CD28 between tolerance and autoimmunity: The side effects of animal models [version 1; referees: 2 approved]

Regulation of immune responses is critical for ensuring pathogen clearance and for preventing reaction against self-antigens. Failure or breakdown of immunological tolerance results in autoimmunity. CD28 is an important co-stimulatory receptor expressed on T cells that, upon specific ligand binding, delivers signals essential for full T-cell activation and for the development and homeostasis of suppressive regulatory T cells. Many in vivo mouse models have been used for understanding the role of CD28 in the maintenance of immune homeostasis, thus leading to the development of CD28 signaling modulators that have been approved for the treatment of some autoimmune diseases. Despite all of this progress, a deeper understanding of the differences between the mouse and human receptor is required to allow a safe translation of pre-clinical studies in efficient therapies. In this review, we discuss the role of CD28 in tolerance and autoimmunity and the clinical efficacy of drugs that block or enhance CD28 signaling, by highlighting the success and failure of pre-clinical studies, when translated to humans

Regulatory T cells ameliorate intrauterine growth retardation in a transgenic rat model for preeclampsia

Preeclampsia is a multisystemic syndrome during pregnancy that is often associated with intrauterine growth retardation. Immunologic dysregulation, involving T cells, is implicated in the pathogenesis. The aim of this study was to evaluate the effect of upregulating regulatory T cells in an established transgenic rat model for preeclampsia. Application of superagonistic monoclonal antibody for CD28 has been shown to effectively upregulate regulatory T cells. In the first protocol (treatment protocol), we applied 1 mg of CD28 superagonist or control antibody on days 11 and 15 of pregnancy. In the second protocol (prevention protocol), the superagonist or control antibody was applied on days 1, 5, and 9. Superagonist increased regulatory T cells in circulation and placenta from 8.49+/-2.09% of CD4-positive T cells to 23.50+/-3.05% and from 3.85+/-1.45% to 23.27+/-7.64%, respectively. Blood pressure and albuminuria (30.6+/-15.1 versus 14.6+/-5.5 mg/d) were similar in the superagonist or control antibody-treated preeclamptic group for both protocols. Rats treated with CD28 superagonist showed increased pup weights in the prevention protocol (2.66+/-0.03 versus 2.37+/-0.05 g) and in the treatment protocol (3.04+/-0.04 versus 2.54+/-0.1 g). Intrauterine growth retardation, calculated by brain:liver weight ratio, was also decreased by the superagonist in both protocols. Further analysis of brain development revealed a 20% increase in brain volume by the superagonist. Induction of regulatory T cells in the circulation and the uteroplacental unit in an established preeclamptic rat model had no influence on maternal hypertension and proteinuria. However, it substantially improved fetal outcome by ameliorating intrauterine growth retardation

Cytokine Expression by Inflammatory Cells Obtained from the Spinal Cords of Lewis Rats with Experimental Autoimmune Encephalomyelitis Induced by Inoculation with Myelin Basic Protein and Adjuvants

Inflammatory cells were obtained from the spinal cords of rats with acute experimental autoimmune encephalomyelitis EAE induced by inoculation with myelin basic protein MBP and adjuvants. Reverse transcriptase-polymerase chain reaction RT-PCR was used to investigate the expression of mRNA for interleukin-2 IL-2 , IL-4, IL-10 and interferon-gamma (IFN-gamma) by cells from groups of rats studied 10-21 days after inoculation. On all days of study, the inflammatory cells, which were predominantly lymphocytes, expressed mRNA for IL-2, IL-4, IL-10 and IFN-gamma. In the mRNA from normal rat spinal cord tissue, there was little expression of cytokine mRNA. Cells from a short-term MBP-reactive T cell line expressed all the cytokines. Densitometry was used to measure the products of PCR, to assess the expression of each cytokine relative to that of beta-actin. IL-2 mRNA was expressed throughout the course of disease and reached a peak on day 18, during late clinical recovery. IFN-gamma was expressed throughout the course of the disease and was also high during late recovery. IL-4 mRNA was present in the spinal cord throughout the course of the disease, with a slight rise during late recovery. Relative expression of IL-10 rose to a peak on days 17-19, during late recovery from clinical disease. This study indicates that IL-2, IL-4, IL-10 and IFN-gamma are expressed by inflammatory cells in the spinal cord in EAE, with the relative expression of all cytokines being high during late clinical recovery

Theoretical Aspects of Charge Ordering in Molecular Conductors

Theoretical studies on charge ordering phenomena in quarter-filled molecular (organic) conductors are reviewed. Extended Hubbard models including not only the on-site but also the inter-site Coulomb repulsion are constructed in a straightforward way from the crystal structures, which serve for individual study on each material as well as for their systematic understandings. In general the inter-site Coulomb interaction stabilizes Wigner crystal-type charge ordered states, where the charge localizes in an arranged manner avoiding each other, and can drive the system insulating. The variety in the lattice structures, represented by anisotropic networks in not only the electron hopping but also in the inter-site Coulomb repulsion, brings about diverse problems in low-dimensional strongly correlated systems. Competitions and/or co-existences between the charge ordered state and other states are discussed, such as metal, superconductor, and the dimer-type Mott insulating state which is another typical insulating state in molecular conductors. Interplay with magnetism, e.g., antiferromagnetic state and spin gapped state for example due to the spin-Peierls transition, is considered as well. Distinct situations are pointed out: influences of the coupling to the lattice degree of freedom and effects of geometrical frustration which exists in many molecular crystals. Some related topics, such as charge order in transition metal oxides and its role in new molecular conductors, are briefly remarked.Comment: 21 pages, 19 figures, to be published in J. Phys. Soc. Jpn. special issue on "Organic Conductors"; figs. 4 and 11 replaced with smaller sized fil

Hydrogen bonding and cooperativity in isolated and hydrated sugars: mannose, galactose, glucose, and lactose.

The conformation of phenyl-substituted monosaccharides (mannose, galactose, and glucose) and their singly hydrated complexes has been investigated in the gas phase by means of a combination of mass selected, conformer specific ultraviolet and infrared double resonance hole burning spectroscopy experiments, and ab initio quantum chemistry calculations. In each case, the water molecule inserts into the carbohydrate at a position where it can replace a weak intramolecular interaction by two stronger intermolecular hydrogen bonds. The insertion can produce significant changes in the conformational preferences of the carbohydrates, and there is a clear preference for structures where cooperative effects enhance the stability of the monosaccharide conformers to which the water molecule chooses to bind. The conclusions drawn from the study of monosaccharide-water complexes are extended to the disaccharide lactose and discussed in the light of the underlying mechanisms that may be involved in the binding of carbohydrate assemblies to proteins and the involvement, or not, of key structural water molecules

Hydrogen bonding and cooperativity in isolated and hydrated sugars: mannose, galactose, glucose, and lactose.

The conformation of phenyl-substituted monosaccharides (mannose, galactose, and glucose) and their singly hydrated complexes has been investigated in the gas phase by means of a combination of mass selected, conformer specific ultraviolet and infrared double resonance hole burning spectroscopy experiments, and ab initio quantum chemistry calculations. In each case, the water molecule inserts into the carbohydrate at a position where it can replace a weak intramolecular interaction by two stronger intermolecular hydrogen bonds. The insertion can produce significant changes in the conformational preferences of the carbohydrates, and there is a clear preference for structures where cooperative effects enhance the stability of the monosaccharide conformers to which the water molecule chooses to bind. The conclusions drawn from the study of monosaccharide-water complexes are extended to the disaccharide lactose and discussed in the light of the underlying mechanisms that may be involved in the binding of carbohydrate assemblies to proteins and the involvement, or not, of key structural water molecules