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Beneficial effect of tolerogenic dendritic cells pulsed with MOG autoantigen in experimental autoimmune encephalomyelitis.

Treatment with tolerogenic dendritic cells (TolDC) is a promising, cell‐based strategy to regulate autoimmune diseases such as multiple sclerosis (MS) in an antigen‐specific way. This technique involves the use of TolDC from MS patients cultured in the presence of vitamin D3 (VitD3) and pulsed with myelin peptides to induce a stable hyporesponsiveness in myelin‐specific autologous T cells.

Baseline Differences in Minor Lymphocyte Subpopulations may Predict Response to Fingolimod in Relapsing-Remitting Multiple Sclerosis Patients.

Fingolimod, oral treatment for relapsing–remitting multiple sclerosis (RRMS), is an agonist of sphingosine and its metabolite S1P that binds their receptors, blocking the egress of lymphocytes from lymph nodes. The aim of this study was immunomonitoring of minor peripheral lymphocyte subpopulations in RRMS patients under treatment with fingolimod and correlation with treatment response.

Similar biological effect of high-dose oral versus intravenous methylprednisolone in multiple sclerosis relapses.

Our aim was to investigate differences in immune mechanisms in multiple sclerosis (MS) relapse, after high-dose oral methylprednisolone (oMP) or intravenous methylprednisolone (ivMP). We measured serum cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α and IFN-γ) in 39 of 49 MS patients with moderate-severe relapse, whom were treated with ivMP or oMP in a placebo-controlled, non-inferiority clinical trial. We assessed these cytokine levels at baseline and at 1 and 4 weeks post-treatment. The cytokine levels between oMP and ivMP were similar at any time. Proinflammatory cytokines (IL-6 and IFN-γ) were significantly decreased in both groups at week 1 (p = 0.05 / p = 0.03) and at week 4 (p = 0.04 / p = 0.05). This study provides further confirmatory evidence that oMP is not inferior to ivMP. Trial registration: clinicaltrials.gov identifier: NCT00753792

Monitoring CD49d receptor occupancy: A method to optimize and personalize natalizumab therapy in multiple sclerosis patients

In natalizumab‐treated relapsing‐remitting MS (RRMS) patients, various extended interval dosing strategies are under evaluation to minimize severe treatment‐associated side effects, mainly progressive multifocal leukoencephalopathy development. Up to now, it has not been presented any approach, even in form of assay design, to determine the optimal percentage of CD49d receptor occupancy (RO) associated with a favorable clinical, radiological, and immunological response.

Characterization of recent thymic emigrants (RTEs), transitional B and Th17 cells in multiple sclerosis (MS).

The finding that APECED syndrome is due to a failure in negative thymic selection has suggested that central tolerance could play a role also in polygenic autoimmunity and that autoimmune patients should have an increase in RTEs. The aim of this work was to assess the frequency of RTEs, transitional B cells and Th17 lymphocytes in MS. PBLs from 55 MS patients [20 relapsing-remitting (RR) with disease modifying drugs (DMD), 20 RRMS without DMD, 10 progressive MS and 5 RRMS patients on relapse] and 32 healthy controls were analysed by FACS for RTEs, naive and memory T cells as well as Th17 cells and transitional B cells. No differences in the percentage of RTEs (CD45RA+CD31+PTK7+) (3.30±2.94 vs 3.05±1.54, 0.933) or B transitional cells (CD19+CD24hiCD38hiCD27-) (8.67±3.62 vs 8.59±3.8, p=0.45) were found between controls and MS. A significant decrease in the percentage of CD4 effector memory (CD45RA-CCR7-CD27+) (23.13±8.76 vs 20.8±6.1, p=0.043), as well as an increase in Th17 cells (6.9±3.2 vs5.49±2.33, p=0.007) was observed in MS vs controls. There were no differences in lymphocyte populations among the clinical forms of MS. RRMS under treatment had similar results to RRMS without DMD. Patients on relapse did show an increased proportion of CD4 effector memory cells, Th17 cells and RTEs and patients with higher EDSS had a higher percentage of Th17 cells (OR 2.3,p=0.045). The results of this preliminary study do not favour a failure in central tolerance in MS but confirm involvement of Th17 cells which are associated with a higher degree of disability.

Predicting therapeutic response to fingolimod treatment in multiple sclerosis patients

Fingolimod, an orally active immunomodulatory drug for relapsing‐remitting multiple sclerosis (RRMS), sequesters T cells in lymph nodes through functional antagonism of the sphingosine‐1‐phosphate receptor, reducing the number of potential autoreactive cells that migrate to the central nervous system. However, not all RRMS patients respond to this therapy. Our aim was to test the hypothesis that by immune‐monitoring RRMS patients leukocyte subpopulations it is possible to find biomarkers associated with clinical response to fingolimod.

Comparative transcriptomic profile of tolerogenic dendritic cells differentiated with vitamin D3, dexamethasone and rapamycin

Tolerogenic dendritic cell (tolDC)-based therapies have become a promising approach for the treatment of autoimmune diseases by their potential ability to restore immune tolerance in an antigen-specific manner. However, the broad variety of protocols used to generate tolDC in vitro and their functional and phenotypical heterogeneity are evidencing the need to find robust biomarkers as a key point towards their translation into the clinic, as well as better understanding the mechanisms involved in the induction of immune tolerance. With that aim, in this study we have compared the transcriptomic profile of tolDC induced with either vitamin D3 (vitD3-tolDC), dexamethasone (dexa-tolDC) or rapamycin (rapa-tolDC) through a microarray analysis in 5 healthy donors. The results evidenced that common differentially expressed genes could not be found for the three different tolDC protocols. However, individually, CYP24A1, MUCL1 and MAP7 for vitD3-tolDC; CD163, CCL18, C1QB and C1QC for dexa-tolDC; and CNGA1 and CYP7B1 for rapa-tolDC, constituted good candidate biomarkers for each respective cellular product. In addition, a further gene set enrichment analysis of the data revealed that dexa-tolDC and vitD3-tolDC share several immune regulatory and anti-inflammatory pathways, while rapa-tolDC seem to be playing a totally different role towards tolerance induction through a strong immunosuppression of their cellular processes.

Immunotheraphy in Allergic Diseases

The prevalence of allergic diseases is increasing worldwide. It is estimated that more than 30% of the world population is now affected by one or more allergic conditions and a high proportion of this increase is in young people. The diagnosis of allergy is dependent on a history of symptoms on exposure to an allergen together with the detection of allergen-specific IgE. Accurate diagnosis of allergies opens up therapeutic options. Allergen specific immunotherapy is the only successful disease-modifying therapy for IgE-mediated allergic diseases. New therapeutic strategies have been developed or are currently under clinical trials. Besides new routes of administration, new types of allergens are being developed. The use of adjuvants may amplify the immune response towards tolerance to the antigens. In this review, we analyze different antigen-specific immunotherapies according to administration route, type of antigens and adjuvants, and we address the special case of food allergy.

Characterization of patients with anti-modified citrullinated vimentin antibodies (MCVA)

Measurament of MCVA is used for the diagnosis of rheumatoid arthritis (RA), with similar sensitivity to but higher specificity than rheumatoid factor. MCVA, have been detected however in other diseases and also in some healthy subjects.

Diagnostic value of different anti-citrullinated peptides antibodies in rheumatoid arthritis

Assays that detect anti-citrullinated peptides antibodies (ACPA) are considered to be more specific than rheumatoid factor in the diagnosis of rheumatoid arthritis (RA). Several tests have been developed using different antigens: first, second and third-generation cyclic-ACPA (CCP1, CCP2, CCP3) and modified citrullinated vimentin (MCV).