Microglial Phagocytosis—Rational but Challenging Therapeutic Target in Multiple Sclerosis

Multiple sclerosis (MS) is the most common autoimmune and demyelinating disease of the central nervous system (CNS), characterized, in the majority of cases, by initial relapses that later evolve into progressive neurodegeneration, severely impacting patients’ motor and cognitive functions. Despite the availability of immunomodulatory therapies effective to reduce relapse rate and slow disease progression, they all failed to restore CNS myelin that is necessary for MS full recovery. Microglia are the primary inflammatory cells present in MS lesions, therefore strongly contributing to demyelination and lesion extension. Thus, many microglial-based therapeutic strategies have been focused on the suppression of microglial pro-inflammatory phenotype and neurodegenerative state to reduce disease severity. On the other hand, the contribution of myelin phagocytosis advocating the neuroprotective role of microglia in MS has been less explored. Indeed, despite the presence of functional oligodendrocyte precursor cells (OPCs), within lesioned areas, MS plaques fail to remyelinate as a result of the over-accumulation of myelin-toxic debris that must be cleared away by microglia. Dysregulation of this process has been associated with the impaired neuronal recovery and deficient remyelination. In line with this, here we provide a comprehensive review of microglial myelin phagocytosis and its involvement in MS development and repair. Alongside, we discuss the potential of phagocytic-mediated therapeutic approaches and encourage their modulation as a novel and rational approach to ameliorate MS-associated pathology.

Use of AUC7 adjuvant carboplatin in patients with stage I seminoma: systematic review of the literature

Purpose: Among the adjuvant options to be proposed to patients with stage I seminoma after orchiectomy, the administration of a single cycle of carboplatin, at the dosage reaching an area under the curve of 7 mg/mL/min (AUC7), is a relatively recent introduction in clinical practice. Methods: On April 1, 2016, we performed a systematic review of the literature to identify studies on the use of AUC7 carboplatin in the adjuvant setting for stage I seminoma patients. The studies were identified by searching the PubMed electronic database from July 2005 up to April 2016. The aim of this review is to clarify the state of art of this adjuvant option. Results: Adjuvant AUC7 carboplatin is an effective adjuvant treatment, able to reduce relapse rate in stage I seminoma patients. The heterogeneity of the methods for estimation and measurement of glomerular filtration rate represents an important issue in the administration of the optimal dose of carboplatin. Even with the lack of validated prognostic factors for relapses, a risk-adapted choice is commonly used to identify the optimal patient to be proposed this treatment. Conclusions: One cycle of AUC7 carboplatin is an effective, feasible, and safe adjuvant option to be discussed with stage I seminoma patients.

Promoting remyelination in multiple sclerosis: Current drugs and future prospects

Myelin destruction due to inflammatory oligodendrocyte cell damage or death in conjunction with axonal degeneration are among the major histopathological hallmarks of multiple sclerosis (MS). The majority of available immunomodulatory medications for MS are approved for relapsing–remitting (RR) MS, for which they reduce relapse rate, MRI measures of inflammation, and the accumulation of disability. These medications are, however, of little benefit during progressive MS where axonal degeneration following demyelination outweighs inflammation. This has sparked great interest in the development of new remyelination therapies aimed at reversing the neurodegenerative damage observed in this disease. Remyelination as a result of oligodendrocyte production from oligodendrocyte precursor cells (OPCs) is considered a promising potential target for the treatment of all stages of MS. In this review we present an overview of a) approved medications (some of them FDA-and EMA-approved for other diseases) with a proposed role in regeneration, b) regenerative treatments under investigation in clinical trials, and c) promising future therapeutic approaches aiming specifically at facilitating endogenous repair.

Comparison of Outcomes After Allogeneic HSCT for Adult Patients with AML in Remission Using in the Conditioning Regimen Either I.V. Busulfex (BU) Plus Cyclophosphamide (Cy) or TBI Plus Cy: An- ALWP-EBMT Survey.

Abstract 195 TBI/CY and oral (p.o) Bu/Cy are the traditional allogeneic HSCT (alloHSCT) myeloablative conditioning regimens for adults with AML with comparable survival and relapse probabilities. Intravenous (i.v.) Bu in contrast to p.o Bu has more predictable pharmacokinetics and a more favorable toxicity profile. Post transplantation outcomes with i.v. Bu/Cy, thus, may be superior to those achieved with TBI/Cy. In order to address these issues, the ALWP of the EBMT performed a survey comparing i.v. Bu/Cy to TBI/Cy as conditioning regimen for adult pts. with AML undergoing alloHSCT. Overall, 603 alloHSCT were analyzed. One hundred pts. underwent alloHSCT with Bu/Cy while 503 with TBI/Cy. Age was 41 (range, 18–57) and 41 (range, 16–61) years and median transplant year was 2004 (2000 – 2005) and 2003 (2000 – 2005) for the Bu/Cy and TBI/Cy groups, respectively. Disease status at alloHSCT were CR1 – 81% vs. 78% and CR2–19% vs. 22% for the Bu/Cy and TBI/Cy groups, respectively. WBC count at diagnosis was 11×109/L and 15×109/L, respectively. Regarding the cytogenetic classification, 10% and 10% were good, 60% and 55% were intermediate and 9% and 6% were poor risk, respectively (data were NA for 21%–26% of pts). Sixty nine percent and 68% of both groups underwent alloHSCT from sibling donors, while 31% and 32% from MUD, respectively. Length of follow up was 37(15–86) and 57 (1–105) months for both groups, respectively. Sixty nine percent and only 41% of the Bu/Cy and TBI/Cy groups received PB, while 31% and 59% received BM grafts, respectively (p<0.0001). Engraftment was similar in the Bu/Cy vs. the TBI/Cy groups, 95% and 96%, respectively. Cumulative incidence of TRM at 2y was 17+4% and 23+2%, respectively (p=0.23). Acute GVHD (II–IV) was also similar between the 2 groups, 28% and 32%, respectively. Two year relapse incidence was 30+5% and 22+2% for Bu/Cy vs. TBI/Cy, respectively (p=0.03) while LFS was comparable 57+5% and 61+2%, respectively (p=0.5). In multivariate analysis Cy/TBI was found to be an independent good prognostic factor for reduce relapse rate (p=0.03, HR-1.67) and there was a trend for higher TRM (p=0.16). Poor prognostic factors for LFS and TRM were age >40y, disease status (CR2 vs. CR1) and MUD vs. Sib. donor. In conclusion, in this retrospective EBMT survey outcomes of alloHSCT in adult pts. with AML in CR using either i.v Bu/Cy or TBI/Cy were comparable. Disclosures: No relevant conflicts of interest to declare.

Identification of HLA Allele Mismatch Combinations and Amino Acid Substitution Positions Associated with GVL Effect after Unrelated HSCT: Analysis from the Japan Marrow Donor Program.

Graft-versus-leukemia (GVL) effect is considered to reduce relapse rate due to eradication of residual leukemia cells after allogeneic hematopoietic stem cell transplantation (HSCT). Segregation it from graft-versus-host disease (GVHD) has been main issue clinically. We recently clarified 16 high-risk HLA mismatch combinations and eight high-risk specific amino acid substitution positions for severe acute GVHD in six HLA loci. In the current study, we clarified HLA allele mismatch combinations and amino acid substitution positions associated with GVL effect. Consecutive 4643 patients transplanted for hematological malignancy (ALL, AML, CML, MDS, MM and ML) with T cell replete marrow from a serologically HLA-A, -B and -DR antigen-matched donor through Japan Marrow Donor Program were registered in this cohort study. All HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles were retrospectively typed. The effect of HLA locus mismatch in allele level, the HLA allele mismatch combinations in HLA six loci and amino acid substitution positions on reduced relapse rate was analyzed using a multivariable competing risk regression model. As results (1) Mismatches of HLA-C (Odds ratio (OR)=0.69; p<0.0001) and HLA-DPB1 (OR=0.78; p<0.0001) were strongly reduced leukemia relapse, and HLA-A (OR=0.99; p=0.9), HLA-B (OR=0.98; p=0.91), HLA-DRB1 (OR=0.93; p=0.54) and HLA-DQB1 (OR=1.06; p=0.54) were not. (2) Total 10 HLA mismatch combinations were significantly associated with GVL effect; four in HLA-C allele (donor Cw*0303- patient Cw*1502 (n=25) OR=0.23, Cw*0102-Cw*1402 (n=16) OR=0, Cw*0801-Cw*0102 (n=10) OR=0 and Cw*1402-Cw*0304 (n=23) OR=0), six in HLA-DPB1 allele (DP*0402-DP*0201 (n=66) OR=0.41,?DP*0501-DP*0201 (n=351) OR=0.7,?DP*0501-DP*0401 (n=53) OR=0.45,?DP*0501-DP*0402?(n=121) OR=0.59, DP*0901-DP*0201 (n=50) OR=0.38 and DP*1301-DP*0201 (n=21) OR=0), but none in HLA-A, -B, -DRB1 and -DQB1 allele. Except two of four combinations in HLA-C, the other two in HLA-C and all six in HLA-DPB1 were different from high-risk one for severe acute GVHD. (3) Specific amino acid substitution at positions 9, 99, 156 in HLA-C molecule was elucidated as significant factors responsible for GVL effect and one of three was different from substitutions responsible for severe acute GVHD. As for HLA-DPB1, no significant association between the positions of specific amino acid substitution and GVL were found. In conclusion, large scale comprehensive analysis made it possible to identify 4 HLA-C and 6 HLA-DPB1 mismatch combinations responsible for GVL effects, some of which are different from one responsible for acute GVHD. Responsible amino acid substitutions on specific position were also elucidated in HLA-C, but not in HLA-DPB1. These findings suggest that donor selection according to these results could segregate GVL from acute GVHD, therefore these strategies might be beneficial for the selection of suitable donor for HSCT. And that, we speculate that the molecular base of GVL caused by the HLA-DPB1 mismatch might be different from that in HLA-C.

Disease-modifying drugs in childhood-juvenile multiple sclerosis: results of an Italian co-operative study

Objective: Immunomodulatory drugs (IDs) (interferon beta (IFNβ) and glatiramer acetate (GA)) reduce relapse rate and disease progression in relapsing-remitting multiple sclerosis (RRMS) but extensive data are not available on the effectiveness and tolerability of these drugs in childhood or adolescence. The aim of this study was to evaluate the impact of IFNβ and GA in MS patients treated before 16 years of age. Methods: A research group (Immunomodulatory Treatment of Early onset MS (ITEMS)) was promoted in Italy to collect a large series of patients affected by clinically definite and RRMS and treated with IDs before 16 years of age. Fifteen centres recognized subjects suitable for inclusion: 76 patients (52 females) were collected with a mean age at onset of 12.4 (SD 2.5) years, a mean disease duration of 18.6 (SD 14.7) and a relapse rate of 3.1 (SD 2.9). Results: Results were evaluated in 65 (45 females) subjects with a pretreatment and a treatment duration >3 months: 38 were treated with IFNβ-1a once weekly (Avonex), 18 with IFNβ three times weekly (16 with Rebif, 2 with Betaferon) and nine with GA (Copaxone). The mean pretreatment period was respectively 20, 18 and 9.2 months. The treatment duration lasted respectively 23.3, 40.7 and 33.3 months. The mean annualized relapse rate decreased dramatically during the treatment: from 2.4 to 0.4 in the Avonex group, from 3.2 to 0.8 in the Rebif-Betaferon group and from 2.8 to 0.25 in the GA group. The mean final EDSS scores were respectively (in brackets the initial scores): 1.3 (1.4), 1.6 (1.8) and 0.6 (1.1). In the whole group, the final score was unchanged or reduced in all subjects except eight. Clinical side effects were recorded in 41/65 subjects (mainly in subjects treated with IFNβ), abnormal laboratory findings were observed in 13/65 subjects: they were transient in most cases. IFNβ was stopped in six cases: in four because of inefficacy and in two cases because of side effects. Conclusions: Sixty-five clinically definite MS subjects were treated during childhood or adolescence with IDs. The treatment reduced the relapse rate and the progression of the disease in most cases. Side effects were common in subjects treated with IFNβ, but were well tolerated in most cases.

Interferon-β-1b and interferon-γ have similar inhibitory effects on apolipoprotein-E production in the monocyte/macrophage

Apolipoprotein-E (Apo-E) is the major lipid carrier in the brain, and is therefore important in the recycling of lipids and cholesterol to regenerating neurons during the remission phase of multiple sclerosis (MS). Interferon (IFN)-γ has been shown to inhibit Apo-E production by a mainly post-transcriptional method in a macrophage cell line, and reduced Apo-E in cerebrospinal fluid is noted during the remission phase in patients. IFN-β-1b is a recombinantly produced, anti-inflammatory cytokine, which has been shown to reduce the severity of MS relapses and reduce relapse rate. We have examined the effects of IFN-γ and IFN-β-1b on the production of Apo-E mRNA, cellular protein and secreted protein in primary monocytes derived from donor blood. IFN-β-1b does not relieve the dose-dependent inhibition of Apo-E seen with IFN-γ at up to 100 U/ml in these cells, and when used alone inhibits Apo-E production in a dose-dependent manner. This inhibition by IFN- β-1b was seen to be at a transcriptional level, and dose dependent up to 100 U/ml. Apo-E genotype, which has also been linked to failure to recover from MS relapses, did not affect this inhibition. The mode of action of IFN-β-1b in MS is therefore not thought to be through modification of Apo-E production.

Interferon β-1b: latest published results, 1995

Interferon β-1b (Betaseron) has been shown in a randomized, double-blind, placebo-controlled study to reduce relapse rate, relapse severity and MRI progression in patients with relapsing-remitting MS. The recently published Betaseron extension trial and studies from the National Institutes of Health provide additional evidence suggesting an important treatment effect The major new findings from these studies are reviewed in this paper. Other findings from these recent studies merit attention, however. Specifically, neutralizing antibody formation was seen in 38% of patients receiving high-dose Betaseron at 3 years. With the development of these antibodies, there was no longer clinical evidence that the drug remained effective. This observation must be considered carefully when initiating Betaseron therapy. The Betaseron trial suggests that MRI is an imperfect predictor of clinical disease activity. Of particular interest was the finding that patients receiving low-dose Betaseron developed ‘confirmed treatment failure’ sooner than placebo-treated patients, despite a clear treatment benefit on MRI-detected evidence of subclinical disease activity.