Towards immunotherapeutic drugs and vaccines against multiple sclerosis

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. Numerous treatment options are available to MS patients; however, these options need to be improved. Herein, we review the current drugs and therapeutic approaches available to MS patients, preclinical trial interventions and recent animal model studies for the potential therapy of MS. Since the current treatment of MS remains elusive and is limited, animal studies and clinical research offers an optimistic outlook.     

Kinetic and modelling studies on the lipase catalysed enantioselective esterification of (±)-perillyl alcohol

Several lipases were kinetically studied with the aim to exploit their enantioselectivity in the esterification of (S)-(−) and (R)-(+)-perillyl alcohol with decanoic acid. Most of the lipases studied exhibited stereopreference towards the R-enantiomer with apparent E-values from 3.8 to 0.6, calculated as the initial esterification rates ratio for the individual enantiomers. In an attempt to interpret the structural basis of enantioselectivity, modelling studies were performed with two of these lipases, Candida cylindracea lipase (CcL) and Pseudomonas cepacia lipase (PcL) based on their previously determined X-ray crystal structures. The results derived from modelling studies confirm their stereopreferences towards the R-enantiomer, since increased conformational energy of the S-ester was found compared to the R-ester.     

Crystal structure of a non-canonical low-affinity peptide complexed with MHC class I: a new approach for vaccine design

Peptides bind with high affinity to MHC class I molecules by anchoring certain side-chains (anchors) into specificity pockets in the MHC peptide-binding groove. Peptides that do not contain these canonical anchor residues normally have low affinity, resulting in impaired pMHC stability and loss of immunogenicity. Here, we report the crystal structure at 1.6 A resolution of an immunogenic, low-affinity peptide from the tumor-associated antigen MUC1, bound to H-2Kb. Stable binding is still achieved despite small, non-canonical residues in the C and F anchor pockets. This structure reveals how low-affinity peptides can be utilized in the design of novel peptide-based tumor vaccines. The molecular interactions elucidated in this non-canonical low-affinity peptide MHC complex should help uncover additional immunogenic peptides from primary protein sequences and aid in the design of alternative approaches for T-cell vaccines.     

Direct processing and presentation of antigen from malaria sporozoites by professional antigen-presenting cells in the induction of CD8 T-cell responses

Irradiated malaria sporozoites induce better protection than viable untreated sporozoites. We observed early differences between irradiated and viable untreated sporozoites in priming responses in vivo to a protective CD8 T-cell epitope, pb9, of the circumsporozoite protein of Plasmodium berghei. Sporozoites were processed for MHC class I presentation by dendritic cells (DC) to prime pb9-specific IFN-gamma-producing CD8 T cells. DC pulsed with untreated and irradiated sporozoites were similarly capable of priming central memory T-cell responses, detectable by the IFN-gamma cultured ELISPOT assay. However, irradiation significantly enhanced sporozoites' ability to prime effector T-cell responses detectable by the IFN-gammaex vivo ELISPOT assay. Irradiation also enhanced the ability of splenic APC to process and present sporozoites in order to re-stimulate pb9-specific polyclonal and clonal T-cell responses. Sporozoites did not stimulate T cells in the absence of APC. Over-irradiation decreased the sporozoites' T-cell stimulating capacity in vitro at high parasite doses, which may indicate that an optimal irradiation dose is necessary to induce protective immunity by sporozoite inoculation. The induction of sporozoite-specific CD8 T-cell responses without the need for liver stage infection identifies a potentially important mechanism in the development of pre-erythrocytic immunity.     

Effect of estrogen on Xenopus laevis albumin mRNA levels

Accurate quantitation of concentrations of albumin mRNA by hybridization to albumin cDNA allows analysis of the estrogen effect on the Xenopus laevis albumin mRNA levels in the liver cytoplasm during the primary stimulation. Administration of estradiol-17 beta to male Xenopus laevis increases the amount of both total cellular RNA and poly(A)-RNA but has no effect on the albumin mRNA level and the amount of albumin mRNA per cell is constant.