Effects of photobiomodulation therapy on muscle function in individuals with multiple sclerosis.

BACKGROUND: In people with multiple sclerosis (pwMS), muscle fatigue and weakness are common issues that can interfere with daily activities. Photobiomodulation therapy (PBMT), comprising light in a 600-1100 nm bandwidth, is a low-level laser therapy thought to improve muscle performance in non-disease populations, in part, by improving mitochondrial function and thus, might be beneficial in pwMS. Given this potential, we aimed to investigate the effects of PBMT on muscle performance in pwMS, both in the short-term and over an extended period. METHODS: This study consisted of two parts with a randomized double-blind crossover design. In study I, muscle function was assessed in four sessions before and after PBMT in ambulatory pwMS (N = 17, F = 14) as follows: maximal voluntary contraction (MVC) and muscle fatigue of the right tibialis anterior (TA) muscle was compared at baseline and following a two-min submaximal fatiguing contraction. Then, PBMT was administered to the belly of TA muscle at different doses of energy of an active device (40 J, 80 J, 120 J) or placebo. The muscle function assessment was then repeated. OUTCOME VARIABLES: muscle force recovery (%), muscle fatigue (%). Statistical tests included McNemar's exact test, Wilcoxon signed-rank test, and the Friedman test. In study II, a subgroup from study I (N = 12, F = 11) received individualized doses (i.e., best dose-effect observed in study I) of active, or placebo PBMT, which was administered on the TA muscle for two weeks. Muscle function assessments were performed pre- and post-PBMT in four sessions similar to study I. OUTCOME VARIABLES: Baseline strength (N), endurance time (s), and muscle fatigue (%). The Wilcoxon signed-rank test was used for statistical analysis. Values are reported as mean (SD). RESULTS: In study I, participants who received a high dose of PBMT showed significant improvement in force recovery (101.89 % (13.55 %)) compared to the placebo group (96.3 % (18.48 %); p = 0.03). Muscle fatigue did not significantly improve with either active PBMT or placebo. In study II, active PBMT resulted in a significant improvement in muscle strength compared to both the baseline (pre-PBMT = 162.70 N (37.52 N); post-PBMT = 185.56 N (33.95 N); p = 0.01) and the placebo group (active PBMT: mean-change = 22.87 N (23.67 N); placebo: mean-change = -4.12 N (31.95 N); p = 0.02). Endurance time and muscle fatigue did not show significant improvement with either active PBMT or placebo. CONCLUSION: Our findings suggest that an individualized dose of PBMT might improve muscle performance, including force recovery and strength in individuals with mild-moderate MS. Therefore, PBMT might be a novel therapeutic modality, either as a standalone treatment or in combination with other interventions, to improve muscle performance in pwMS.

Photobiomodulation at 830 nm Reduced Nitrite Production by Peripheral Blood Mononuclear Cells Isolated from Multiple Sclerosis Subjects.

Background: Multiple sclerosis (MS) is a neurodegenerative condition characterized by high concentration of nitric oxide leading to the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), a condition known as nitrosative stress. ROS and RNS produce the inhibition of the mitochondrial electron transport chain leading to mitochondrial dysfunction, reduction of adenosine triphosphate, and death of neurons, producing severe and irreversible damage in the central nervous system of people with MS (PwMS). Current drug treatments for MS focus on the regulation of immune response in acute stages of disease, but they do not regulate nitrosative stress which is present in the acute and chronic stages of disease. Previously, our laboratory showed that photobiomodulation (PBM) on experimental autoimmune encephalomyelitis mice, the animal model of MS, reduced clinical severity of disease, gene expression of inducible nitric oxide synthase (iNOS), and the levels of nitrite in in vivo and in vitro experiments. Objective: We evaluated the effect of PBM on the regulation of nitrosative stress in PwMS. Methods: PBM was applied on peripheral blood mononuclear cells (PBMCs) obtained from PwMS to evaluate PBM on the regulation of nitrate as a marker of nitrosative stress. Results: PBM at 830 nm (10 J/cm2 at 72 h) reduced the levels of nitrite and this reduction was in relationship with the increase of interleukin-10 and the reduction of interferon-γ produced by the PBMCs regardless of the severity of disease present in the participants. Conclusions: PBM at 830 nm can potentially be used to reduce nitrosative stress at any point of disease in PwMS.

Photobiomodulation Modulates Interleukin-10 and Interferon Gamma Production by Mononuclear Cells from Healthy Donors and Persons with Multiple Sclerosis.

Background: Photobiomodulation (PBM) therapy was previously shown to reduce the clinical severity of disease and modulated pro- and anti-inflammatory cytokines in an animal model of multiple sclerosis (MS). Objective: Previous observations were extended to determine the effect of PBM therapy on peripheral blood mononuclear cells and CD4+ T cells isolated from persons with MS (PwMS) and healthy donors. Methods: Using an in vitro cell culture system, isolated cells were activated and treated with red or near-infrared light wavelengths to determine the effect of PBM on the production of interferon gamma and interleukin-10 (IL-10). Results: PBM modulated cytokine production in MS subjects and healthy donors in a dose- and wavelength-dependent manner, with MS subjects and healthy donors responding differently to administered light. In addition, disease severity affected the response of immune cells, for instance, 670 nm increased IL-10 production associated with increased disease severity. Conclusions: The data show that PBM therapy has the potential to modulate pro- and anti-inflammatory cytokines in PwMS over the course of disease. Further experiments applying PBM treatment directly on patients should be carried out with extreme caution to avoid severe imbalance in the immune response.

Exposure to Systemic Immunosuppressive Ultraviolet Radiation Alters T Cell Recirculation through Sphingosine-1-Phosphate.

Systemic suppression of adaptive immune responses is a major way in which UV radiation contributes to skin cancer development. Immune suppression is also likely to explain how UV protects from some autoimmune diseases, such as multiple sclerosis. However, the mechanisms underlying UV-mediated systemic immune suppression are not well understood. Exposure of C57BL/6 mice to doses of UV known to suppress systemic autoimmunity led to the accumulation of cells within the skin-draining lymph nodes and away from non-skin-draining lymph nodes. Transfer of CD45.1+ cells from nonirradiated donors into CD45.2+ UV-irradiated recipients resulted in preferential accumulation of donor naive T cells and a decrease in activated T cells within skin-draining lymph nodes. A single dose of immune-suppressive UV was all that was required to cause a redistribution of naive and central memory T cells from peripheral blood to the skin-draining lymph nodes. Specifically, CD69-independent increases in sphingosine-1-phosphate (S1P) receptor 1-negative naive and central memory T cells occurred in these lymph nodes. Mass spectrometry analysis showed UV-mediated activation of sphingosine kinase 1 activity, resulting in an increase in S1P levels within the lymph nodes. Topical application of a sphingosine kinase inhibitor on the skin prior to UV irradiation eliminated the UV-induced increase in lymph node S1P and T cell numbers. Thus, exposure to immunosuppressive UV disrupts T cell recirculation by manipulating the S1P pathway.

Clinical and Radiologic Disease Activity in Pregnancy and Postpartum in MS.

OBJECTIVE: To evaluate radiologic and clinical inflammatory activity in women with MS during pregnancy and postpartum. METHODS: We performed a retrospective analysis of prospectively collected clinical and MRI reports for women who became pregnant while followed at the University of California, San Francisco MS Center between 2005 and 2018. Proportion of brain MRIs with new T2-hyperintense or gadolinium enhancing (Gd+) lesions (primary outcome) and annualized relapse rate (ARR; secondary) were compared before and after pregnancy. RESULTS: We identified 155 pregnancies in 119 women (median Expanded Disability Status Scale [EDSS] 2.0). For the 146 live birth pregnancies, prepregnancy ARR was 0.33; ARR decreased during pregnancy, particularly the third trimester (ARR 0.10, p = 0.017) and increased in the 3 months postpartum (ARR 0.61, p = 0.012); and 16% of women experienced a clinically meaningful increase in EDSS. Among 70 pregnancies with paired brain MRIs available, 53% had new T2 and/or Gd+ lesions postpartum compared with 32% prepregnancy (p < 0.001). Postpartum clinical relapses were associated with Gd+ lesions (p < 0.001). However, even for patients without postpartum relapses, surveillance brain MRIs revealed new T2 and/or Gd+ lesions in 31%. Protective effects of exclusive breastfeeding for ≥3 months (odds ratio = 0.3, 95% confidence interval 0.1-0.9) were observed for relapses. CONCLUSIONS: Building on previous reports of increased relapse rate in the first 3 months postpartum, we report a significant association between inflammation on MRI and this clinical activity. We also detected postpartum radiologic activity in the absence of relapses. Both clinical and radiologic reassessment may inform optimal treatment decision-making during the high-risk early postpartum period.

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-ß-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.

Sensory-motor and cardiorespiratory sensory rehabilitation associated with transcranial photobiomodulation in patients with central nervous system injury: Trial protocol for a single-center, randomized, double-blind, and controlled clinical trial.

BACKGROUND: Central nervous system diseases such as stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis can be fatal or cause sequelae, affecting sensorimotor and cardiorespiratory systems and quality of life. These subjects present a low response to aerobic and resistance exercise, due to decreased recruitment of muscle fibers and reduction of metabolic capacity. Aerobic exercises bring benefits in terms of fatigue retardation, gait improvement, regulation of the autonomic nervous system, neuroprotection of the brain, stimulation of the production of endogenous neutrotransmitters related to general well-being, and a favoring of neuroplasticity. Photobiomodulation (PBM Therapy) (previously known as low-level laser therapy), and especially transcranial PBM Therapy, has shown benefits in animals and humans such as cognitive improvement, memory, and behavioral improvement, including attenuation of depression and anxiety, and increased cortical oxygenation. The aims of this trial will be to evaluate the parameters related to the function of the musculoskeletal and cardiorespiratory system and the impact of PBM therapy on these parameters, as part of a rehabilitation and training program for people with reduced mobility. METHODS: This is a randomized, double-blind, placebo-controlled trial with 3 groups: Control, only cardiorespiratory rehabilitation (CCR), CCR with PBM Therapy (CR-PBM), CCR and placebo PBM Therapy (CR-PlaceboPBM). n = 90, 30 per group. PBM Therapy parameters: 810 nm laser, 0.028 cm, 100 mW, 3.5 W/cm, 30 seconds per point, 3 J per point, 107.1 J /cm to 3 electroencephalogram points F7 and F8 and AFz. The trial will be conducted at the University Clinics and the sessions will be 1 hour twice a week for 9 weeks. Baseline, intermediate (4th week), final (9th week), and 2-month follow-up will be performed. Muscular activation, heart rate variability, lung volumes and capacities, fatigability, exercise tolerance, cognition, and quality of life at baseline will be evaluated. Subsequent to baseline evaluations, the PBM Therapy groups will be offered laser therapy (active or inactive); all groups will then receive CCR. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID - NCT03751306 (approval date: November 22, 2018).

Effectiveness and safety of Rituximab in multiple sclerosis: an observational study from Southern Switzerland.

BACKGROUND: Despite positive results from phase II and observational studies, Rituximab (RTX) is not currently approved for multiple sclerosis (MS) treatment and can only be used off-label. OBJECTIVE: To characterize MS patients treated with RTX and investigate its effectiveness and safety in a clinical practice setting. METHODS: Observational analysis of data collected from MS patients at the Neurocenter of Southern Switzerland. Relapses, EDSS worsening, MRI lesion accrual and "evidence of disease activity" (EDA) status were described by Cox regression. RTX and natalizumab treated patients were matched by propensity scores. RESULTS: Out of 453 MS patients, 82 were treated with RTX, 43 (52.4%) relapsing-remitting (RRMS) and 39 (47.6%) progressive MS (median age = 48 [40-54] years, females n = 60 [73.2%], EDSS = 4.0 [2.5-6.0], median follow-up = 1.5 [1.0-2.5] years). Three relapses occurred and 59 (75.6%) patients had not EDA at follow-up end. Time to EDA was similar in RTX and natalizumab treated RRMS patients (HR = 1.64, 95%CI = 0.46-5.85, p = 0.44). Twenty-four patients presented non infusion related adverse events (infections), requiring RTX discontinuation in 6 individuals. CONCLUSION: These results provide further evidence for RTX being effective in MS treatment, to a similar extent to natalizumab in RRMS. Clinicians must be vigilant for the potential occurrence of infections.

Stereotactic radiosurgery for medically refractory multiple sclerosis-related tremor.

OBJECTIVE Multiple sclerosis (MS) is a neurodegenerative disease that can lead to severe intention tremor in some patients. In several case reports, conventional radiotherapy has been reported to possibly exacerbate MS. Radiosurgery dramatically limits normal tissue irradiation to potentially avoid such a problem. Gamma Knife thalamotomy (GKT) has been established as a minimally invasive technique that is effective in treating essential tremor and Parkinson's disease-related tremor. The goal in this study was to analyze the outcomes of GKT in patients suffering from medically refractory MS-related tremor. METHODS The authors retrospectively studied the outcomes of 15 patients (mean age 46.5 years) who had undergone GKT over a 15-year period (1998-2012). Fourteen patients underwent GKT at a median maximum dose of 140 Gy (range 130-150 Gy) using a single 4-mm isocenter. One patient underwent GKT at a dose of 140 Gy delivered via two 4-mm isocenters (3 mm apart). The posteroinferior region of the nucleus ventralis intermedius (VIM) was the target for all GKTs. The Fahn-Tolosa-Marin clinical tremor rating scale was used to evaluate tremor, handwriting, drawing, and drinking. The median time to the last follow-up was 39 months. RESULTS After GKT, 13 patients experienced tremor improvement on the side contralateral to surgery. Four patients noted tremor arrest at a median of 4.5 months post-GKT. Seven patients had excellent tremor improvement and 6 had good tremor improvement. Four patients noted excellent functional improvement, 8 noted good functional improvement, and 1 noted satisfactory functional improvement. Three patients experienced diminished tremor relief at a median of 18 months after radiosurgery. Two patients experienced temporary adverse radiation effects. Another patient developed a large thalamic cyst 60 months after GKT, which was successfully managed with Ommaya reservoir placement. CONCLUSIONS Gamma Knife thalamotomy was found to be a minimally invasive and beneficial procedure for medically refractory MS tremor.

From natalizumab to fingolimod in eight weeks - Immunological, clinical, and radiological data in quest of the optimal switch.

Natalizumab (NZB) discontinuation during a treatment change is associated with recurrence of disease activity in a significant proportion of multiple sclerosis (MS) patients. The immunological basis why disease reactivation occurs in selected patients is unresolved. In search of a prognostic biomarker for a safe and effective transition from NZB to fingolimod, we monitored five parameters related to pharmacokinetic and pharmacodynamic effects of the two drugs in 12 MS patients until six months on fingolimod. Clearance of free and cell-bound NZB, re-expression of alpha-4, and fingolimod-mediated changes on CD8+ and CD4+ T cell subsets showed pronounced interindividual variability. Higher frequencies of memory CD8+ T cells after six months on fingolimod were the sole association with disease reactivation. None of the investigated parameters thus had potential as prognostic biomarker for the outcome of the switch. Our findings rather support the thesis of broad interindividual differences in the immunopathogenesis of MS.

Neurological deficit following stereotactic radiosurgery for trigeminal neuralgia.

We report a unique case of neurological deficit from late onset multiple sclerosis (MS), in a 65-year-old woman, after stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). At 3.5months post-SRS for TN, the patient developed ataxia and left leg paraesthesiae and brain MRI showed altered signal and enhancement in the vicinity of the right trigeminal root entry zone (REZ). The symptoms remitted following treatment with intravenous methylprednisolone, however, 10months post-SRS, the patient developed gait ataxia and left lower limb weakness. MRI showed persistent T2 changes at the REZ and multiple new non-enhancing white matter lesions in the cerebrum and spinal cord; and oligoclonal bands were present in the cerebrospinal fluid but not serum. A diagnosis of multiple sclerosis (MS) was made. This report raises the issue of whether the risk of radiation-induced toxicity is increased in patients with MS treated with SRS. We hypothesise that breakdown in the blood brain barrier secondary to the radiosurgery may have triggered a vigorous local inflammatory response.

[Application of laser therapy in the physiotherapy of patients with multiple sclerosis]. / Zastosowanie promieniowania laserowego w fizjoterapii chorych na stwardnienie rozsiane.

Multiple sclerosis is a chronic disease of the nervous system, which main manifestations are disseminated demyelinated the changes in the central nervous system. The pathogenesis of this disease is still not known, the curative treatment is not possible. In connection with the alleged autoimmune genesis of MS patients are administered immunomodulatory drugs. Patients with multiple sclerosis suffer from a number of symptoms associated with this disease. The aim of this article is to present the main clinical symptoms characteristic of MS and to present biological effects of low-energy lasers used in the treatment of multiple sclerosis.

Complications in MS patients after CCSVI procedures abroad (Calgary, AB).

BACKGROUND: The "chronic cerebrospinal venous insufficiency" or "CCSVI" hypothesis, namely that multiple sclerosis (MS) is caused by abnormalities in the azygous and internal jugular veins with subsequent alterations in venous hemodynamics in the central nervous system, has been a dominant topic in MS care in Canada over the past year. Although there is no methodologically rigorous evidence to support this hypothesis presently, a considerable number of MS patients have undergone endovascular CCSVI procedures. Such procedures include angioplasty or stent placement in jugular and azygous veins. The safety and efficacy of these procedures is unknown, but not without risk. METHODS: Chart and patient review of five patients with confirmed MS followed in Calgary were undertaken after patients came to medical attention by referral or admission secondary to complications believed to be associated with CCSVI procedures. RESULTS: Complications upon investigation and review included internal jugular vein stent thrombosis, cerebral sinovenous thrombosis, stent migration, cranial nerve injury and injury associated with venous catheterization. CONCLUSIONS: As the debate about CCSVI and its relationship to MS continues, the complications and risks associated with venous stenting and angioplasty in jugular and azygous veins are becoming clearer. As increasing numbers of MS patients are seeking such procedures, these five cases represent the beginning of a wave of complications for which standardized care guidelines do not exist. Our experience and that of our colleagues will be used to develop guidelines and strategies to monitor and manage these patients as their numbers increase.

Utilization of extremely low frequency (ELF) magnetic fields in chronic disease; five years experience: three case reports.

We present three examples of the use of ELF magnetic therapy, two cases of multiple sclerosis and one of chronic pulmonary disease. In each of the two MS cases the Seqex device was applied as an adjunct to antioxidant medication two times a week for six weeks. Radiological and MRI examination indicated improvement in the two MS patients and stabilization in the patient with obstructive pulmonary disease following merely five treatments.

Multiple sclerosis, brain radiotherapy, and risk of neurotoxicity: the Mayo Clinic experience.

PURPOSE: The aim of this study was a retrospective assessment of neurotoxicity in patients with multiple sclerosis (MS) receiving external beam radiotherapy (EBRT) to the brain. METHODS AND MATERIALS: We studied 15 consecutively treated patients with MS who received brain EBRT. Neurologic toxicity was assessed with the Common Toxicity Criteria v.3.0. RESULTS: Median follow-up for the 5 living patients was 6.0 years (range, 3.3-27.4 years). No exacerbation of MS occurred in any patient during EBRT. Five patients had Grade 4 neurologic toxicity and 1 had possible Grade 5 toxicity. Kaplan-Meier estimated risk of neurotoxicity greater than Grade 4 at 5 years was 57% (95% confidence interval, 27%-82%). Toxicity occurred at 37.5 to 54.0 Gy at a median of 1.0 year (range, 0.2-4.3 years) after EBRT. Univariate analysis showed an association between opposed-field irradiation of the temporal lobes, central white matter, and brainstem and increased risk of neurotoxicity (p < 0.04). Three of 6 cases of toxicity occurred in patients treated before 1986. CONCLUSIONS: External beam radiotherapy of the brain in patients with MS may be associated with an increased risk of neurotoxicity compared with patients without demyelinating illnesses. However, this risk is associated with treatment techniques that may not be comparable to modern, conformal radiotherapy.

Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis.

BACKGROUND: Certain stem cell transplantation procedures might slow down inflammatory pathology in multiple sclerosis (MS). AIMS: To halt disease progression in aggressive MS by a bone marrow transplantation (BMT) protocol aimed at maximum T cell suppression. METHODS: Autologous BMT was performed in 14 patients with rapid secondary progressive MS (median EDSS score at baseline, 6; median disease duration, five years). To accomplish rigorous T cell ablation, a strong conditioning protocol was chosen--cyclophosphamide, total body irradiation, and antithymocyte globulin. To minimise the possibility of reinfusing mature T cells in the graft, bone marrow, not peripheral blood, was used as the CD34+ stem cell source. RESULTS: Median follow up was 36 months (range, 7-36). Post-transplant haemopoietic recovery was successful in all patients. Early toxicity included Epstein-Barr virus related post-transplantation lymphoproliferative disorder. Longterm effects were development of antithyroid antibodies (three) and myelodysplastic syndrome (one). One patient died of progressive disease five years after transplantation. Treatment failure, defined by EDSS increase sustained for six months or more, was seen in nine patients and stabilisation or improvement in five. Other clinical parameters generally showed the same outcome. No gadolinium enhanced lesions were seen on post-treatment magnetic resonance imaging, in either cerebral or spinal cord scans. However, cerebrospinal fluid oligoclonal bands remained positive in most cases. CONCLUSIONS: This strong immunosuppressive regimen did not prevent clinical progression in patients with aggressive secondary MS. The lack of efficacy, together with some serious side effects, does not favour the use of similar rigorous T cell depleting protocols in the future.

Gamma irradiation of human dendritic cells influences proliferation and cytokine profile of T cells in autologous mixed lymphocyte reaction.

Dendritic cells (DC) are the most potent antigen-presenting cells (APC); their ability to induce proliferation of T cells in a mixed lymphocyte reaction (MLR) assay is commonly used for the evaluation of their function. It is a general thought that gamma irradiation of APC does not influence their ability to activate T-cell proliferation, but the data from several studies are controversial. To further determine the mechanisms involved in DC-induced T-cell activation in MLR assay, human DC induced from peripheral blood mononuclear cells (PBMC) were gamma-irradiated and determine their effects on the proliferation and cytokine profiles of T cells in an autologous MLR. DC were induced from the PBMC of 11 multiple sclerosis (MS) patients with RMPI 640 medium containing recombinant human GM-CSF (rhGM-CSF; 800 U/ml) and recombinant human IL-4 (rhIL-4; 500 U/ml). DC harvested on day 7 were divided into two equal parts. One part was not irradiated (naive DC); the other was gamma-irradiated at a dose of 30 Gy. Cell surface molecules were analyzed by flow cytometry. T-cell proliferation was determined using a beta-scintillation counter. The levels of IL-2, IL-4, IL-6 and IL-10 in co-culture supernatants were measured by ELISA. The results indicated that gamma irradiation reduced expression of CD86, CD80 and HLA-DR molecules on DC, especially CD86 (P=0.0072). DC, irradiated or non-irradiated, effectively stimulated autologous T-cell proliferation. Compared to naive DC, irradiated DC showed a markedly lower capacity to promote T-cell proliferation (P=0.0073), and strikingly up-regulated secretion of IL-4 (P=0.0145) and IL-2 (P=0.0323) by autologous T cells. No significant differences were noted in IL-6 and IL-10 production between T cells co-cultured with naive DC and irradiated DC (P>0.05). It is concluded that gamma irradiation of DC not only influences the phenotype of DC but also alters their capacity to stimulate the proliferation and the cytokine profiles of autologous T cells in a MLR.

Modified total lymphoid irradiation and low dose corticosteroids in progressive multiple sclerosis.

In a double-blind prospective randomized trial, we assessed the efficacy and safety of modified total lymphoid irradiation (TLI) plus low dose prednisone (TLI-LDP) as compared to sham TLI plus identical prednisone therapy (sham TLI-LDP) in 46 patients with progressive forms of multiple sclerosis (MS). No significant difference existed between groups at study entry in patient age, sex, duration of MS, or disability status. However, following treatment, significantly fewer TLI patients showed a sustained one point decline in the Expanded Disability Status Scale, the primary study endpoint, as compared to the sham TLI group using the Kaplan-Meier Product-limit survival analysis, (P<0.005). Risk for relapse requiring treatment with intravenous methylprednisolone was reduced by 54% in the TLI-treated group (P<0.05). Significantly fewer TLI-LDP patients had gadolinium enhancing plus new T2-weighted lesions (P=0.018) when compared to the sham group post-treatment. There was also a substantial and significant decrease in blood lymphocytes in the TLI-LDP group when compared to either pretreatment values or to sham TLI-LDP through at least 12 months post-therapy. Side effects secondary to TLI were generally mild and well-tolerated. These results further support the hypothesis that TLI and systemic immunosuppression have a beneficial effect in progressive forms of MS.