Development of neural repair therapy for chronic spinal cord trauma: soluble Nogo receptor decoy from discovery to clinical trial.

PURPOSE OF REVIEW: After traumatic spinal cord injury (SCI), neurological deficits persist due to the disconnection of surviving neurons. While repair of connectivity may restore function, no medical therapy exists today.This review traces the development of the neural repair-based therapeutic AXER-204 from animal studies to the recent clinical trial for chronic cervical SCI. RECENT FINDINGS: Molecular studies reveal a Nogo-66 Receptor 1 (NgR1, RTN4R) pathway inhibiting axon regeneration, sprouting, and plasticity in the adult mammalian central nervous system (CNS). Rodent and nonhuman primate studies demonstrate that the soluble receptor decoy NgR(310)ecto-Fc or AXER-204 promotes neural repair and functional recovery in transection and contusion SCI. Recently, this biological agent completed a first-in-human and randomized clinical trial for chronic cervical SCI. The intervention was safe and well tolerated. Across all participants, upper extremity strength did not improve with treatment. However, posthoc and biomarker analyses suggest that AXER-204 may benefit treatment-naïve patients with incomplete SCI in the chronic stage. SUMMARY: NgR1 signaling restricts neurological recovery in animal studies of CNS injury. The recent clinical trial of AXER-204 provides encouraging signals supporting future focused trials of this neural repair therapeutic. Further, AXER-204 studies provide a roadmap for the development of additional and synergistic therapies for chronic SCI.

Dynamic induction of the myelin-associated growth inhibitor Nogo-A in perilesional plasticity regions after human spinal cord injury.

The myelin-associated inhibitor Nogo-A (Reticulon 4, RTN4) restricts axonal outgrowth, plasticity, and neural circuitry formation in experimental models of spinal cord injury (SCI) and is targeted in clinical interventions starting treatment within 4 weeks post-SCI. Specifically, Nogo-A expressed by oligodendroglia restricts compensatory neurite sprouting. To interrogate the hypothesis of an inducible, lesion reactive Nogo-A expression over time, we analyzed the spatiotemporal Nogo-A expression at the spinal lesion core (region of tissue necrosis and axonal damage/pruning) and perilesional rim (region of plasticity formation). Spinal cord specimens of SCI subjects (n = 22) were compared to neuropathologically unaltered controls (n = 9). Nogo-A expression was investigated ranging from acute (0-3 days), early subacute (4-21 days), late subacute (22-90 days) to early chronic-chronic (91 days to 1.5 years after SCI) stages after SCI. Nogo-A expression in controls is confined to motoneurons in the anterior horn and to oligodendrocytes in gray and white matter. After SCI, the number of Nogo-A+ and TPPP/p25+ oligodendrocytes (i) inclined at the organizing perilesional rim specifically, (ii) increased further over time, and (iii) peaked at chronic stages after SCI. By contrast, at the lesion core, the number of Nogo-A+ and TPPP/p25+ oligodendrocytes did not increase. Increasing numbers of Nogo-A+ oligodendrocytes coincided with oligodendrogenesis corroborated by Nogo-A coexpression of Ki67+ , TPPP/p25+ proliferating oligodendrocytes. Nogo-A oligodendrocyte expression emerges at perilesional (plasticity) regions over time and suggests an extended therapeutical window for anti-Nogo-A pathway targeting interventions beyond 4 weeks in patients after SCI.

Inosine augments the effects of a Nogo receptor blocker and of environmental enrichment to restore skilled forelimb use after stroke.

Stroke is the leading cause of disability in much of the world, with few treatment options available. Following unilateral stroke in rats, inosine, a naturally occurring purine nucleoside, stimulates the growth of projections from the undamaged hemisphere into denervated areas of the spinal cord and improves skilled use of the impaired forelimb. Inosine augments neurons' intrinsic growth potential by activating Mst3b, a component of the signal transduction pathway through which trophic factors regulate axon outgrowth. The present study investigated whether inosine would complement the effects of treatments that promote plasticity through other mechanisms. Following unilateral stroke in the rat forelimb motor area, inosine combined with NEP1-40, a Nogo receptor antagonist, doubled the number of axon branches extending from neurons in the intact hemisphere into the denervated side of the spinal cord compared with either treatment alone, and restored rats' level of skilled reaching using the impaired forepaw to preoperative levels. Similar functional improvements were seen when inosine was combined with environmental enrichment (EE). The latter effect was associated with changes in gene expression in layer 5 pyramidal neurons of the undamaged cortex well beyond those seen with inosine or EE alone. Inosine is now in clinical trials for other indications, making it an attractive candidate for the treatment of stroke patients.

Management strategies for acute spinal cord injury: current options and future perspectives.

PURPOSE OF REVIEW: Spinal cord injury is a devastating acute neurological condition with loss of function and poor long-term prognosis. This review summarizes current management strategies and innovative concepts on the horizon. RECENT FINDINGS: The routine use of steroids in patients with spinal cord injuries has been largely abandoned and considered a 'harmful standard of care'. Prospective trials have shown that early spine stabilization within 24  h results in decreased secondary complication rates. Neuronal plasticity and axonal regeneration in the adult spinal cord are limited due to myelin-associated inhibitory molecules, such as Nogo-A. The experimental inhibition of Nogo-A ameliorates axonal sprouting and functional recovery in animal models. SUMMARY: General management strategies for acute spinal cord injury consist of protection of airway, breathing, oxygenation and control of blood loss with maintenance of blood pressure. Unstable spine fractures should be stabilized early to allow unrestricted mobilization of patients with spinal cord injuries and to decrease preventable complications. Steroids are largely considered obsolete and have been abandoned in clinical guidelines. Nogo-A represents a promising new pharmacological target to promote sprouting of injured axons and restore function. Prospective clinical trials of Nogo-A inhibition in patients with spinal cord injuries are currently under way.

Specific T-cell proliferation to myelin peptides in relapsing-remitting multiple sclerosis.

BACKGROUND: The identification of major immunogenic peptides in multiple sclerosis (MS) is of great importance for the development of antigen-specific therapies. Cellular reactivity against a selected mix of seven myelin peptides was evaluated in vitro. The evolution of this reactivity over time and its correlation with clinical variables was also analysed. MATERIAL AND METHODS: Forty-two patients with MS, 15 with other demyelinating diseases and 40 healthy donors (HD) were studied. Cell proliferation was measured by 3[H] thymidine incorporation into samples obtained at 0, 3, 6 and 12months of MS patient follow-up. RESULTS: A positive reaction to the peptide mix was detected in 31 of the 42 patients (74%), 12 of the 40 HD (30%) and 6 of the 15 (40%) patients with other demyelinating diseases. Patients with positive proliferation had greater disability (EDSS score, 3 [1-5.5] vs. 1.0[1-2], P=0.021), higher number of relapses (7±4.1 vs. 3±1.2, P<0.001) and shorter time since the last relapse (9±7.5 vs. 32±12.3months, P=0.036). After 12months of follow-up, cell reactivity was maintained in 33 patients (78%). CONCLUSION: A high percentage of patients exhibit a significant and maintained reactivity to myelin peptides over time. Therefore, this mix may be useful as a source of antigen in the development of protocols aimed at inducing specific tolerance in MS.

Neuroprotective effects of NEP1-40 and fasudil on Nogo-A expression in neonatal rats with hypoxic-ischemic brain damage.

The hypoxic-ischemic encephalopathy caused by peripartum asphyxia is a serious disease in newborn infants, and effective therapies need to be developed to reduce injury-related disorders. We evaluated the effects of NEP1-40 and fasudil on Nogo-A expression in neonatal hypoxic-ischemic brain damage (HIBD) rats. Seven-day-old Wistar rats were randomly divided into control, HIBD, NEP1-40, and fasudil groups. NEP1-40 and fasudil groups were injected intraperitoneally with these compounds. Rat brains at 6, 24, 72 h, and 7 days after HIBD were collected to determine histopathological damage and the expression levels of Nogo-A. Histopathological damage was reduced in NEP1-40 and fasudil groups compared with the untreated HIBD group. The expression of Nogo-A in the HIBD group was significantly higher than that in control, NEP1-40 and fasudil groups at the same times. Compared with the fasudil group, the expression levels of Nogo-A were significantly reduced in the NEP1-40 group. We conclude that NPE1-40 and fasudil have potential for neuroprotective effects in the neonatal rat HIBD model, mediated by inhibiting Nogo-A/ Rho pathways.

Early detection of the chemical changes occurring during the induction and prevention of autoimmune-mediated demyelination detected by FT-IR imaging.

Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Despite progress in understanding immunogenetic aspects of this disease, the mechanisms involved in lesion formation are unknown. To gain new insights into the neuropathology of MS, we used an innovative integration of Fourier transform infrared (FT-IR) microspectroscopy, bioinformatics, and a synchrotron light source to analyze macromolecular changes in the CNS during the course and prevention of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. We report that subtle chemical and structural changes not observed by conventional histology were detected before the onset of clinical signs of EAE. Moreover, trained artificial neural networks (ANNs) could discriminate, with excellent sensitivity and specificity, pathology from surrounding tissues and the early stage of the disease progression. Notably, we show that this novel measurement platform can detect characteristic differences in biochemical composition of lesion pathology in animals partially protected against EAE by vaccination with Nogo-A, an inhibitor of neural outgrowth, demonstrating the potential for automated screening and evaluation of new therapeutic agents.

Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis.

The role of epitope spreading in the pathology of relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) was examined. Using peripherally induced immunologic tolerance as a probe to analyze the neuropathologic T cell repertoire, we show that the majority of the immunopathologic reactivity during the acute phase of R-EAE in SJL/J mice induced by active immunization with the intact proteolipid (PLP) molecule is directed at the PLP139-151 epitope and that responses to secondary encephalitogenic PLP epitopes may contribute to the later relapsing phases of disease. Intermolecular epitope spreading was demonstrated by showing the development of T cell responses to PLP139-151 after acute disease in mice in which R-EAE was initiated by the transfer of T cells specific for the non-cross-reactive MBP84-104 determinant. Intramolecular epitope spreading was demonstrated by showing that endogenous host T cells specific for a secondary encephalitogenic PLP epitope (PLP178-191) are demonstrable by both splenic T cell proliferative and in vivo delayed-type hypersensitivity responses in mice in which acute central nervous system damage was initiated by T cells reactive with the immunodominant, non-cross-reactive PLP139-151 sequence. The PLP178-191-specific responses are activated as a result of and correlate with the degree of acute tissue damage, since they do not develop in mice tolerized to the initiating epitope before expression of acute disease. Most importantly, we show that the PLP178-191-specific responses are capable of mediating R-EAE upon adoptive secondary transfer to naive recipient mice. Furthermore, induction of tolerance to intact PLP (which inhibits responses to both the initiating PLP139-151 epitope and to the PLP178-191 epitope) after the acute disease episode is sufficient to prevent relapsing disease. These results strongly support a contributory role of T cell responses to epitopes released as a result of acute tissue damage to the immunopathogenesis of relapsing clinical episodes and have important implications for the design of antigen-specific immunotherapies for the treatment of chronic autoimmune disorders in humans.

Modulation of MS-like disease by a multi epitope protein is mediated by induction of CD11c+CD11b+Gr1+ myeloid-derived dendritic cells.

Specific neutralization of the pathogenic autoimmune cells is the ultimate goal in therapy of Multiple Sclerosis (MS). However, the pathogenic autoimmunity in MS, can be directed against several major target antigens, and therefore targeting pathogenic T-cells directed against a single target antigen is unlikely to be effective. To overcome this multiplicity and the potential complexity of pathogenic autoreactivities in MS, we have put forward the concept of concomitant multi-antigen/multi-epitope targeting as, a conceivably more effective approach to immunotherapy of MS. We constructed an (Experimental Autoimmune Encephalomeylitis (EAE)/MS-related synthetic human Target Autoantigen Gene (MS-shMultiTAG) designed to encode in tandem only EAE/MS related epitopes of all known encephalitogenic proteins. The MS-related protein product (designated Y-MSPc) was immunofunctional and upon tolerogenic administration, it effectively suppressed and reversed EAE induced by a single encephalitogenic protein. Furthermore, Y-MSPc also fully abrogated the development of "complex EAE" induced by a mixture of five encephalitogenic T-cell lines, each specific for a different encephalitogenic epitope of MBP, MOG, PLP, MOBP and OSP. Strikingly, Y-MSPc was consistently more effective than treatment with the single disease-specific peptide or with the peptide cocktail, both in suppressing the development of "classical" or "complex" EAE and in ameliorating ongoing disease. Overall, the modulation of EAE by Y-MSPc was associated with anergizing the pathogenic autoreactive T-cells, downregulation of Th1/Th17 cytokine secretion and upregulation of TGF-ß secretion. Moreover, we show that both suppression and treatment of ongoing EAE by tolerogenic administration of Y-MSPc is associated also with a remarkable increase in a unique subset of dendritic-cells (DCs), CD11c+CD11b+Gr1+-myeloid derived DCs in both spleen and CNS of treated mice. These DCs, which are with strong immunoregulatory characteristics and are functional in down-modulation of MS-like-disease displayed increased production of IL-4, IL-10 and TGF-ß and low IL-12. Functionally, these myeloid DCs suppress the in-vitro proliferation of myelin-specific T-cells and more importantly, the cells were functional in-vivo, as their adoptive transfer into EAE induced mice resulted in strong suppression of the disease, associated with a remarkable induction of CD4 + FoxP3+ regulatory cells. These results, which highlight the efficacy of "multi-epitope-targeting" agent in induction of functional regulatory CD11c+CD11b+Gr1+myeloid DCs, further indicate the potential role of these DCs in maintaining peripheral tolerance and their involvement in downregulation of MS-like-disease.

The NCAM-derived P2 peptide facilitates recovery of cognitive and motor function and ameliorates neuropathology following traumatic brain injury.

The neural cell adhesion molecule (NCAM) plays a crucial role during development and regeneration of the nervous system, mediating neuronal differentiation, survival and plasticity. Moreover, NCAM regulates learning and memory. A peptide termed P2, corresponding to a 12-amino-acid sequence in the second immunoglobulin (Ig)-like module of NCAM, represents the natural cis-binding site for the first NCAM Ig module. The P2 peptide targets NCAM, thereby inducing a number of intracellular signaling events leading to the stimulation of neurite outgrowth and promotion of neuronal survival in vitro. The present study evaluated the effect of the P2 peptide on functional and histological outcomes following traumatic brain injury inflicted by a cortical cryogenic lesion. Lesioned rats were injected subcutaneously with P2 peptide, 5 mg/kg daily for 15 days beginning 2 h after injury. This treatment significantly improved postlesion recovery of motor and cognitive function, reduced neuronal degeneration, protected cells against oxidative stress, and increased reactive astrogliosis and neuronal plasticity in the sublesional area. P2 appeared rapidly in blood and cerebrospinal fluid after subcutaneous administration and remained detectable in blood for up to 5 h. The results suggest that P2 has therapeutic potential for the treatment of traumatic brain injury.

Nogo-66 receptor antagonist peptide (NEP1-40) administration promotes functional recovery and axonal growth after lateral funiculus injury in the adult rat.

OBJECTIVE: The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal axons and recovery of motor function following a dorsal hemisection. The authors used a similar design to examine recovery and repair after a lesion that interrupts the rubrospinal tract (RST). METHODS: Rats received a lateral funiculotomy at C4 and NEP1-40 or vehicle was delivered to the cervical spinal cord for 4 weeks. Outcome measures included motor and sensory tests and immunohistochemistry. RESULTS: Gait analysis showed recovery in the NEP1-40-treated group compared to operated controls, and a test of forelimb usage also showed a beneficial effect. The density of labeled RST axons increased ipsilaterally in the NEP1-40 group in the lateral funiculus rostral to the lesion and contralaterally in both gray and white matter. Thus, rubrospinal axons exhibited diminished dieback and/or growth up to the lesion site. This was accompanied by greater density of 5HT and calcitonin gene-related peptide axons adjacent to and into the lesion/matrix site in the NEP1-40 group. CONCLUSIONS: NgR blockade after RST injury is associated with axonal growth and/or diminished dieback of severed RST axons up to but not into or beyond the lesion/matrix site, and growth of serotonergic and dorsal root axons adjacent to and into the lesion/matrix site. NgR blockade also supported partial recovery of function. The authors' results indicate that severed rubrospinal axons respond to NEP1-40 treatment but less robustly than corticospinal, raphe-spinal, or dorsal root axons.

Trans-activator of transcription-mediated delivery of NEP1-40 protein into brain has a neuroprotective effect against focal cerebral ischemic injury via inhibition of neuronal apoptosis.

BACKGROUND: The Nogo-66 antagonistic peptide (NEP1-40) is a potential candidate for therapeutic intervention of neuronal injury. However, delivery of the proteins across the blood-brain barrier is severely limited by its size and biochemical properties. The current study was designed to evaluate the transducible effects of the trans-activator of transcription (TAT) transduction system for NEP1-40 to cross the blood-brain barrier and to clarify whether intraperitoneal administration of TAT-NEP1-40 could protect cerebral neurons from ischemic injury. METHODS: Adult male Sprague-Dawley rats were submitted to a 120-min focal ischemia and received an intraperitoneal injection of No-TAT-NEP1-40, TAT-NEP1-40, TAT-beta-galactosidase, or vehicle. The existence of the proteins in the brain was analyzed with immunofluorescence and Western blot techniques at 6 h after injection. Brain ischemic injury was evaluated by neurologic deficit scores, infarction volumes, terminal deoxynucleotidyl transferase-mediated dUDP-biotin nick end labeling staining, and assay of caspase-3 activity. RESULTS: Western blot analysis and immunofluorescence staining confirmed the presence of TAT-NEP1-40 protein in the brains 6 h after injection. Intraperitoneal injection of TAT-NEP1-40 could attenuate the numbers of terminal deoxynucleotidyl transferase-mediated dUDP-biotin nick end labeling-positive cells and activated caspase-3 positive cells, and increase the viability of the cells in the ischemic bounder zone, compared with that treated with No-TAT-NEP1-40, TAT-beta-Gal, or vehicle. Furthermore, treatment with TAT-NEP1-40 significantly improved the neurologic outcomes and reduced the size of the infarction in rats. CONCLUSIONS: The results demonstrate that the TAT-NEP1-40 could be efficiently delivered into the rat brains and improve ischemia-induced neurologic outcomes through attenuating cell apoptosis in ischemic brains.

Nogo-A is involved in secondary axonal degeneration of thalamus in hypertensive rats with focal cortical infarction.

We investigate whether Nogo-A is involved in the secondary axonal degeneration in the thalamus after distal middle cerebral artery occlusion (MCAO) in stroke-prone renovascular hypertensive rats (RHRSP). The expression of Nogo-A in ipsilateral ventroposterior nucleus (VPN) of the thalamus in RHRSP was observed at 1, 2 and 4 weeks after distal MCAO. In addition, intracerebroventricular infusion of NEP1-40, a Nogo-66 receptor (NgR) antagonist peptide, was administered starting 24 h after MCAO and continued for 1, 2 and 4 weeks, respectively. Axonal damage and regeneration were evaluated by analysis of the immunoreactivity (IR) of amyloid betaA4 precursor protein (APP), growth associated protein 43 (GAP-43) and microtubule associated protein 2 (MAP-2) in ipsilateral VPN of the thalamus at 1, 2 and 4 weeks after distal MCAO. Following ischemia, the expression of Nogo-A in oligodendrocytes increased persistently and its localization became redistributed around damaged axons and dendrites. Administration of NEP1-40 downregulated the expression of Nogo-A, reduced axonal injury and enhanced axonal regeneration. Our data suggest that Nogo-A is involved in secondary axonal degeneration and that inhibition of Nogo-A can reduce neuronal damage in the thalamus after distal MCAO.

Neuropsychiatric involvement in lupus is associated with the Nogo-a/NgR1 pathway.

Neuroinflammation- and neurodegeneration-induced nerve injury may represent important components of neuropsychiatric lupus (NPSLE). Myelin-associated neurite outgrowth inhibitor (Nogo)-a and its receptor, NgR1, limit recovery of the adult central nervous system after injury. We detected a soluble Nogo-a product in the cerebral spinal fluid of patients with NPSLE. In a mouse model of lupus, aging was associated with an increase in Nogo-a positive neurons, diminished myelin sheaths, enhanced pro-inflammatory cytokines, and impaired cognition and memory. Treatment with the Nogo-66 antagonist promoted myelin repair, improved cognition and memory, and downregulated pro-inflammatory factors. Our data imply the Nogo-a/NgR1 pathway is involved in NPSLE.

Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury.

Traumatized axons possess an extremely limited ability to regenerate within the adult mammalian CNS. The myelin-derived axon outgrowth inhibitors Nogo, oligodendrocyte-myelin glycoprotein, and myelin-associated glycoprotein, all bind to an axonal Nogo-66 receptor (NgR) and at least partially account for this lack of CNS repair. Although the intrathecal application of an NgR competitive antagonist at the time of spinal cord hemisection induces significant regeneration of corticospinal axons, such immediate local therapy may not be as clinically feasible for cases of spinal cord injury. Here, we consider whether this approach can be adapted to systemic therapy in a postinjury therapeutic time window. Subcutaneous treatment with the NgR antagonist peptide NEP1-40 (Nogo extracellular peptide, residues 1-40) results in extensive growth of corticospinal axons, sprouting of serotonergic fibers, upregulation of axonal growth protein SPRR1A (small proline-rich repeat protein 1A), and synapse re-formation. Locomotor recovery after thoracic spinal cord injury is enhanced. Furthermore, delaying the initiation of systemic NEP1-40 administration for up to 1 week after cord lesions does not limit the degree of axon sprouting and functional recovery. This indicates that the regenerative capacity of transected corticospinal tract axons persists for weeks after injury. Systemic Nogo-66 receptor antagonists have therapeutic potential for subacute CNS axonal injuries such as spinal cord trauma.

Animal models of central nervous system immune-mediated diseases: therapeutic interventions with bioactive peptides and mimetics.

Experimental allergic encephalomyelitis (EAE) is a T helper 1 (Th1) mediated autoimmune disease and the principal animal model for multiple sclerosis (MS). Like MS, EAE is characterized by a coordinated inflammatory attack on the myelin sheath in the central nervous system (CNS), with damage to axons. No matter whether the ideal animal model is not yet available, much knowledge concerning the pathogenesis of MS has been achieved through studies on EAE. Dissecting the underlying immune mechanisms provided recognition of several myelin antigens that are vulnerable in autoimmune attack. The beneficial effect and the mechanism of action of a number of the currently used immunomodulating agents in MS therapy were first indicated in EAE. Altered peptide ligands (APL) can modulate T-cell responses to native peptide antigens implicated in the pathogenesis of autoimmune diseases such as MS and EAE. However, peptide therapy is hindered due to the sensitivity of peptides to proteolytic enzymes as well as due to some immune-mediated side effects. A number of cyclic myelin peptide analogs seem to be potential candidates in maintaining the biological function of the original peptide and effective in controlling inflammation in EAE. Additional data regarding the immunomodulating and neuroprotective effect of these much promising agents is required. Based on the data from studies on EAE models, clinical trials should also be designed in order to elucidate the impact of such APL-induced immune responses in MS disease activity. These clinical trials should carefully incorporate monitoring of both clinical, neuroimaging and immunological parameters.

Sustained dual drug delivery of anti-inhibitory molecules for treatment of spinal cord injury.

Myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs) are major contributors to axon growth inhibition following spinal cord injury and limit functional recovery. The NEP1-40 peptide competitively binds the Nogo receptor and partially blocks inhibition from MAIs, while chondroitinase ABC (ChABC) enzymatically digests CSPGs, which are upregulated at the site of injury. In vitro studies showed that the combination of ChABC and NEP1-40 increased neurite extension compared to either treatment alone when dissociated embryonic dorsal root ganglia were seeded onto inhibitory substrates containing both MAIs and CSPGs. Furthermore, the ability to provide sustained delivery of biologically active ChABC and NEP1-40 from biomaterial scaffolds was achieved by loading ChABC into lipid microtubes and NEP1-40 into poly (lactic-co-glycolic acid) (PLGA) microspheres, obviating the need for invasive intrathecal pumps or catheters. Fibrin scaffolds embedded with the drug delivery systems (PLGA microspheres and lipid microtubes) were capable of releasing active ChABC for up to one week and active NEP1-40 for over two weeks in vitro. In addition, the loaded drug delivery systems in fibrin scaffolds decreased CSPG deposition and development of a glial scar, while also increasing axon growth after spinal cord injury in vivo. Therefore, the sustained, local delivery of ChABC and NEP1-40 within the injured spinal cord may block both myelin and CSPG-associated inhibition and allow for improved axon growth.

Multiple sclerosis as a by-product of the failure to sustain protective autoimmunity: a paradigm shift.

Autoimmune diseases are traditionally viewed as an outcome of a chaotic situation in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis, a disease of the white matter of the central nervous system (CNS), the immune attack is directed against myelin proteins. In this article, the authors propose a paradigm shift in the perception of autoimmune disease. They suggest that an autoimmune disease may be viewed as a by-product of the malfunctioning of a physiological autoimmune response whose purpose is protective. The proposed view is based on observations by their group suggesting that an autoimmune response is the body's own mechanism for coping with CNS damage. According to this view, all individuals are endowed with the potential ability to evoke an autoimmune response to CNS injuries. However, the inherent ability to control this response so that its beneficial effect will be expressed is limited and is correlated with the individual's inherent ability to resist autoimmune disease induction. The same autoimmune T cells are responsible for neuroprotection and for disease development. In patients with CNS trauma or neurodegenerative disorders, it might be possible to gain maximal autoimmune protection and avoid autoimmune disease induction by boosting the immune response, using myelin-associated peptides that are nonpathogenic or antigens that simulate the activities of such peptides. In patients with multiple sclerosis and other neurodegenerative diseases, where the aim is to block the autoimmune disorder while deriving the potential benefit of the autoimmune response, the effect of treatment should be immunomodulatory rather than immunosuppressive. In this article, the authors present a novel concept of protective autoimmunity and propose that autoimmune disease is a by-product of failure to sustain it. They summarize the basic findings that led them to formulate the new concept and offer an explanation for the commonly observed presence of cells and antibodies directed against self-components in healthy individuals. The therapeutic implications of the new concept and their experimental findings are discussed.

Theiler's virus encephalomyelitis is unaffected by treatment with myelin components.

Treatment of SJL/J mice with myelin components prior to infection with Theiler's picornavirus did not effect the development of inflammatory demyelinating lesions characteristic of Theiler's mouse encephalomyelitis. These results suggest that the pathogenesis of this disease differs from experimental autoimmune encephalomyelitis, which can be suppressed by such a treatment.

Antigen-specific tolerance induction and the immunotherapy of experimental autoimmune disease.

Antigen-specific tolerance induction is the ultimate goal for specific immunotherapy of autoimmune diseases. Here we will discuss recent experiments designed to induce tolerance following mucosal administration of antigens in a mouse model of experimental autoimmune encephalomyelitis (EAE). We were unable to induce oral tolerance either with whole myelin, myelin basic protein (MBP) or the immunodominant peptide antigen. Oral tolerance was possible, however, with an analogue of the immunodominant peptide modified to increase its affinity for the restricting major histocompatibility complex (MHC) antigen. By contrast, intranasal deposition of peptide antigen proved highly effective for both prevention and treatment of EAE. Prevention of disease was directly related to the antigenic property of the peptide which, in itself, was related to affinity for MHC. Notably, administration of a single peptide was shown to inhibit disease involving multiple epitopes. We investigated the resulting bystander regulation by studying the cellular basis of peripheral tolerance in a transgenic model. These studies indicate that bystander regulation may be the consequence of selective cytokine secretion.