Tolerability, treatment satisfaction and quality of life outcomes in stable multiple sclerosis patients switched from injectable therapies to auto injected intramuscular interferon beta 1a: The SFERA study.

BACKGROUND: Interferon beta (IFNB) and Glatiramer acetate, long-term first line disease modifying treatments (DMTs) for multiple sclerosis (MS), have different injection frequencies crucial for injection site related side effects. We aimed at investigating whether switching to intramuscular IFNB-1a injected once/week with the Avonex®Pen™ device improves treatment tolerability and quality of life in stable MS patients. METHODS: Clinically stable MS patients, whom their treating neurologist switched from high frequency injectable DMTs to weekly intramuscular IFNB-1a because of bothersome injection site reactions, were included. Injection site and systemic tolerability were measured by a composite 100 mm visual analogue scale at screening, months 4 and 12. Treatment satisfaction, quality of life, relapses and EDSS progression were also recorded. The primary endpoint was change in injection site tolerability from screening to Month 4. Descriptive statistics and Wilcoxon paired signed-rank tests were applied. RESULTS: The median injection site tolerability and systemic tolerability were significantly improved at months 4 (n = 36) and 12 (n = 33) [change -51.60 (IQR: -60.13, -39.60) mm (p < 0.0001); -26.00 (-54.00, 2.25) mm (p = 0.002)]. Median treatment satisfaction was significantly improved at month 12 [change of 18.00 (2.00, 47.50) mm (p = 0.0003)]. Physical and mental components of the SF-36 did not change significantly, and 30/33 (90.9%) and 33/33 (100%) patients were free from relapses and EDSS progression at month 12. CONCLUSIONS: Weekly intramuscular IFNB-1a may represent an alternative treatment option for clinically stable MS patients suffering from intolerable injection-related side effects under treatment with high frequency injectable DMTs.

Using distinct molecular signatures of human monocytes and dendritic cells to predict adjuvant activity and pyrogenicity of TLR agonists.

We present a systematic study that defines molecular profiles of adjuvanticity and pyrogenicity induced by agonists of human Toll-like receptor molecules in vitro. Using P(3)CSK(4), Lipid A and Poly I:C as model adjuvants we show that all three molecules enhance the expansion of IFNgamma(+)/CD4(+) T cells from their naïve precursors following priming with allogeneic DC in vitro. In contrast, co-culture of naive CD4(+) T cells with allogeneic monocytes and TLR2/TLR4 agonists only resulted in enhanced T cell proliferation. Distinct APC molecular signatures in response to each TLR agonist underline the dual effect observed on T cell responses. Using protein and gene expression assays, we show that TNF-alpha and CXCL10 represent DC-restricted molecular signatures of TLR2/TLR4 and TLR3 activation, respectively, in sharp contrast to IL-6 produced by monocytes upon stimulation with P(3)CSK(4) and Lipid A. Furthermore, although all TLR agonists are able to up-regulate proIL-1beta specific gene in both cell types, only monocyte activation with Lipid A results in detectable IL-1beta release. These molecular profiles, provide a simple screen to select new immune enhancers of human Th1 responses suitable for clinical application.

Synthetic bacterial lipopeptide analogs: structural requirements for adjuvanticity.

Modern vaccines aim at conferring immune protection, independently of the nature of the etiological agent causing the disease. These new therapeutics are based on highly purified antigenic moieties that offer potential advantages over traditional vaccines, including a high degree of safety and the capacity of eliciting highly specific immune responses. In spite of these advantages however, subunit vaccines tend to be poorly immunogenic in vivo, and require the coadministration of adjuvants that indirectly enhance cellular immunity. Thus, recombinant vaccines development is dependent on the design of new molecules, non-immunogenic per se, but endowed with immune modulatory properties. Synthetic analogs of bacterial lipoproteins were described more than a decade ago, but their capacity to act as adjuvants has been only recently dissected. These low molecular weight non-immunogenic molecules can be reproducibly synthetized, are safe, and of easy handling and administration. Furthermore, new experimental data from our laboratory reveal their powerful adjuvant effect on human HLA-I/II restricted T cell responses and identify the molecular and cellular requirements for optimal adjuvanticity.

Synthetic bacterial lipopeptide analogs facilitate naive CD4+ T cell differentiation and enhance antigen-specific HLA-II-restricted responses.

Synthetic di- and tri-palmitoylated bacterial lipopeptide analogs (BLpA) can enhance HLA-I-restricted immune responses. Here we show that BLpA indirectly promote antigen-driven differentiation of naive CD4+ T lymphocytes in vitro, with mechanisms that require DC and are inhibited by CTLA-4/Ig. In mixed cultures of cord blood-derived PBMC and allogeneic DC, P3CSK4 lipopeptide facilitated the transition from CCR7(+)/CD45RA(+)/CD62L+ to CCR7(-)/CD45RA(-)/CD62L(dim) T cells with kinetics significantly exceeding those obtained with the unlipidated CSK4 analog. Moreover, P3CSK4 and P2CSK4, but neither the mono-palmitoylated PCSK4 analog nor the CSK4 peptide, increased the frequency of IFN-gamma-producing T cells expanded under similar conditions. Along with this, P2CSK4 and P3CSK4, but not PCSK4, restored the in vitro antigenicity of MDP-OspA, a non-immunogenic analog of Borrelia burgdorferi major outer surface lipoprotein A, and enhanced the frequency of in vitro expanded T cells specific for the tetanus toxoid (TT) and hepatitis B surface antigen (HBsAg) peptides TT(947-967) and HBsAg(19-33) and for TT. Altogether, BLpA bearing at least two ester-bonded palmitoyl side chains indirectly enhance antigen-driven CD4+ T cell differentiation. BLpA adjuvanticity is independent of covalent bonding to Ag and Ag formulation. This information may be helpful to generate more potent recombinant vaccines.