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International Journal of Molecular... Sep 2022Autologous hematopoietic stem cell transplantation (aHSCT) is a highly efficient treatment of multiple sclerosis (MS), and hence it likely normalizes pathological and/or...
Autologous hematopoietic stem cell transplantation (aHSCT) is a highly efficient treatment of multiple sclerosis (MS), and hence it likely normalizes pathological and/or enhances beneficial processes in MS. The disease pathomechanisms include neuroinflammation, glial cell activation and neuronal damage. We studied biomarkers that in part reflect these, like markers for neuroinflammation (C-X-C motif chemokine ligand (CXCL) 9, CXCL10, CXCL13, and chitinase 3-like 1 (CHI3L1)), glial perturbations (glial fibrillary acidic protein (GFAP) and in part CHI3L1), and neurodegeneration (neurofilament light chain (NfL)) by enzyme-linked immunosorbent assays (ELISA) and single-molecule array assay (SIMOA) in the serum and cerebrospinal fluid (CSF) of 32 MS patients that underwent aHSCT. We sampled before and at 1, 3, 6, 12, 24 and 36 months after aHSCT for serum, as well as before and 24 months after aHSCT for CSF. We found a strong increase of serum CXCL10, NfL and GFAP one month after the transplantation, which normalized one and two years post-aHSCT. CXCL10 was particularly increased in patients that experienced reactivation of cytomegalovirus (CMV) infection, but not those with Epstein-Barr virus (EBV) reactivation. Furthermore, patients with CMV reactivation showed increased Th1 phenotype in effector memory CD4+ T cells. Changes of the other serum markers were more subtle with a trend for an increase in serum CXCL9 early post-aHSCT. In CSF, GFAP levels were increased 24 months after aHSCT, which may indicate sustained astroglia activation 24 months post-aHSCT. Other CSF markers remained largely stable. We conclude that MS-related biomarkers indicate neurotoxicity early after aHSCT that normalizes after one year while astrocyte activation appears increased beyond that, and increased serum CXCL10 likely does not reflect inflammation within the central nervous system (CNS) but rather occurs in the context of CMV reactivation or other infections post-aHSCT.
Topics: Biomarkers; Chitinases; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Glial Fibrillary Acidic Protein; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Humans; Ligands; Multiple Sclerosis; Transplantation, Autologous
PubMed: 36142860
DOI: 10.3390/ijms231810946 -
Diagnostics (Basel, Switzerland) Mar 2022Free light chains kappa (FLCκ) in cerebrospinal fluid (CSF) are a part of the intrathecal immune response. This observational study was conducted to investigate the...
Free light chains kappa (FLCκ) in cerebrospinal fluid (CSF) are a part of the intrathecal immune response. This observational study was conducted to investigate the effects of different disease-modifying therapies (DMT) on the humoral intrathecal immune response in the CSF of patients with multiple sclerosis (MS). FLCκ were analyzed in CSF and serum samples from MS patients taking DMT (n = 60) and those in a control cohort of treatment-naïve MS patients (n = 90). DMT was classified as moderately effective (including INFß-1a, INFß-1b, glatiramer acetate, dimethyl fumarate, teriflunomide, triamcinolone); highly effective (including fingolimod, daclizumab) and very highly effective (alemtuzumab, natalizumab, rituximab/ocrelizumab, mitoxantrone). FLCκ were measured using a nephelometric FLCκ kit. Intrathecal FLCκ and IgG concentrations were assessed in relation to the hyperbolic reference range in quotient diagrams. Intrathecal FLCκ concentrations and IgG concentrations were significantly lower in samples from the cohort of MS patients taking very highly effective DMT than in samples from the cohort of MS patients taking highly effective DMT and in the treatment-naïve cohort (FLCκ: p = 0.004, p < 0.0001 respectively/IgG: p = 0.013; p = 0.021). The reduction in FLCκ could contribute to an anti-inflammatory effect in the CNS through this mechanism. There was no difference in the appearance of CSF-specific oligoclonal bands (p = 0.830). Longitudinal analyses are required to confirm these results.
PubMed: 35328273
DOI: 10.3390/diagnostics12030720 -
JAMA Network Open Aug 2019Median survival after lung transplant is less than 6 years. Standard maintenance therapy typically includes tacrolimus and an antimetabolite (mycophenolate mofetil or... (Comparative Study)
Comparative Study
IMPORTANCE
Median survival after lung transplant is less than 6 years. Standard maintenance therapy typically includes tacrolimus and an antimetabolite (mycophenolate mofetil or azathioprine). Replacing the antimetabolite with sirolimus after postoperative wound healing may improve long-term survival due to antifibrotic, antiproliferative, and antiaging effects of sirolimus.
OBJECTIVES
To compare survival between patients receiving sirolimus plus tacrolimus vs mycophenolate mofetil plus tacrolimus (the most common maintenance therapy) and to identify the combination of induction and maintenance therapy associated with the highest survival.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study of US recipients of lung transplants from January 1, 2003, through August 31, 2016, analyzed United Network for Organ Sharing (UNOS) data from January 1 through September 13, 2018. Because initiation of sirolimus therapy is usually delayed 3 to 12 months after lung transplant, primary analyses were based on patients alive and free of chronic rejection and malignant disease at 1 year in all groups, whereas sensitivity analyses used appropriate methods to include all patients from transplant time. Regression models adjusted for available potential confounders, including transplant center performance.
EXPOSURES
Cell cycle inhibitor maintenance therapies, including sirolimus (n = 219), mycophenolate mofetil (n = 5782), mycophenolate sodium (n = 408), azathioprine (n = 2556), and concurrent sirolimus plus mycophenolate mofetil (n = 54), were compared within a tacrolimus-based regimen. Combinations of each induction (basiliximab, daclizumab, antithymocyte globulin, alemtuzumab, or none) and maintenance (tacrolimus plus sirolimus, mycophenolate mofetil, or azathioprine) therapy were also compared.
MAIN OUTCOMES AND MEASURES
Survival was the primary outcome; chronic rejection incidence and subsequent mortality were secondary outcomes.
RESULTS
Among this population of 9019 patients (median age, 57 years [interquartile range {IQR}, 46-63 years]; 5194 men [57.6%]), sirolimus plus tacrolimus was associated with better survival than mycophenolate mofetil plus tacrolimus (median, 8.9 years [IQR, 4.4-12.7 years] vs 7.1 years [IQR, 3.6-12.1 years]; adjusted hazard ratio [aHR], 0.71; 95% CI, 0.56-0.89; P = .003). Chronic rejection incidence (aHR, 0.75; 95% CI, 0.61-0.92) and mortality after chronic rejection (aHR, 0.52; 95% CI, 0.31-0.81) were lower with sirolimus plus tacrolimus. Compared with mycophenolate mofetil plus tacrolimus, survival differences for sirolimus plus mycophenolate mofetil plus tacrolimus (aHR, 1.14; 95% CI, 0.79-1.65), mycophenolate sodium plus tacrolimus (aHR, 0.95; 95% CI, 0.77-1.17), and azathioprine plus tacrolimus (aHR, 0.93; 95% CI, 0.84-1.02) were not significant. The induction-maintenance combination with the highest survival was sirolimus plus tacrolimus without induction therapy (median survival, 10.7 years [IQR, 7.3-12.7 years]; aHR, 0.48; 95% CI, 0.31-0.76; P = .002) compared with mycophenolate mofetil plus tacrolimus with induction therapy (median survival, 7.4 years [IQR, 3.9-12.6 years]).
CONCLUSIONS AND RELEVANCE
Sirolimus plus tacrolimus was associated with improved patient survival after lung transplant compared with mycophenolate mofetil plus tacrolimus; no antibody induction therapy with sirolimus plus tacrolimus was associated with maximal survival.
Topics: Drug Therapy, Combination; Enzyme Inhibitors; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Lung Transplantation; Male; Middle Aged; Mortality; Mycophenolic Acid; Retrospective Studies; Sirolimus; Survival Analysis; Tacrolimus; Transplant Recipients; United States
PubMed: 31461151
DOI: 10.1001/jamanetworkopen.2019.10297 -
European Radiology Feb 2020Recent studies have created awareness that facial features can be reconstructed from high-resolution MRI. Therefore, data sharing in neuroimaging requires special...
BACKGROUND
Recent studies have created awareness that facial features can be reconstructed from high-resolution MRI. Therefore, data sharing in neuroimaging requires special attention to protect participants' privacy. Facial features removal (FFR) could alleviate these concerns. We assessed the impact of three FFR methods on subsequent automated image analysis to obtain clinically relevant outcome measurements in three clinical groups.
METHODS
FFR was performed using QuickShear, FaceMasking, and Defacing. In 110 subjects of Alzheimer's Disease Neuroimaging Initiative, normalized brain volumes (NBV) were measured by SIENAX. In 70 multiple sclerosis patients of the MAGNIMS Study Group, lesion volumes (WMLV) were measured by lesion prediction algorithm in lesion segmentation toolbox. In 84 glioblastoma patients of the PICTURE Study Group, tumor volumes (GBV) were measured by BraTumIA. Failed analyses on FFR-processed images were recorded. Only cases in which all image analyses completed successfully were analyzed. Differences between outcomes obtained from FFR-processed and full images were assessed, by quantifying the intra-class correlation coefficient (ICC) for absolute agreement and by testing for systematic differences using paired t tests.
RESULTS
Automated analysis methods failed in 0-19% of cases in FFR-processed images versus 0-2% of cases in full images. ICC for absolute agreement ranged from 0.312 (GBV after FaceMasking) to 0.998 (WMLV after Defacing). FaceMasking yielded higher NBV (p = 0.003) and WMLV (p ≤ 0.001). GBV was lower after QuickShear and Defacing (both p < 0.001).
CONCLUSIONS
All three outcome measures were affected differently by FFR, including failure of analysis methods and both "random" variation and systematic differences. Further study is warranted to ensure high-quality neuroimaging research while protecting participants' privacy.
KEY POINTS
• Protecting participants' privacy when sharing MRI data is important. • Impact of three facial features removal methods on subsequent analysis was assessed in three clinical groups. • Removing facial features degrades performance of image analysis methods.
Topics: Aged; Aged, 80 and over; Algorithms; Alzheimer Disease; Brain; Confidentiality; Face; Female; Glioblastoma; Humans; Image Interpretation, Computer-Assisted; Information Dissemination; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Neuroimaging; Reproducibility of Results; Tumor Burden
PubMed: 31691120
DOI: 10.1007/s00330-019-06459-3 -
Frontiers in Neurology 2020Daclizumab was approved by the FDA and the EMA in 2016 for the treatment of relapsing forms of multiple sclerosis (MS). Cases of severe inflammatory brain disease with...
Daclizumab was approved by the FDA and the EMA in 2016 for the treatment of relapsing forms of multiple sclerosis (MS). Cases of severe inflammatory brain disease with fatal outcome led to the withdrawal of approval in Europe and the US on March 2, 2018. Approximately 8,000 patients worldwide received daclizumab, but little is known about the further therapy management of these patients after the withdrawal of daclizumab. The aim of this study is to further analyze therapy management in MS patients after safety warnings and market withdrawal. Data from two registries in Germany, the German MS Registry (GMSR) and REGIMS, were used for this analysis. In total, 267 patients were included in this study. For almost 25% of patients (in the GMSR) daclizumab was the initial treatment. Most common pre-treatments were fingolimod, dimethyl fumarate, and natalizumab; various injectables summed up to 25.9%. The most common follow-up therapies were ocrelizumab and fingolimod. In most patients, follow-up therapies were administered shortly after discontinuation of daclizumab. The wash-out time for subsequent therapies varied between 1.2 and 4.0 months. Warnings and decisions by authorities led to a rapid decline and termination of therapies in both cohorts, indicating that such warnings have an immediate impact on the treatment landscape. Therapies that were started within a short time after the discontinuation of daclizumab were subsequently replaced by other therapies and may be considered as bridging therapies.
PubMed: 33013658
DOI: 10.3389/fneur.2020.00996 -
Clinical Transplantation Dec 2020Older (≥65) KT recipients differ from their younger counterparts in their immune response to immunosuppression (IS) and may have a different risk of malignancy after...
BACKGROUND
Older (≥65) KT recipients differ from their younger counterparts in their immune response to immunosuppression (IS) and may have a different risk of malignancy after receiving induction.
METHODS
We identified 66 700 adult KT recipients treated with anti-thymocyte globulin (ATG) (n = 40 443) or interleukin-2 receptor antagonist (IL-2RA) (n = 26 327) induction (1/1/1999-12/31/2014) using USRDS/Medicare data. We estimated the risk of first-diagnosed post-KT malignancy associated with induction (ATG vs. IL-2RA) using Cox proportional hazard models. We then tested whether these risks differed between older and younger recipients (Wald test for interaction). Models incorporated inverse probability of treatment weights to adjust for confounders.
RESULTS
The 3-year cumulative incidences of any diagnosed malignancy were 11.5%. ATG was associated with a higher malignancy risk (HR = 1.12, 95%CI:1.06-1.18). This association differed (p = 0.04) between younger (HR = 1.12, 95%CI:1.06-1.18) and older recipients (HR = 1.03, 95%CI:0.96-1.09). ATG was also associated with higher risk of skin (HR = 1.18, 95%CI:1.08-1.29), lung (HR = 1.24, 95%CI:1.05-1.47), and ovary malignancies (HR = 1.94, 95%CI:1.08-3.48). However, only the association of ATG with post-KT skin malignancy differed (p = 0.01) between younger (HR = 1.18; 95%CI:1.08-1.29) and older (HR = 1.01; 95%CI:0.93-1.09) recipients.
CONCLUSIONS
Compared with IL-2RA induction, ATG was associated with elevated post-KT malignancy risk but only among younger recipients. Transplant centers may need to tailor induction IS for younger recipients to mitigate malignancy risk.
Topics: Adult; Aged; Antilymphocyte Serum; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Medicare; Neoplasms; Prospective Studies; United States
PubMed: 33048385
DOI: 10.1111/ctr.14121 -
Journal of Neuroimmunology Apr 2021NK/T-cell ratios predict disease activity in relapsing remitting multiple sclerosis (RRMS). We investigated in 50 RRMS patients whether interleukin-2 receptor...
NK/T-cell ratios predict disease activity in relapsing remitting multiple sclerosis (RRMS). We investigated in 50 RRMS patients whether interleukin-2 receptor alpha-chain (IL-2Rα) expression and shedding associates with NK/T-cell balance, as suggested by daclizumab-trials in RRMS. A subsample (N = 31) was genotyped for IL2RA-associated MS risk SNPs. CD56 NK-cell/IL-17ACD4 T-cell ratios correlated negatively with plasma and PBMC-culture supernatant sIL-2Rα-levels [R = -0.209; p = 0.038 and R = -0.254; p = 0.012, resp.], and with CD4 T-cell CD25 MFI [R = -0.341; p = 0.001]. Carriers of the rs3118470 risk-allele showed higher sIL-2Rα-levels (P = 0.031) and a lower CD56 NK-cell/IL-17ACD4 T-cell ratio (P = 0.038). Therefore, IL-2Rα may be involved in the interplay between NK-cells and T-cells.
Topics: Adult; CD4-Positive T-Lymphocytes; Female; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-2 Receptor alpha Subunit; Killer Cells, Natural; Lymphocyte Count; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Polymorphism, Single Nucleotide
PubMed: 33529846
DOI: 10.1016/j.jneuroim.2021.577499 -
Cytotherapy Jan 2021Certain therapies (e.g., daclizumab) that promote expansion of natural killer (NK) cells are associated with clinical amelioration of disease in the context of multiple...
BACKGROUND AIMS
Certain therapies (e.g., daclizumab) that promote expansion of natural killer (NK) cells are associated with clinical amelioration of disease in the context of multiple sclerosis and associated mouse models. The clinical benefits are putatively attributable to an enhanced capacity of NK cells to kill activated pathogenic T cells. Whether a parallel approach will also be effective in systemic lupus erythematosus (lupus), a multi-organ autoimmune disease driven by aberrant responses of self-reactive T and B cells, is unclear.
METHODS
In the present study, the authors assess the therapeutic impact of IL-2- and IL-15-based strategies for expanding NK cells on measures of lupus-like disease in a mouse model.
RESULTS
Unexpectedly, cytokine-mediated expansion of cytotoxic lymphocytes aggravated immunological measures of lupus-like disease. Depletion studies revealed that the negative effects of these cytokine-based regimens can largely be attributed to expansion of CD8 T cells rather than NK cells.
CONCLUSIONS
These results provoke caution in the use of cytokine-based therapeutics to treat co-morbid cancers in patients with lupus and highlight the need for new methods to selectively expand NK cells to further assess their clinical value in autoimmune disease.
Topics: Animals; CD8-Positive T-Lymphocytes; Humans; Immunomodulation; Interleukin-15; Interleukin-2; Killer Cells, Natural; Lupus Erythematosus, Systemic; Lymphocyte Activation; Male; Mice
PubMed: 33092988
DOI: 10.1016/j.jcyt.2020.09.003 -
BMJ Neurology Open 2021Daclizumab is an anti-CD25 monoclonal antibody developed for the treatment of relapsing remitting multiple sclerosis, which was withdrawn worldwide in March 2018, due to...
BACKGROUND
Daclizumab is an anti-CD25 monoclonal antibody developed for the treatment of relapsing remitting multiple sclerosis, which was withdrawn worldwide in March 2018, due to emerging serious immune-mediated systemic andcentral nervous system adverse events. We report a case of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis occurring 14 weeks after stopping daclizumab, which responded to the proteasome inhibitor bortezomib.
METHODS
Following lack of effective clinical response to first line (corticosteroid, plasma exchange, intravenous immunoglobulin) and second line (rituximab) treatments, bortezomib therapy was commenced. The patient received six cycles of bortezomib treatment.
RESULTS
Clinical improvement was noted 4 weeks after the first of six cycles of bortezomib and the patient experienced sustained clinical improvement.
CONCLUSION
Our case provides further class IV evidence of the use of bortezomib therapy for treatment refractory anti-NMDAR encephalitis.
PubMed: 34079936
DOI: 10.1136/bmjno-2020-000096 -
BMC Bioinformatics Dec 2019Multiple Sclerosis (MS) is an immune-mediated inflammatory disease of the Central Nervous System (CNS) which damages the myelin sheath enveloping nerve cells thus...
BACKGROUND
Multiple Sclerosis (MS) is an immune-mediated inflammatory disease of the Central Nervous System (CNS) which damages the myelin sheath enveloping nerve cells thus causing severe physical disability in patients. Relapsing Remitting Multiple Sclerosis (RRMS) is one of the most common form of MS in adults and is characterized by a series of neurologic symptoms, followed by periods of remission. Recently, many treatments were proposed and studied to contrast the RRMS progression. Among these drugs, daclizumab (commercial name Zinbryta), an antibody tailored against the Interleukin-2 receptor of T cells, exhibited promising results, but its efficacy was accompanied by an increased frequency of serious adverse events. Manifested side effects consisted of infections, encephalitis, and liver damages. Therefore daclizumab has been withdrawn from the market worldwide. Another interesting case of RRMS regards its progression in pregnant women where a smaller incidence of relapses until the delivery has been observed.
RESULTS
In this paper we propose a new methodology for studying RRMS, which we implemented in GreatSPN, a state-of-the-art open-source suite for modelling and analyzing complex systems through the Petri Net (PN) formalism. This methodology exploits: (a) an extended Colored PN formalism to provide a compact graphical description of the system and to automatically derive a set of ODEs encoding the system dynamics and (b) the Latin Hypercube Sampling with PRCC index to calibrate ODE parameters for reproducing the real behaviours in healthy and MS subjects.To show the effectiveness of such methodology a model of RRMS has been constructed and studied. Two different scenarios of RRMS were thus considered. In the former scenario the effect of the daclizumab administration is investigated, while in the latter one RRMS was studied in pregnant women.
CONCLUSIONS
We propose a new computational methodology to study RRMS disease. Moreover, we show that model generated and calibrated according to this methodology is able to reproduce the expected behaviours.
Topics: Computational Biology; Computer Simulation; Disease Progression; Female; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Pregnancy; Recurrence
PubMed: 31822261
DOI: 10.1186/s12859-019-3196-4