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Peter A Calabresi

Publications and source records attributed to Peter A Calabresi.

At least 19 recordsLinked to original sources
PubMed2026

Genome-wide association analyses highlight the neuronal contribution to multiple sclerosis susceptibility.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Previous genetic studies have identified susceptibility loci that primarily impact immune cells and microglia. Here we performed a multi-ancestry genome-wide association study of 20,831 MS cases and 729,220 controls and identified 236 susceptibility variants outside of the major histocompatibility complex, including four novel genomic loci. We also derived a polygenic score for MS; while optimized for European ancestry, it is informative for African American and Latino individuals. Integrating single-cell data from blood and brain tissue, we identified 76 candidate causal genes. Inhibitory neurons emerged as a key target cell type for MS-associated variants, with seven loci, including STAT3, displaying altered expression only in these cells. The STAT3 variant is also associated with cognition and white matter integrity in individuals with no MS and greater sNfL levels in individuals with MS, suggesting that MS susceptibility may reflect reduced central nervous system resilience to inflammatory challenges.

Humans↗
PubMed2022

Association of Vitamin D Polygenic Risk Scores and Disease Outcome in People With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Observational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS. METHODS: We generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 &#xd7; 10-8) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modified p value threshold for inclusion in the PGS (5 &#xd7; 10-5) and applying Mendelian randomization (MR) rather than using PGS. RESULTS: Initial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS: 3.08%, 95% CI: 1.77%, 4.42%; p = 4.33e-06; R2 = 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87-1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87-1.28), change in T25FW (per 1SD: 0.07%; 95% CI: -0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: -0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using other p value thresholds or those applying MR. DISCUSSION: Genetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS.

Humans↗
PubMed2006

Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases.

Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+ CCR7- CD45RA- effector memory T cells (T(EM) cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (T(CM)) cells. In T(EM) cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvbeta2, SAP97, ZIP, p56(lck), and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific T(EM) cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.

Animals↗
PubMed2006

Memory lineage relationships in HTLV-1-specific CD8+ cytotoxic T cells.

Cytotoxic memory T cells play a critical role in combating viral infections; however, in some diseases they may contribute to tissue damage. In HAM/TSP, HTLV-1 Tax 11-19+ cells proliferate spontaneously in vitro and can be tracked using the Tax 11-19 MHC Class I tetramer. Immediately ex vivo, these cells were a mix of CD45RA-/CCR7- TEM and CD45RA+/CCR7- TDiff memory CTL. The subsequent proliferating Tax 11-19 tetramer+ population expressed low levels of IL-7Ralpha, failed to respond to IL-7 and IL-15, and did not develop a TCM phenotype. Thus, chronic exposure to viral antigen may result in a sustained pool of TEM cells that home to the CNS and mediate the spinal cord pathology seen in this disease.

Gene Products, tax↗
PubMed2006

Granzyme B mediates neurotoxicity through a G-protein-coupled receptor.

Neuroinflammatory diseases such as multiple sclerosis (MS) are characterized by focal regions of demyelination and axonal loss associated with infiltrating T cells. However, the role of activated T cells in causing neuronal injury remains unclear. CD4 and CD8 T cells were isolated from normal donors and polyclonally activated using plate-bound anti-CD3 and soluble anti-CD28. The conditioned T cell supernatants caused toxicity to cultured human fetal neurons, which could be blocked by immunodepleting the supernatants of granzyme B (GrB). Recombinant GrB also caused toxicity in neurons by caspase-dependent pathways but no toxicity was seen in astrocytes. The neurotoxicity was independent of perforin and could not be blocked by mannose-6-phosphate. However, GrB-induced neurotoxicity was sensitive to pertussis toxin, implicating the stimulation of Gialpha protein-coupled receptors. GrB caused a decrease in cAMP levels but only modest increases in intracellular calcium. The effect on intracellular calcium could be markedly potentiated by stromal-derived factor 1alpha. GrB-induced neurotoxicity could also be blocked by vitamin E and a neuroimmunophilin ligand. In conclusion, GrB may be an important mediator of neuronal injury in T cell-mediated neuroinflammatory disorders.

Antioxidants↗
PubMed2006

Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.

BACKGROUND: Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an alpha4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. METHODS: We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. RESULTS: Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02). Kaplan-Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T(2)-weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. CONCLUSIONS: Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966.).

Adolescent↗
PubMed2006

Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis.

PURPOSE: To examine the relation of visual function to retinal nerve fiber layer (RNFL) thickness as a structural biomarker for axonal loss in multiple sclerosis (MS), and to compare RNFL thickness among MS eyes with a history of acute optic neuritis (MS ON eyes), MS eyes without an optic neuritis history (MS non-ON eyes), and disease-free control eyes. DESIGN: Cross-sectional study. PARTICIPANTS: Patients with MS (n = 90; 180 eyes) and disease-free controls (n = 36; 72 eyes). METHODS: Retinal never fiber layer thickness was measured using optical coherence tomography (OCT; fast RNFL thickness software protocol). Vision testing was performed for each eye and binocularly before OCT scanning using measures previously shown to capture dysfunction in MS patients: (1) low-contrast letter acuity (Sloan charts, 2.5% and 1.25% contrast levels at 2 m) and (2) contrast sensitivity (Pelli-Robson chart at 1 m). Visual acuity (retroilluminated Early Treatment Diabetic Retinopathy charts at 3.2 m) was also measured, and protocol refractions were performed. MAIN OUTCOME MEASURES: Retinal nerve fiber layer thickness measured by OCT, and visual function test results. RESULTS: Although median Snellen acuity equivalents were better than 20/20 in both groups, RNFL thickness was reduced significantly among eyes of MS patients (92 mum) versus controls (105 mum) (P<0.001) and particularly was reduced in MS ON eyes (85 mum; P<0.001; accounting for age and adjusting for within-patient intereye correlations). Lower visual function scores were associated with reduced average overall RNFL thickness in MS eyes; for every 1-line decrease in low-contrast letter acuity or contrast sensitivity score, the mean RNFL thickness decreased by 4 mum. CONCLUSIONS: Scores for low-contrast letter acuity and contrast sensitivity correlate well with RNFL thickness as a structural biomarker, supporting validity for these visual function tests as secondary clinical outcome measures for MS trials. These results also suggest a role for ocular imaging techniques such as OCT in trials that examine neuroprotective and other disease-modifying therapies. Although eyes with a history of acute optic neuritis demonstrate the greatest reductions in RNFL thickness, MS non-ON eyes have less RNFL thickness than controls, suggesting the occurrence of chronic axonal loss separate from acute attacks in MS patients.

Acute Disease↗
PubMed2006

Cleavage of cystatin C in the cerebrospinal fluid of patients with multiple sclerosis.

OBJECTIVE: The diagnosis of multiple sclerosis (MS) can be challenging because of the lack of a specific diagnostic test. Recent advances in proteomics, however, offer new opportunities for biomarker discovery and the study of disease pathogenesis. METHODS: We analyzed cerebrospinal fluid (CSF) samples from 29 patients with MS or clinically isolated syndromes (CIS), 27 patients with transverse myelitis (TM), 50 patients with human immunodeficiency virus (HIV) infection, and 27 patients with other neurological diseases (ONDs) by surface-enhanced laser desorption/ionization time-of-flight mass spectroscopy. RESULTS: We found a unique protein of 12.5 kDa that was 100% specific for MS/CIS compared with TM or OND. Low levels of this protein were found in some patients with HIV infection. Tandem mass spectroscopy of a tryptic digest of this 12.5 kDa protein identified it as a cleavage product of full-length cystatin C (13.4 kDa), an important inhibitor of cysteine proteases including the cathepsins. Although total cystatin C levels in the MS patients was not different compared with controls, the patients with the highest 12.5/13.4 peak ratios also had the greatest cathepsin B inhibitory activity. INTERPRETATION: This suggests that cleavage of cystatin C may be an adaptive host response and may identify a subgroup of patients with MS.

Adolescent↗
PubMed2006

Potassium channels Kv1.3 and Kv1.5 are expressed on blood-derived dendritic cells in the central nervous system.

OBJECTIVE: Potassium (K(+)) channels on immune cells have gained attention recently as promising targets of therapy for immune-mediated neurological diseases such as multiple sclerosis (MS). We examined K(+) channels on dendritic cells (DCs), which infiltrate the brain in MS and may impact disease course. METHODS: We identified K(+) channels on blood-derived DCs by whole-cell patch-clamp analysis, confirmed by immunofluorescent staining. We also stained K(+) channels in brain sections from MS patients and control subjects. To test functionality, we blocked K(v)1.3 and K(v)1.5 in stimulated DCs with pharmacological blockers or with an inducible dominant-negative K(v)1.x adenovirus construct and analyzed changes in costimulatory molecule upregulation. RESULTS: Electrophysiological analysis of DCs showed an inward-rectifying K(+) current early after stimulation, replaced by a mix of voltage-gated K(v)1.3- and K(v)1.5-like channels at later stages of maturation. K(v)1.3 and K(v)1.5 were also highly expressed on DCs infiltrating MS brain tissue. Of note, we found that CD83, CD80, CD86, CD40, and interleukin-12 upregulation were significantly impaired on K(v)1.3 and K(v)1.5 blockade. INTERPRETATION: These data support a functional role of K(v)1.5 and K(v)1.3 on activated human DCs and further define the mechanisms by which K(+) channel blockade may act to suppress immune-mediated neurological diseases.

Adenoviridae↗
PubMed2006

Pulsed magnetization transfer imaging with body coil transmission at 3 Tesla: feasibility and application.

Pulsed magnetization transfer (MT) imaging has been applied to quantitatively assess brain pathology in several diseases, especially multiple sclerosis (MS). To date, however, because of the high power deposition associated with the use of short, rapidly repeating MT prepulses, clinical application has been limited to lower field strengths. The contrast-to-noise ratio (CNR) of MT is limited, and this method would greatly benefit from the use of higher magnetic fields and phased-array coil reception. However, power deposition is proportional to the square of the magnetic field and scales with coil size, and MT experiments are already close to the SAR limit at 1.5T even when smaller transmit coils are used instead of the body coil. Here we show that these seemingly great obstacles can be ameliorated by the increased T(1) of tissue water at higher field, which allows for longer maintenance of sufficiently high saturation levels while using a reduced duty cycle. This enables a fast (5-6 min) high-resolution (1.5 mm isotropic) whole-brain MT acquisition with excellent anatomical visualization of gray matter (GM) and white matter (WM) structures, and even substructures. The method is demonstrated in nine normal volunteers and five patients with relapsing remitting MS (RRMS), and the results show a clear delineation of heterogeneous lesions.

Adult↗
PubMed2005

Inhibition of FLT3 signaling targets DCs to ameliorate autoimmune disease.

Autoimmune diseases often result from inappropriate or unregulated activation of autoreactive T cells. Traditional approaches to treatment of autoimmune diseases through immunosuppression have focused on direct inhibition of T cells. In the present study, we examined the targeted inhibition of antigen-presenting cells as a means to downregulate immune responses and treat autoimmune disease. Dendritic cells (DCs) are the central antigen-presenting cells for the initiation of T cell responses, including autoreactive ones. A large portion of DCs are derived from hematopoietic progenitors that express FLT3 receptor (CD135), and stimulation of the receptor via FLT3 ligand either in vivo or in vitro is known to drive expansion and differentiation of these progenitors toward a DC phenotype. We hypothesized that inhibition of FLT3 signaling would thus produce an inhibition of DC-induced stimulation of T cells, thereby inhibiting autoimmune responses. To this end, we used small-molecule tyrosine kinase inhibitors targeted against FLT3 and examined the effects on DCs and their role in the promulgation of autoimmune disease. Results of our studies show that inhibition of FLT3 signaling induces apoptosis in both mouse and human DCs, and thus is a potential target for immune suppression. Furthermore, targeted inhibition of FLT3 significantly improved the course of established disease in a model for multiple sclerosis, experimental autoimmune encephalomyelitis, suggesting a potential avenue for treating autoimmune disease.

Animals↗
PubMed2005

IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis.

Transverse myelitis (TM) is an immune-mediated spinal cord disorder associated with inflammation, demyelination, and axonal damage. We investigated the soluble immune derangements present in TM patients and found that IL-6 levels were selectively and dramatically elevated in the cerebrospinal fluid and directly correlated with markers of tissue injury and sustained clinical disability. IL-6 was necessary and sufficient to mediate cellular injury in spinal cord organotypic tissue culture sections through activation of the JAK/STAT pathway, resulting in increased activity of iNOS and poly(ADP-ribose) polymerase (PARP). Rats intrathecally infused with IL-6 developed progressive weakness and spinal cord inflammation, demyelination, and axonal damage, which were blocked by PARP inhibition. Addition of IL-6 to brain organotypic cultures or into the cerebral ventricles of adult rats did not activate the JAK/STAT pathway, which is potentially due to increased expression of soluble IL-6 receptor in the brain relative to the spinal cord that may antagonize IL-6 signaling in this context. The spatially distinct responses to IL-6 may underlie regional vulnerability of different parts of the CNS to inflammatory injury. The elucidation of this pathway identifies specific therapeutic targets in the management of CNS autoimmune conditions.

Adult↗
PubMed2005

The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain.

Multiple Sclerosis (MS) is characterized by central nervous system perivenular and parenchymal mononuclear cell infiltrates consisting of activated T cells and macrophages. We recently demonstrated that elevated expression of the voltage-gated potassium channel, Kv1.3, is a functional marker of activated effector memory T (T(EM)) cells in experimental allergic encephalomyelitis and in myelin-specific T cells derived from the peripheral blood of patients with MS. Herein, we show that Kv1.3 is highly expressed in postmortem MS brain inflammatory infiltrates. The expression pattern revealed not only Kv1.3(+) T cells in the perivenular infiltrate but also high expression in the parenchyma of demyelinated MS lesions and both normal appearing gray and white matter. These cells were uniformly chemokine receptor 7 negative (CCR7(-)), consistent with an effector memory phenotype. Using double-labeling immunohistochemistry and confocal microscopy, we demonstrated colocalization of Kv1.3 with CD3, CD4, CD8, and some CD68 cells. The expression patterns mirrored in vitro experiments showing polarization of Kv1.3 to the immunological synapse. Kv1.3 was expressed in low to moderate levels on CCR7(+) central memory T cells from cerebrospinal fluid, but, when these cells were stimulated in vitro, they rapidly became Kv1.3(high)/CCR7(-) T(EM), suggesting that a subset of cerebrospinal fluid cells existed in a primed state ready to become T(EM). These studies provide further rationale for the use of specific Kv1.3 antagonists in MS.

Adult↗
PubMed2005

Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale.

The symptoms, severity, and course of multiple sclerosis (MS) vary among patients, leading to complex treatment issues. In recent years, research has focused on specific adhesion molecules that participate in the activation and function of lymphocytes, especially the migration of these cells to sites of inflammation. In particular, the integrin, very late activation antigen (VLA)-4, has been implicated in mediating adhesion and migration of immune cells through interaction with its ligand, vascular cell adhesion molecule (VCAM)-1. VLA-4 is comprised of alpha4/beta1 and is critical in mediating Th-1 cell migration in the animal model of MS, experimental autoimmune encephalomyelitis, and has been the target of several recent clinical trials in MS. The humanized monoclonal antibody to alpha4 integrin, natalizumab (Tysabri, Biogen Idec/Elan), was recently approved in the United States for the treatment of relapsing MS. The authors discuss the mechanisms by which alpha4 integrins alter lymphocyte function as a rationale for anti-alpha4 integrin use in MS.

Animals↗
PubMed2005

Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases.

The voltage-gated Kv1.3 K(+) channel is a novel target for immunomodulation of autoreactive effector memory T (T(EM)) cells that play a major role in the pathogenesis of autoimmune diseases. We describe the characterization of the novel peptide ShK(L5) that contains l-phosphotyrosine linked via a nine-atom hydrophilic linker to the N terminus of the ShK peptide from the sea anemone Stichodactyla helianthus. ShK(L5) is a highly specific Kv1.3 blocker that exhibits 100-fold selectivity for Kv1.3 (K(d) = 69 pM) over Kv1.1 and greater than 250-fold selectivity over all other channels tested. ShK(L5) suppresses the proliferation of human and rat T(EM) cells and inhibits interleukin-2 production at picomolar concentrations. Naive and central memory human T cells are initially 60-fold less sensitive than T(EM) cells to ShK(L5) and then become resistant to the peptide during activation by up-regulating the calcium-activated K(Ca)3.1 channel. ShK(L5) does not exhibit in vitro cytotoxicity on mammalian cell lines and is negative in the Ames test. It is stable in plasma and when administered once daily by subcutaneous injection (10 mug/kg) attains "steady state" blood levels of approximately 300 pM. This regimen does not cause cardiac toxicity assessed by continuous EKG monitoring and does not alter clinical chemistry and hematological parameters after 2-week therapy. ShK(L5) prevents and treats experimental autoimmune encephalomyelitis and suppresses delayed type hypersensitivity in rats. ShK(L5) might prove useful for therapy of autoimmune disorders.

Animals↗
PubMed2005

Bystander modulation of chemokine receptor expression on peripheral blood T lymphocytes mediated by glatiramer therapy.

BACKGROUND: Glatiramer acetate therapy is thought to be effective for multiple sclerosis (MS) by promoting T(H)2 cytokine deviation, possibly in the brain, but the exact mechanism and site of action are incompletely understood. Determining the site of action and effect of glatiramer on cell trafficking is of major importance in designing rational combination therapy clinical trials. OBJECTIVE: To determine whether glatiramer therapy will also act in the peripheral blood through bystander modulation of chemokine receptor (CKR) expression and cytokine production on T lymphocytes. DESIGN: Before-and-after trial. SETTING: A university MS specialty center. PATIENTS: Ten patients with relapsing-remitting MS. INTERVENTIONS: Treatment with glatiramer for 12 months and serial phlebotomy. MAIN OUTCOME MEASURES: Cytokine production, CKR expression, and cell migration. RESULTS: The glatiramer-reactive T cells were T(H)2 cytokine biased, consistent with previous studies. We found a significant reduction in the expression of the T(H)1 inflammation associated with the CKRs CXCR3, CXCR6, and CCR5 on glatiramer- and myelin-reactive T cells generated from patients with MS receiving glatiramer therapy vs baseline. Conversely, expression of the lymph node-homing CKR, CCR7, was markedly enhanced on the glatiramer-reactive T cells derived from patients with MS undergoing glatiramer therapy. There was a reduction in the percentage of CD4+ glatiramer-reactive T cells and an increase in the number of CD8+ glatiramer-reactive T cells. CONCLUSIONS: Glatiramer may suppress autoreactive CD4+ effector memory T cells and enhance CD8+ regulatory responses, and bystander modulation of CKRs may occur in the periphery.

Bystander Effect↗