of pearl through the use of mantles from different species of shellfish. However, a transplanted heterogeneous mantle would be rejected by the immune system of the Akoya oyster. We have therefore developed a new method to suppress the Akoya immune system that archives immune tolerance to other shellfish. It is generally known that small quantities of antigens can be used to produce archived immunological tolerance in a clinical setting. We successfully suppressed the Akoya pearl oyster immune response against a Mabé pearl oyster graft through repeat injections of mantle homogenates. We then transplanted a Mabé pearl oyster mantle graft into the immunologically tolerant Akoya pearl oyster and obtained a Mabé pearl from an Akoya pearl oyster. Our new technique thus makes the production of novel and different pearls in the Akoya possible. We believe that this has significant future potential for the advancement of the pearl industry.