[15th Post-ECTRIMS Meeting: a review of the latest developments presented at the 2022 ECTRIMS Congress (Part II)]. / XV Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2022 (II).

INTRODUCTION: On 4 and 5 November 2022, Madrid hosted the 15th edition of the Post-ECTRIMS Meeting, where neurologists specialised in multiple sclerosis outlined the latest developments presented at the 2022 ECTRIMS Congress, held in Amsterdam from 26 to 28 October. AIM: To synthesise the content presented at the 15th edition of the Post-ECTRIMS Meeting, in an article broken down into two parts. DEVELOPMENT: This second part describes the new developments in terms of therapeutic strategies for escalation and de-escalation of disease-modifying therapies (DMT), when and in whom to initiate or switch to highly effective DMT, the definition of therapeutic failure, the possibility of treating radiologically isolated syndrome and the future of personalised treatment and precision medicine. It also considers the efficacy and safety of autologous haematopoietic stem cell transplantation, different approaches in clinical trial design and outcome measures to assess DMT in progressive stages, challenges in the diagnosis and treatment of cognitive impairment, and treatment in special situations (pregnancy, comorbidity and the elderly). In addition, results from some of the latest studies with oral cladribine and evobrutinib presented at ECTRIMS 2022 are shown.

TITLE: XV Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2022 (II).Introducción. El 4 y el 5 de noviembre se celebró en Madrid la Reunión Post-ECTRIMS, en la que neurólogos expertos en esclerosis múltiple resumieron las principales novedades presentadas en el congreso de ECTRIMS 2022, celebrado entre el 26 y el 28 de octubre en Ámsterdam. Objetivo. Sintetizar las ponencias que tuvieron lugar en la Reunión Post-ECTRIMS, en un artículo desglosado en dos partes. Desarrollo. En esta segunda parte, se presentan las novedades sobre las estrategias terapéuticas de escalado y desescalado de los tratamientos modificadores de la enfermedad (TME), cuándo y a quién iniciar o cambiar a TME de alta eficacia, la definición de fracaso terapéutico, la posibilidad de tratar el síndrome radiológico asilado, el futuro del tratamiento personalizado y la medicina de precisión, la eficacia y seguridad del autotrasplante de células madre hematopoyéticas, diferentes aproximaciones en el diseño de ensayos clínicos y en las medidas de resultados para evaluar TME en fases progresivas, retos en el diagnóstico y tratamiento del deterioro cognitivo, y tratamiento en situaciones especiales (embarazo, comorbilidad y personas mayores). Además, se muestran los resultados de algunos de los últimos estudios realizados con cladribina oral y evobrutinib presentados en el ECTRIMS 2022.

12th Post-ECTRIMS Meeting: review of the novelties from the 2019 ECTRIMS Congress (II). / XII Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2019 (II).

INTRODUCTION: Like every year, after the ECTRIMS Congress, renowned Spanish neurologists who are experts in multiple sclerosis presented the main novelties in research in this field at the Post-ECTRIMS Meeting. AIM: To summarise the content presented at the 12th edition of the Post-ECTRIMS Meeting, which took place in September 2019 in Sevilla and is presented in two parts. DEVELOPMENT: In this second part, the most recent evidence on the use of disease-modifying treatments during pregnancy is presented. Details are provided concerning the results of phase 3 clinical trials conducted to evaluate the efficacy and safety of two potential disease-modifying treatments for relapsing-remitting multiple sclerosis: ponesimod and ofatumumab. For the progressive forms, both available disease modifying treatments and others still in the research phase are reviewed. In the field of stem cell therapies, the article includes the results of the only clinical trial carried out to date comparing patients with relapsing-remitting multiple sclerosis treated with autologous haematopoietic stem cell transplantation and those treated with disease-modifying therapies. There are no important developments as regards symptomatic treatments, although the European Academy of Neurology has published a guide on palliative care. The various sources of information that collect pharmacovigilance data in the post-marketing setting are reviewed. CONCLUSIONS: Patients diagnosed in recent years tend to have less severe multiple sclerosis, probably due to the fact that it is diagnosed in its milder stages together with the steady increase in the number of treatments available.

TITLE: XII Reunión Post-ECTRIMS: revisión de las novedades presentadas en el Congreso ECTRIMS 2019 (II).Introducción. Como cada año, tras la celebración del Congreso del ECTRIMS, reconocidos neurólogos españoles expertos en esclerosis múltiple expusieron en la Reunión Post-ECTRIMS las principales novedades en investigación en este ámbito. Objetivo. Sintetizar el contenido presentado en la XII edición de la Reunión Post-ECTRIMS, que tuvo lugar en septiembre de 2019 en Sevilla y que se presenta en dos partes. Desarrollo. En esta segunda parte, se exponen las evidencias más recientes sobre el uso de tratamientos modificadores de la enfermedad durante el embarazo. Se detallan los resultados de ensayos clínicos en fase 3 en los que se ha evaluado la eficacia y la seguridad de dos potenciales tratamientos modificadores de la enfermedad para la esclerosis múltiple remitente recurrente: ponesimod y ofatumumab. Para las formas progresivas, se revisan los tratamientos modificadores de la enfermedad disponibles y en investigación. En el ámbito de las terapias con células madre, se incluyen los resultados del único ensayo clínico hasta la fecha que compara a pacientes con esclerosis múltiple remitente recurrente tratados con trasplante autólogo de células madre hematopoyéticas y a los tratados con tratamientos modificadores de la enfermedad. No hay grandes novedades sobre tratamientos sintomáticos, aunque la Academia Europea de Neurología ha publicado una guía sobre cuidados paliativos. Se revisan las distintas fuentes de información que recogen datos de farmacovigilancia en el entorno poscomercialización. Conclusiones. Los pacientes diagnosticados en los últimos años tienden a tener una menor gravedad de la esclerosis múltiple, probablemente debido al diagnóstico desde sus estadios más leves y al continuo aumento de tratamientos disponibles.

Review of the novelties presented at the 2018 ECTRIMS Congress: 11th Post-ECTRIMS Meeting (II). / Revision de las novedades presentadas en el Congreso ECTRIMS 2018: XI Reunion Post-ECTRIMS (II).

The Post-ECTRIMS Meeting was held for the eleventh consecutive year in October 2018 in Madrid, with the aim of analysing the advances made in multiple sclerosis that were highlighted at the latest ECTRIMS annual congress. Based on the issues discussed at this meeting, attended by the nation's foremost opinion leaders on multiple sclerosis, two review articles are presented. This second part includes the growing body of evidence confirming the safety of exposure to disease-modifying treatments in women planning a pregnancy, and the beneficial effect of breastfeeding, provided that the disease is not very active. It addresses data showing how the application of the 2017 McDonald criteria in the paediatric population has significantly improved diagnosis compared to the previous criteria. With regard to progressive multiple sclerosis, the results of neuroprotective drugs are inconclusive, but biomarkers are proposed to improve the evaluation of the therapeutic response. Studies on myelin repair treatments suggest that remyelination in multiple sclerosis is possible. Likewise, there are favourable indications for haematopoietic stem cell transplantation, provided that patients are selected appropriately. On the other hand, we also conduct a review of the similarities and differences of the recommendations in the new clinical practice guidelines. Finally, the positive results of cognitive and motor rehabilitation with the use of new technologies point to the systematic incorporation of these tools in the treatment of the disease in the near future.

TITLE: Revision de las novedades presentadas en el Congreso ECTRIMS 2018: XI Reunion Post-ECTRIMS (II).La reunion Post-ECTRIMS se celebro por undecimo año consecutivo el pasado octubre de 2018 en Madrid, con el objetivo de analizar los avances en esclerosis multiple destacados en el ultimo congreso anual ECTRIMS. Fruto de esta reunion, formada por los lideres de opinion en esclerosis multiple de ambito nacional, se presentan dos articulos de revision. En esta segunda parte, se incluye el creciente numero de evidencias que confirman la seguridad de la exposicion a los tratamientos modificadores de la enfermedad en mujeres que planifican un embarazo, y el efecto beneficioso de la lactancia, siempre y cuando la enfermedad no este muy activa. Se abordan los datos que muestran como la aplicacion de los criterios de McDonald de 2017 en poblacion pediatrica ha mejorado considerablemente el diagnostico en comparacion con los criterios anteriores. En cuanto a la esclerosis multiple progresiva, los resultados de los farmacos neuroprotectores son poco concluyentes, pero se proponen biomarcadores para mejorar la evaluacion de la respuesta terapeutica. Los estudios sobre tratamientos de reparacion de la mielina sugieren que la remielinizacion en la esclerosis multiple es posible. De igual manera, se exponen indicios favorables sobre el trasplante de celulas madre hematopoyeticas, siempre que se seleccione adecuadamente a los pacientes. Por otro lado, se revisan las similitudes y diferencias de las recomendaciones de las nuevas guias de practica clinica publicadas. Por ultimo, los resultados positivos de la rehabilitacion cognitiva y motora con el uso de las nuevas tecnologias vaticinan la incorporacion sistematica de estas herramientas en el tratamiento de la enfermedad en un futuro proximo.

Ocrelizumab: its efficacy and safety in multiple sclerosis. / Ocrelizumab: eficacia y seguridad en la esclerosis multiple.

INTRODUCTION: Ocrelizumab is a humanised monoclonal antibody that targets the CD20 antigen on B cells. It has recently been approved by the US (Food and Drug Administration) and European health agencies (European Medicines Agency) for the treatment of multiple sclerosis (MS) and is the first drug marketed for both relapsing-remitting MS (RRMS) and primary progressive MS (PPMS). The clinical trials conducted for both the relapsing forms (OPERA I/II) and the progressive forms of the disease (ORATORIO) have demonstrated its efficacy. The aim of this review is to address the main aspects of the efficacy and safety of ocrelizumab in MS. DEVELOPMENT: Using PubMed, a literature review was conducted of studies published at the ECTRIMS 2017 Congress and of active studies in ClinicalTrials. In order to evaluate the efficacy and safety of ocrelizumab in MS, both randomised clinical trials and their extension and follow-up studies were reviewed, and information about its safety obtained from monitoring programmes of the Food and Drug Administration and European Medicines Agency was included. CONCLUSIONS: Ocrelizumab is the first drug that has been shown to be able to significantly slow disability progression at 12 and 24 weeks in patients with PPMS. It is also effective in controlling clinical and radiological activity in patients with RRMS forms, and it is approved and indicated for both phenotypes of the disease. To date, the safety profile of ocrelizumab matches that observed in clinical trials, without any unexpected alerts.

TITLE: Ocrelizumab: eficacia y seguridad en la esclerosis multiple.Introduccion. El ocrelizumab es un anticuerpo monoclonal humanizado contra el antigeno CD20 de las celulas B. Ha sido aprobado recientemente por las agencias sanitarias estadounidense (Food and Drug Administration) y europea (European Medicines Agency) para el tratamiento de la esclerosis multiple (EM), y supone el primer farmaco comercializado tanto para la EM remitente recurrente (EMRR) como para la EM primariamente progresiva (EMPP). Los ensayos clinicos, tanto pa­ra formas recurrentes (OPERA I/II) como para las formas progresivas de la enfermedad (ORATORIO), han demostrado su eficacia. El objetivo de esta revision es abordar los principales aspectos de eficacia y seguridad del ocrelizumab en la EM. Desarrollo. Se ha realizado una revision bibliografica a traves de PubMed de trabajos publicados en el congreso ECTRIMS 2017 y de estudios activos en ClinicalTrials. Con el fin de evaluar la eficacia y seguridad del ocrelizumab en la EM, se han revisado ensayos clinicos aleatorizados, asi como sus estudios de extension y de seguimiento, y se ha incluido informacion sobre seguridad de los programas de monitorizacion de la Food and Drug Administration y la European Medicines Agency. Conclusiones. El ocrelizumab es el primer farmaco que ha demostrado poder frenar de forma significativa la progresion de la discapacidad en 12 y 24 semanas en pacientes con EMPP. Es tambien eficaz en el control de la actividad clinica y radiologica en pacientes con formas de EMRR, y su aprobacion e indicacion engloban ambos fenotipos de la enfermedad. Hasta ahora, el perfil de seguridad del ocrelizumab se ajusta a lo observado en los ensayos clinicos, sin alertas inesperadas.

Netrin-1 and multiple sclerosis: a new biomarker for neuroinflammation?

BACKGROUND AND PURPOSE: Netrin-1, an axon guidance protein, reduces serum levels of pro-inflammatory mediators and stabilizes the blood-brain barrier limiting the entrance of immune cells into the central nervous system. The aim was to investigate its presence in the experimental autoimmune encephalomyelitis (EAE) model and in multiple sclerosis (MS) patients with and without clinical activity. METHODS: Netrin-1 levels were evaluated in EAE mouse tissues. Afterwards, serum netrin-1 was cross-sectionally quantified in 90 patients with different MS phenotypes and 30 control subjects. An additional group of 10 relapsing-remitting MS (RRMS) patients was longitudinally evaluated throughout a relapse (RRMSr) with an interval of 60 days. Tumour necrosis factor α (TNFα), a reference inflammatory cytokine, and netrin-1 were quantified by enzyme-linked immunosorbent assay. RESULTS: Experimental autoimmune encephalomyelitis mice showed significantly lower netrin-1 levels and higher TNFα amounts in sera, spinal cord and cerebella than healthy control mice. MS patients showed significantly lower serum netrin-1 levels than controls (511.62 ± 209.30 and 748.32 ± 103.24 pg/ml, respectively; P ≤ 0.005). The lowest protein levels were found in RRMSr, remaining significantly lower throughout the relapse. TNFα serum concentrations were higher in MS patients compared to controls, and negatively correlated with netrin-1 levels (r = -0.3734, P ≤ 0.0001). CONCLUSIONS: Netrin-1 decreased in EAE and in MS patients, mainly during relapse, suggesting an anti-inflammatory role of netrin-1. Further research should be performed in a larger cohort of patients to validate netrin-1 as a biomarker of MS inflammatory activity.

Review of the novelties presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (II).

The most relevant data presented at the 28th edition of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) held in October 2012 in France have been summarised in the fifth edition of the Post-ECTRIMS Expert Meeting held in Madrid in October 2012. This review is the result of the meeting, which is being published in three parts. This second part of the Post-ECTRIMS review discusses the biology of recovery and remyelination in multiple sclerosis (MS) as well as the different repair and endogenous and exogenous remyelination strategies currently being evaluated based on the fact that resident microglia and oligodendroglial progenitor cells have been implicated in the remyelination process. This review also discusses the current state and future use of biomarkers in MS and proposes as markers of neurodegeneration the following: T2 lesion volume and brain atrophy using MRI and the loss of the ganglion cell layer as assessed by optical coherence tomography. A greater future utility for double inversion recovery (DIR) sequences is proposed to correlate cognitive impairment with MS impairment, given its higher diagnostic yield in locating and defining cortical lesions. The availability of novel biomarkers in the future requires strict validation. In this context, this paper proposes possible areas of action to improve the current situation and also presents the latest research results in identifying potential candidates with useful diagnostic characteristics, prognostic characteristics, treatment responses, and safety procedures.

TITLE: Revision de las novedades presentadas en el XXVIII Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS) (II).Los datos mas relevantes presentados en la XXVIII edicion del Congreso del Comite Europeo para el Tratamiento e Investigacion en Esclerosis Multiple (ECTRIMS), celebrado en octubre de 2012 en Francia, han sido resumidos en la quinta edicion de la Reunion de Expertos Post-ECTRIMS celebrada en Madrid en octubre de 2012, fruto de la cual nace esta revision que se publica en tres partes. En esta segunda parte de la revision Post-ECTRIMS se analiza la biologia de la recuperacion y remielinizacion en la esclerosis multiple (EM), y se discuten las diferentes estrategias de reparacion y remielinizacion endogena y exogena que actualmente estan siendo evaluadas, sobre la base de que la microglia residente y las celulas precursoras de oligodendrocitos se han visto implicadas en el proceso de remielinizacion. Asimismo, se expone el estado actual y uso futuro de los biomarcadores en EM, y se proponen como marcadores de neurodegeneracion el volumen lesional en T2 y la atrofia cerebral mediante resonancia magnetica, asi como la perdida de capa de celulas ganglionares mediante tomografia de coherencia optica. Se plantea una mayor utilidad futura de las secuencias DIR para correlacionar las alteraciones cognitivas con las alteraciones de la EM, dado su mayor rendimiento diagnostico en localizar y definir lesiones corticales. La disponibilidad de nuevos biomarcadores en un futuro requiere una validacion estricta. En este sentido, se plantean posibles areas de actuacion dirigidas a mejorar la situacion actual, y ademas se presentan los resultados de las investigaciones mas recientes en la identificacion de posibles candidatos con utilidad diagnostica, pronostica, de respuesta al tratamiento y de seguridad.

[Change of treatment in patients with multiple sclerosis and its consequences in clinical practice]. / Cambio de tratamiento en pacientes con esclerosis multiple y sus consecuencias en la practica clinica.

INTRODUCTION: Thirty per cent of patients with multiple sclerosis (MS) present a suboptimal response to treatment in the first few years. The real impact of the change of treatment has still not been well established. AIMS: To describe our clinical practice with regard to the change of treatment in MS patients with a suboptimal response and to analyse their progress depending on our therapeutic decisions. PATIENTS AND METHODS: The study is observation-based and retrospective. The sample was made up of patients with relapsing-remitting MS and at least one event after establishing immunomodulatory treatment. Both the intention to change treatment and the delays until the actual change took place were taken into account. The theoretical consequences of these strategies were measured by the changes in the expected curve of the Multiple Sclerosis Severity Scale (MSSS). RESULTS: A comparison of those who changed immunomodulator with those that did not showed that 64.3% versus 35.3%, respectively, improved on the expected curve of the MSSS (p > 0.05). Patients who improved the expected curve of the MSSS had changed treatment before those who did not improve (1.9 months versus 6 months), although the differences were not significant. The mean time that elapsed between taking the decision to change and actually changing the treatment was 2.70 ± 3.55 months. CONCLUSIONS: Despite limitations due to the size of the sample, the patients with a suboptimal response who changed treatment early could benefit from an improvement in their expected progression on the MSSS.

ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis.

Escalation therapy with mitoxantrone (MX) in highly active multiple sclerosis is limited by partially dose-dependent side-effects. Predictors of therapeutic response may result in individualized risk stratification and MX dosing. ATP-binding cassette-transporters ABCB1 and ABCG2 represent multi-drug resistance mechanisms involved in active cellular MX efflux. Here, we investigated the role of ABC-gene single nucleotide polymorphisms (SNPs) for clinical MX response, corroborated by experimental in vitro and in vivo data. Frequencies of ABCB1 2677G>T, 3435C>T and five ABCG2-SNPs were analysed in 832 multiple sclerosis patients (Germany, Spain) and 264 healthy donors. Using a flow-cytometry-based in vitro assay, MX efflux in leukocytes from individuals with variant alleles in both ABC-genes (designated genotype ABCB1/ABCG2-L(ow), 22.2% of patients) was 37.7% lower than from individuals homozygous for common alleles (ABCB1/ABCG2-H(igh), P < 0.05, 14.8% of patients), resulting in genotype-dependent MX accumulation and cell death. Addition of glucocorticosteroids (GCs) inhibited MX efflux in vitro. ABC-transporters were highly expressed in leukocyte subsets, glial and neuronal cells as well as myocardium, i.e. cells/tissues potentially affected by MX therapy. In vivo significance was further corroborated in experimental autoimmune encephalomyelitis in Abcg2(-/-) animals. Using a MX dose titrated to be ineffective in wild-type animals, disease course and histopathology in Abcg2(-/-) mice were strongly ameliorated. Retrospective clinical analysis in MX monotherapy patients (n = 155) used expanded disability status scale, relapse rate and multiple sclerosis functional composite as major outcome parameters. The clinical response rate [overall 121 of 155 patients (78.1%)] increased significantly with genotypes associated with decreasing ABCB1/ABCG2-function [ABCB1/ABCG2-H 15/24 (62.5%) responders, ABCB1/ABCG2-I(ntermediate) 78/98 (79.6%), ABCB1/ABCG2-L 28/33 (84.8%), exact Cochran-Armitage test P = 0.039]. The odds ratio for response was 1.9 (95% CI 1.0-3.5) with each increase in ABCB1/ABCG2 score (from ABCB1/ABCG2-H to -I-, and -I to -L). In 36 patients with severe cardiac or haematological side effects no statistically relevant difference in genotype frequency was observed. However, one patient with biopsy proven cardiomyopathy only after 24 mg/m2 MX exhibited a rare genotype with variant, partly homozygous alleles in 3 ABC-transporter genes. In conclusion, SNPs in ABC-transporter genes may serve as pharmacogenetic markers associated with clinical response to MX therapy in multiple sclerosis. Combined MX/GC-treatment warrants further investigation.

Induction of serum soluble tumor necrosis factor receptor II (sTNF-RII) and interleukin-1 receptor antagonist (IL-1ra) by interferon beta-1b in patients with progressive multiple sclerosis.

BACKGROUND: Cytokine inhibitors, such as soluble tumor necrosis factor receptor II (sTNFRII) and interleukin-1 receptor antagonist (IL-1ra) are possible regulators of proinflammatory cytokine activity. Although previous studies have shown induction of sTNF-RII and IL-1ra by interferon-beta (IFNbeta) in patients with relapse-onset forms of multiple sclerosis (MS), to date no studies of these cytokine inhibitors have been performed in patients with essentially progressive forms of MS. OBJECTIVE: To address the effects of IFNbeta on serum levels of sTNF-RII and IL-1ra in a cohort of progressive MS patients and to assess the relationship between levels and changes of sTNF-RII and IL-1ra and clinical and radiological variables. Methods Serial blood samples were obtained from a cohort of 73 patients with progressive MS who participated in a placebo-controlled clinical trial with IFNbeta-1b. Serum levels of sTNF-RII and IL-1ra were measured by multiplex enzyme-linked immunosorbent assay at baseline and after 3, 6, 12, and 24 months. EDSS and MSFC scores were recorded at the time of blood sampling, and MR scans were obtained at baseline and after 12 and 24 months. RESULTS: Treatment with IFNbeta was associated with significant increases of sTNF-RII and IL-1ra serum levels during the followup period. A strong correlation at 24 months was observed between levels of sTNF-RII and EDSS scores in the placebo group. Finally, a trend for negative association was found between changes in sTNFRII and percentage change in T2-weighted lesion load at 24 months in the IFNbeta treated group. CONCLUSIONS: sTNF-RII and IL-1ra levels are increased in the serum of progressive MS patients during IFNbeta therapy and may be one mechanism by which IFNbeta mediates its effects in the treatment of MS.

Adenoviral overproduction of interleukin-1 receptor antagonist increases beta cell replication and mass in syngeneically transplanted islets, and improves metabolic outcome.

AIMS/HYPOTHESIS: Interleukin-1 receptor antagonist (IL1RN, also known as IL1RA) is a naturally occurring inhibitor of IL-1 action and its overproduction protects pancreatic islets from the deleterious effects of IL-1beta on beta cell replication, apoptosis and function. The aim of this study was to determine whether viral gene transfer of the Il1rn gene into rat islets ex vivo had a beneficial effect on the outcome of the graft. MATERIALS AND METHODS: Streptozotocin-diabetic Lewis rats were syngeneically transplanted with 500 or 800 Ad-Il1rn-infected or uninfected islets. Islet grafts were collected on day 3, 10 or 28 after transplantation and beta cell apoptosis, replication, size and mass were determined. RESULTS: Animals transplanted with 500 islets remained hyperglycaemic throughout the follow-up, as expected. Beta cell replication increased in the Ad-Il1rn group on days 3, 10 and 28 after transplantation compared with normal pancreas. In uninfected islets, by contrast, beta cell replication was increased only on day 10. Beta cell apoptosis was increased in all transplanted groups; it was 25% lower in the Ad-Il1rn than in uninfected groups, but differences were not statistically significant. The initially transplanted beta cell mass was reduced on day 3, increasing subsequently in Ad-Il1rn grafts, but not in uninfected grafts. When 800 islets were transplanted, all animals grafted with Ad-Il1rn-infected islets, but only 40% of those transplanted with uninfected islets, achieved normoglycaemia 14 days after transplantation. CONCLUSIONS/INTERPRETATION: Overproduction of IL1RN increased beta cell replication and mass of islet grafts and reduced the beta cell number required to achieve normoglycaemia.

Adenoviral overexpression of interleukin-1 receptor antagonist protein increases beta-cell replication in rat pancreatic islets.

The naturally occurring inhibitor of interleukin-1 (IL-1) action, interleukin-1 receptor antagonist protein (IRAP), binds to the type 1 IL-1 receptor but does not initiate IL-1 signal transduction. In this study, we have determined the effects of IL-1beta and IRAP overexpression on adult beta-cell replication and viability. IL-1beta reduced dramatically beta-cell replication in adult rat islets both at 5.5 mM (control: 0.29+/-0.04%; IL-1beta: 0.02+/-0.02%, P<0.05) and 22.2 mM glucose (control: 0.84+/-0.2%; IL-1beta: 0.05+/-0.05%, P<0.05). This effect was completely prevented in islets overexpressing IRAP after adenoviral gene transfer at 5.5 mM (Ad-IL-1Ra+IL-1beta: 0.84+/-0.1%, P<0.05) and 22.2 mM glucose (Ad-IL-1Ra+IL-1beta: 1.22+/-0.2%, P<0.05). Moreover, overexpression of IRAP increased glucose-stimulated beta-cell replication in the absence of IL-1beta exposure (Ad-IL-1Ra: 1.59+/-0.5%, P<0.05). beta-Cell death (TUNEL technique) was increased in IL-1beta-exposed islets but not in Ad-IL-1Ra-infected islets (control: 0.82+/-0.2%; control+IL-1beta: 1.77+/-0.2; IRAP: 0.61+/-0.2%; IRAP+IL-1beta: 0.86+/-0.1%, P<0.05). Comparable results were obtained by flow cytometry. To determine the effect of IRAP overexpression on beta-cell replication in vivo, Ad-IL-1Ra-transduced islets were transplanted into streptozotocin diabetic rats. beta-Cell replication was significantly increased in IRAP-overexpressing islet grafts (0.98+/-0.3%, P<0.05) compared to normal pancreas (0.35+/-0.02%), but not in control islet grafts (0.50+/-0.1%). This study shows that in addition to the effects of IL-1beta on beta-cell viability, this cytokine exerts a deleterious action on beta-cell replication, which can be prevented by IRAP overexpression, and provides support for the potential use of IRAP as a therapeutic tool.