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Biomedical subjects

A M Rostami

Publications and source records attributed to A M Rostami.

18 recordsLinked to original sources
PubMed2006

Retinal ganglion cell damage induced by spontaneous autoimmune optic neuritis in MOG-specific TCR transgenic mice.

Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are marked by inflammatory demyelinating lesions throughout the central nervous system, including optic nerve. Neuronal loss also occurs in EAE, including retinal ganglion cell (RGC) loss in eyes with optic neuritis, but the finding of RGC loss in relation to optic nerve inflammation differs in different EAE settings. Recently, Myelin oligodendrocyte glycoprotein (MOG)-specific TCR transgenic mice were found to develop spontaneous isolated optic neuritis in the absence of EAE. In the current study, the relationship of inflammation to retinal ganglion cell (RGC) loss during isolated optic neuritis is examined. RGCs of MOG-specific TCR transgenic mice were labeled with Flourogold and then treated with pertussis toxin (PT) or observed untreated. At various time points, RGCs were counted, retinas were TUNEL labeled, and optic nerves were examined for inflammatory cell infiltrates. 29% of untreated MOG-specific TCR transgenic mice developed periocular inflammation by 4 months of age, and 32% of optic nerves of TCR transgenic mice had histological lesions in the optic nerve. Incidence of histological optic neuritis was 20% at day 8 following injection of PT and increased to 48% by day 12, and 68% by day 16. In contrast, no RGC loss or TUNEL staining was detected in eyes with optic neuritis until day 12 in the mice injected with PT. A 28% reduction in RGC numbers at day 12 increased to 39% by day 16, and RGC loss of eyes with severe or massive inflammation was significantly higher than that of eyes with mild or moderate inflammation. No RGC loss occurred in TCR transgenic mouse eyes without optic neuritis. The fact that inflammation precedes RGC loss suggests that neuronal loss during optic neuritis occurs secondary to the inflammatory process in isolated optic neuritis.

Animals↗
PubMed2006

Pathophysiology of interleukin-23 in experimental autoimmune encephalomyelitis.

Interleukin-23 (IL-23) is a heterodimeric cytokine that is composed of a p40 subunit, shared with the closely related cytokine IL-12, and a smaller IL-23p19 subunit. It belongs to a family of heterodimeric cytokines that also includes IL-12 and IL-27. Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease that serves as a model for multiple sclerosis, an inflammatory demyelinating disease of the central nervous system that is a frequent cause of disability in young adults. EAE is thought to be initiated by CD4+ T cells. The production of interferon-gamma and tumor necrosis factor-alpha (T helper 1 [Th1] phenotype) was considered a marker for the ability of such cells to induce disease. Consistent with this view, IL-12, a cytokine that induces the differentiation of Th1 cells, was considered essential for EAE susceptibility. However, it is now clear that IL-23 rather than IL-12 is required for EAE susceptibility. IL-23 induces a population of IL-17-producing cells that is more critically involved in EAE pathogenesis than Th1 cells. Here, we review the role of the IL-23 system in the pathophysiology of EAE.

Animals↗
PubMed2000

Chemokines and chemokine receptors in the pathogenesis of multiple sclerosis.

In recent years we have seen growing evidence for the role of chemokines in the pathogenesis of several infectious and non-infectious inflammatory CNS disease states, including Multiple Sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE). An increase in proinflammatory chemokines has been associated with demyelinating lesions and clinical neurological dysfunction in patients with MS; these chemokines could be potential targets for MS therapy. Besides a clearly defined role in mediating leukocyte migration, these and other chemokines may act as immunoregulatory molecules in the driving to Th1/Th2 responses, switch of cytokine profiles, and the induction of tolerance. Since chemokine receptors have now been identified on macrophages, microglia, astrocytes, and endothelial cells as well as neurons in the CNS, chemokine/receptor interactions may mediate functional responses in a variety of CNS cell types during the course of inflammatory disease states. Therefore, clarification of the roles of chemokines and their receptors in the pathogenesis of EAE and MS will be useful in establishing immunotherapeutic strategies for these neurological autoimmune disorders.

Chemokines↗
PubMed1999

Serial evoked potential studies and MRI imaging in chronic progressive multiple sclerosis.

Measurements of serial evoked potential latencies and plaque burden on MRI scans are often obtained during clinical studies of multiple sclerosis patients to provide additional information to the disability-based primary endpoints. The ideal laboratory-based marker of progression would be expected to significantly change over the time period of study. Serial visual (VEP) and brainstem auditory evoked potentials (BAEP) and MRI scans of 11 chronic progressive MS patients were obtained over a 1.5 year period in a clinical study. Over this period, there was no significant change in disability as measured by the Kurtzke EDSS, Ambulation Index or Neurological Rating Score. The VEP P100 significantly progressed over the period of study. However, the MRI T(2) plaque burden and BAEP I-V intrapeak latency did not significantly progress over the 1.5 years. We conclude that, in chronic progressive MS, serial visual evoked potential tests may complement standard disability-based endpoints to assess disease progression.

Disability Evaluation↗
PubMed1999

IL-12 reverses the suppressive effect of the CD40 ligand blockade on experimental autoimmune encephalomyelitis (EAE).

Blockade of the CD40 ligand (CD40L)-CD40 interaction suppresses experimental autoimmune encephalomyelitis (EAE). Since this interaction induces IL-12, an essential cytokine for EAE induction, we hypothesized that CD40L blockade may suppress EAE through IL-12 inhibition. Here we show that exogenous IL-12 abolishes the ability of anti-CD40L monoclonal antibodies to prevent EAE. Anti-IL-12 antibodies prevent this reversal and protect from EAE. These results show that IL-12 is sufficient to overcome CD40L blockade and suggest that, of the multiple consequences of the CD40L-CD40 interaction, IL-12 induction is an essential one for induction of EAE.

Animals↗
PubMed1999

A double-blind, placebo-controlled trial of extracorporeal photopheresis in chronic progressive multiple sclerosis.

Extracorporeal photopheresis is a safe therapy for cutaneous T-cell lymphoma and may have efficacy in certain autoimmune disorders. We performed a randomized, double-blinded, placebo-controlled trial of monthly photopheresis therapy in 16 patients with clinically definite multiple sclerosis (MS). All patients had progressed during the preceding year with entry Expanded Disability Status Scale (EDSS) scores between 3.0 and 7.0. Patients received photopheresis or sham therapy for 1 year and were followed for an additional 6 to 12 months. Patients were clinically evaluated by three disability scales: (1) EDSS; (2) Ambulation index and (3) Scripp's quantitative neurologic assessment. No serious side effects occurred in either group. There were no differences between the photopheresis and sham therapy groups by the disability measures. Additionally, there were no differences in progression of MRI plaque burden or evoked potential latencies. In this limited study, photopheresis was found to be safe but did not significantly alter the course of chronic progressive MS.

Adult↗
PubMed1999

Chemokines and peripheral nerve demyelination.

It has been speculated that beta-chemokines play a pivotal role in the development of peripheral nervous system (PNS) disorders characterized by mononuclear cell infiltration. In experimental allergic neuritis (EAN), an animal model for human Guillain-Barré syndrome (GBS) with mononuclear cell infiltration, we found by quantitative PCR that beta-chemokine messages were upregulated during the active stage. Moreover, an increase in the monocyte chemoattractant protein-1 (MCP-1) message was found in the preclinical stage of EAN, suggesting the critical role of MCP-1 for inducing mononuclear cell infiltrations in this model. Since many cell lineages other than immune cells can produce chemokines, this early upregulation of MCP-1 may be mediated by non-immune cells, probably endothelia or Schwann cells. To date, apart from MCP-1, only RANTES (Regulated on activation, normal T cell expressed and secreted) and macrophage inflammatory protein (MIP)-1alpha have been examined in EAN and found to have similar kinetics of induction. Therefore, understanding the regulation of production of these chemokines as well as mechanisms of inhibiting chemokine/receptor interactions in the PNS may ultimately lead to disease-specific therapy for GBS and related demyelinating disorders.

Animals↗
PubMed1998

Pathogenesis of neuroimmunologic diseases. Experimental models.

Animal models of autoimmune diseases have greatly improved our current understanding of the pathogenesis of human autoimmunity and have provided the potential for therapies based on manipulation of the immune system. In our laboratory, we have investigated the immunopathogenesis of autoimmune diseases of the nervous system and muscle. We have developed immune-based approaches for the suppression of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), and experimental autoimmune neuritis (EAN), a model for the Guillain-Barré syndrome (GBS). These approaches included induction of peripheral tolerance, immunotoxin targeting of activated T cells, and cytokine manipulations. In addition, we identified the antigen and characterized immunopathologically an autoimmune inflammatory disease of skeletal muscle, experimental autoimmune myositis (EAM), a model for the human inflammatory muscle disease polymyositis.

Animals↗
PubMed1998

Free light chains in multiple sclerosis urine.

We measured free kappa (kappa) and lambda (lambda) light chains in urine from patients with definite multiple sclerosis (MS), other neurologic diseases (OND), and normal controls by using an enzyme linked immunosorbent assay. Both kappa and lambda light chains were higher in MS than OND or controls. In seven of eight relapsing-remitting (R-R) MS patients serial studies showed that urinary kappa chains were elevated during periods of worsening, and decreased during clinical recovery. In contrast, the levels of kappa chains did not correlate with clinical activity in 10 progressive (P) MS patients. Further correlation of urinary light chains with neurologic evaluations in R-R and P MS patients over a longer period are needed to determine their clinical and biological relevance.

Biomarkers↗
PubMed1997

P2-reactive T cells in inflammatory demyelination of the peripheral nerve.

Lewis rats immunized with P2 protein, a 14.5-kDa protein of the peripheral nerve myelin, develop experimental allergic neuritis, a paralytic disorder with clinical, histologic, and electrophysiologic features similar to those of human Guillain-Barré syndrome (GBS). T cells reactive to P2 protein or a peptide corresponding to 53-78 residues of the protein can transfer the disease to naive animals. The mechanisms by which these T cells induce demyelination are not well understood; however, they may induce inflammation and demyelination in the nerves by production of Th1 cytokines. Th2 cytokines may lead to suppression of the inflammation and eventual recovery. There is no conclusive evidence that P2 protein plays a role in the pathogenesis of GBS, with or without association with Campylobacter jejuni; however, studies of the immunopathogenesis of P2 protein-induced experimental allergic neuritis are important for understanding the pathogenesis of inflammatory demyelination in the peripheral nerves, the hallmark of GBS.

Adoptive Transfer↗
PubMed1995

Guillain-Barré syndrome: clinical and immunological aspects.

Immune-mediated PNS disorders comprise a significant segment of diseases of the nervous system. Studies on GBS as a prototype of these disorders and its experimental model EAN have helped to elucidate some of the mechanisms responsible for myelin injury in the PNS. These mechanisms, although partially understood have been useful in implementing therapies such as plasmapheresis and IVIG and various other immunomodulators. The question of whether an infectious agent such as a virus can directly damage the myelin sheath and/or Schwann cells or whether the agent triggers an immune response against self through antigenic mimicry remains unanswered. The association between C. jejuni infection and GBS has opened new areas of investigation in understanding the immunopathogenesis of the disease. Similar observations with other environmental factors may be made in the future, pointing to the possibility that GBS may not be caused by a single agent but could be the result of an immunological attack on the PNS myelin assembly by a variety of agents or factors. Regardless of the etiology, if the myelin injury is aggravated by product of the immune cells, such as various cytokines, neutralization of these factors could help lessen the burden of injury to the nerves. Future research in autoimmune disorders of the PNS needs to focus on identifying environmental factors that directly, or indirectly through antigen mimicry, damage the PNS myelin. In parallel, further understanding of the immunopathogenesis by dissecting the immunological phenomenon at the systemic and local levels, especially the role of cytokines, growth factors, and adhesion molecules will pave the way for more rational therapies, even if the causative factors are not known. Studies in laboratory animals have demonstrated the efficacy of selective immunotherapy through modulation of the trimolecular complex, i.e., T cell receptor, MHC/molecule, and antigen. Immunological tolerance, presumably through deletion of autoreactive clones, clonal anergy, or active suppression, has proven effective in animals. Other modes of immunotherapy such as nonspecific depletion of T or B cells or down-regulation of activated cells have also been shown to abolish or decrease the severity of experimental autoimmune neurological disorders, including EAN. These immunotherapeutic modalities may become applicable to human autoimmune neuropathies.

Animals↗
PubMed1994

Urinary free kappa light chain levels in chronic progressive multiple sclerosis.

Previous studies have shown elevated levels of free kappa light chains (FKLC) in the urine of patients with relapsing-remitting multiple sclerosis (MS). The levels correlated well with clinical relapses, indicating that they could serve as useful markers of disease activity. In this study, we performed monthly measurements of urinary FKLC in patients with the chronic progressive form of MS, and correlated them with clinical indicators of disease activity, as expressed by Kurtzke's expanded disability status scale (EDSS) and brain magnetic resonance imaging (MRI). We noted wide fluctuations in the FKLC levels, which correlated poorly with EDSS scores or MRI changes. Longer follow-up periods may be needed before definite conclusions can be drawn.

Adult↗
PubMed1994

Magnetic resonance imaging of the cauda equina in Guillain-Barré syndrome.

We report three patients (two children and one adult) with Guillain-Barré syndrome and magnetic resonance imaging evidence of gadolinium enhancement of the cauda equina and lumbar nerve roots. All three patients exhibited symmetric ascending paralysis and areflexia, and two (one child, one adult) suffered urinary incontinence and retention. Similar enhancement has been observed in patients with chronic inflammatory demyelinating polyneuropathy and suggests proximal nerve inflammation. Magnetic resonance imaging in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy may have diagnostic utility.

Cauda Equina↗
PubMed1993

Pathogenesis of immune-mediated neuropathies.

A variety of peripheral neuropathies are believed to be immune-mediated. Acute inflammatory demyelinating polyneuropathy or Guillain-Barré syndrome (GBS) is the prototype of these neuropathies. GBS is characterized by acute progressive motor weakness of the extremities and of bulbar and facial musculature. Deep tendon reflexes are reduced or absent, and sensory symptoms are mild. Respiratory failure and autonomic dysfunction may be seen. The cerebrospinal fluid shows increased protein and no or very few cells. The nerve conduction velocity is slowed, and the pathology shows segmental demyelination with mononuclear cell infiltration. Studies from man and experimental animals suggest an immunologic basis for demyelination of the peripheral nerves in GBS, but the mechanism is not well understood. Experimental allergic neuritis, an animal model of GBS, is induced in laboratory animals by immunization with myelin P2 protein, some peptides of P2 protein, and galactocerebroside. The animals develop weakness and show electrophysiologic and pathologic features similar to GBS. P2-reactive T cells and antigalactocerebroside antisera can adoptively transfer experimental allergic neuritis. Various antibodies to peripheral nerve myelin and circulating immune complexes have been found in patients with GBS. The target antigen(s) for these antibodies are not well understood, but neutral glycolipids cross-reactive with Forssman antigen and gangliosides are possible candidates. The mainstay of therapy is the management of the paralyzed patient. Steroids are ineffective. Plasmapheresis, especially early in the course of the disease, can shorten the duration of paralysis and intubation. Results from a multicenter study in the Netherlands demonstrate the efficacy of high-dose immune globulin therapy in GBS.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Search for antibodies to galactocerebroside in the serum and cerebrospinal fluid in human demyelinating disorders.

To determine if galactocerebroside (GalC) is a target antigen in the human demyelinating disorders multiple sclerosis, Guillain-Barré syndrome, and chronic demyelinating inflammatory polyneuropathy, we examined the serum and cerebrospinal fluid from patients with these disorders and from control subjects using four assay systems. In none of these assays could we detect significant differences in anti-GalC antibody titer between patients with demyelinating diseases and normal subjects or patients with other neurological disorders. Our data suggest that there is no humoral immune response to GalC in human demyelinating disorders.

Antibodies↗