Regulatory T Cells in γ Irradiation-Induced Immune Suppression

Sublethal total body γ irradiation (TBI) of mammals causes generalized immunosuppression, in part by induction of lymphocyte apoptosis. Here, we provide evidence that a part of this immune suppression may be attributable to dysfunction of immune regulation. We investigated the effects of sublethal TBI on T cell memory responses to gain insight into the potential for loss of vaccine immunity following such exposure. We show that in mice primed to an MHC class I alloantigen, the accelerated graft rejection T memory response is specifically lost several weeks following TBI, whereas identically treated naïve mice at the same time point had completely recovered normal rejection kinetics. Depletion in vivo with anti-CD4 or anti-CD25 showed that the mechanism involved cells consistent with a regulatory T cell (T reg) phenotype. The loss of the T memory response following TBI was associated with a relative increase of CD4+CD25+ Foxp3+ expressing T regs, as compared to the CD8+ T effector cells requisite for skin graft rejection. The radiation-induced T memory suppression was shown to be antigen-specific in that a third party ipsilateral graft rejected with normal kinetics. Remarkably, following the eventual rejection of the first MHC class I disparate skin graft, the suppressive environment was maintained, with markedly prolonged survival of a second identical allograft. These findings have potential importance as regards the immunologic status of T memory responses in victims of ionizing radiation exposure and apoptosis-inducing therapies

On the nonlinear anelastic behavior of AHSS

It has been widely observed that the loading/unloading behavior of metals which have previously undergone plastic deformation is nonlinear. Furthermore it shows a hysteresis behavior upon further unloading/reloading cycles. The origin of this nonlinearity is attributed to additional dislocation based micro-mechanics which contribute to the total reversible strain, referred to as anelastic strain. Compared to a FE model prediction using only elastic contribution to reversible strain the actual springback will be larger. In this work the unloading behavior of DP800 AHSS is analyzed in detail and a mixed physical-phenomenological model is proposed to describe the observed nonlinearity for different levels of pre-strain. This one dimensional uniaxial model is generalized to a 3D constitutive model incorporating elastic, anelastic and plastic strains. The performance of the model is evaluated by comparing the predicted cyclic unloading/reloading stress-strain curves with the experimental ones. It is shown that by incorporating anelastic behavior in the model the prediction of the cyclic behavior of the material is significantly improved

Vitamin D3 receptor is expressed in the endometrium of cycling mice throughout the estrous cycle

Objective: To investigate the expression and localization of vitamin D3 receptor (VDR) in reproductive organs of cycling mice. Design: Experimental animal study. Setting: Academic research center. Animal(s): Mature (8 to 12 weeks old) cycling female Balb/c mice. Intervention(s): Reproductive tissue, including endometrium, ovary, and fallopian tubes, were collected at each phase of estrous cycle to examine VDR expression. Main Outcome Measure(s): Expression of VDR messenger (mRNA) was determined by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). The presence and localization of VDR was assessed by immunohistochemistry, and the intensity of VDR expression was quantified with U.S. National Institutes of Health image-analysis software. Result(s): The VDR mRNA was expressed in the endometrium throughout the estrous cycle. The relative expression of VDR mRNA at the estrus phase was more prominent compared with the other phases. Immunohistochemical analysis revealed that dendritic cells, macrophages, and luminal and glandular epithelial cells of the endometrium, granulosa, and cumulus oophorus cells of the ovary and fallopian epithelial cells strongly express VDR, particularly during the estrus phase. Conclusion(s): Our findings have demonstrated, for the first time, that VDR is present and differentially expressed in murine reproductive organs throughout the estrous cycle. Further studies are required to evaluate the functional immunologic role of VDR. © 2010 American Society for Reproductive Medicine

A therapeutic combination of GPCR modulators that protects photoreceptors from degeneration

Degeneration of retinal photoreceptor cells can arise from environmental and/or genetic causes. Since photoreceptor cells, the retinal pigment epithelium (RPE), neurons, and glial cells of the retina are intimately associated, all cell types eventually are affected by retinal degenerative diseases. Such diseases often originate either in rod and/or cone photoreceptor cells or the RPE. Of these, cone cells located in the central retina are especially important for daily human activity. Here we describe the protection of cone cells by a combination therapy consisting of the G protein-coupled receptor modulators metoprolol, tamsulosin, and bromocriptine. These drugs were tested in Abca4-/-Rdh8-/- mice, a preclinical model for retinal degeneration. The specificity of these drugs was determined with an essentially complete panel of human G protein-coupled receptors. Significantly, the combination of metoprolol, tamsulosin, and bromocriptine had no deleterious effects on electroretinographic responses of wild-type mice. Moreover, putative G protein-coupled receptor targets of these drugs were shown to be expressed in human and mouse eyes by RNA sequencing and quantitative polymerase chain reaction. Liquid chromatography together with mass spectrometry using validated internal standards confirmed that metoprolol, tamsulosin, and bromocriptine individually or together penetrate the eye after either intraperitoneal delivery or oral gavage. Collectively, these findings support human trials with combined therapy composed of lower doses of metoprolol, tamsulosin, and bromocriptine designed to safely impede retinal degeneration associated with certain genetic diseases (e.g., Stargardt disease). The same low-dose combination also could protect the retina against diseases with complex or unknown etiologies such as age-related macular degeneration