Blockade of the CD40/CD154 pathway potently attenuates T-cell responses in models of autoimmunity, inflammation, and transplantation. Indeed, CD40 pathway blockade remains one of the most powerful methods of prolonging graft survival in models of transplantation. But despite this effectiveness, the cellular and molecular mechanisms underlying the protective effects of CD40 pathway blockade are incompletely understood. Furthermore, the relative contributions of deletion, anergy, and regulation have not been measured in a model in which donor-reactive CD4 + and CD8 + T-cell responses can be assessed simultaneously. To investigate the impact of CD40/CD154 pathway blockade on graft-specific T-cell responses, a transgenic mouse model was used in which recipients containing ovalbumin-specific CD4 + and CD8 + TCR transgenic T cells were grafted with skin expressing ovalbumin in the presence or absence of anti-CD154 and donor-specific transfusion. The results indicated that CD154 blockade altered the kinetics of donorreactive CD8 + T-cell expansion, delaying differentiation into IFN-γ + TNF + multifunctional cytokine producers. The eventual differentiation of cytokine-producing effectors in tolerant animals coincided with the emergence of an antigen-specific CD4 + CD25 hi Foxp3 + T-cell population, which did not arise from endogenous natural T reg but rather were peripherally generated from naïve Foxp3 − precursors.costimulation blockade B lockade of the CD40/CD154 pathway has long been appreciated as a potent means of inhibiting alloreactive T-cell responses and prolonging graft survival. But despite this pronounced effect on allograft survival in both murine and nonhuman primate models (1-3), clinical trials using anti-CD154 mAbs in transplantation were halted due to thromboembolic complications, likely related to the expression of CD154 on platelets (4, 5). However, recent studies using anti-CD40 mAbs in both murine and nonhuman primate models demonstrated comparable efficacy to CD154 blockade, and thus significant interest in the pathway remains (6-9).Early studies by Parker et al. (3) described the treatment combination of anti-CD154 and donor-specific transfusion (DST) for the induction of immune tolerance in transplantation. Several groups have since demonstrated the potent effects of this combined therapy in the prolongation of islet (3, 10, 11), cardiac (12), skin (10, 13), and kidney (14, 15) allograft survival in murine and nonhuman primate models. Although costimulation blockade has been associated with T-cell anergy (16) or deletion (17, 18), elucidation of the precise independent and synergistic effects of DST and anti-CD154 on the kinetics of donor-reactive CD4 + and CD8 + effector T-cell expansion has been limited because of the inability to identify and track graft-specific T cells in fully allogeneic models.Importantly, studies by Taylor et al. (19) demonstrated that CD4 + CD25 + regulatory T cells (T reg ) are required for tolerance induced via CD40/CD154 pathway blockade in a graft-versushost model....

ObjectivesThe clinical outcome of prenatally diagnosed congenital heart defects (CHD)

Previous evidence suggests that a homeostatic germinal center (GC) response may limit bortezomib desensitization therapy. We evaluated the combination of costimulation blockade with bortezomib in a sensitized non-human primate kidney transplant model. Sensitized animals were treated with bortezomib, belatacept, and anti-CD40 mAb twice weekly for a month (n = 6) and compared to control animals (n = 7). Desensitization therapy-mediated DSA reductions approached statistical significance (P = .07) and significantly diminished bone marrow PCs, lymph node follicular helper T cells, and memory B cell proliferation. Graft survival was prolonged in the desensitization group (P = .073). All control animals (n = 6) experienced graft loss due to antibody-mediated rejection (AMR) after kidney transplantation, compared to one desensitized animal (1/5). Overall, histological AMR scores were significantly lower in the treatment group (n = 5) compared to control (P = .020). However, CMV disease was common in the desensitized group (3/5). Desensitized animals were sacrificed after long-term follow-up with functioning grafts. Dual targeting of both plasma cells and upstream GC responses successfully prolongs graft survival in a sensitized NHP model despite significant infectious complications and drug toxicity. Further work is planned to dissect underlying mechanisms, and explore safety concerns.

Several mechanisms regarding the adverse health effects of nanomaterials have been proposed. Among them, oxidative stress is considered to be one of the most important. Many in vitro studies have shown that nanoparticles generate reactive oxygen species, deplete endogenous antioxidants, alter mitochondrial function and produce oxidative damage in DNA. 8-Hydroxy-2'-deoxyguanosine is a major type of oxidative DNA damage, and is often analyzed as a marker of oxidative stress in human and animal studies. In this study, we focused on the in vivo toxicity of metal oxide and silver nanoparticles. In particular, we analyzed the induction of micronucleated reticulocyte formation and oxidative stress in mice treated with nanoparticles (CuO, Fe3O4, Fe2O3, TiO2, Ag). For the micronucleus assay, peripheral blood was collected from the tail at 0, 24, 48 and 72 h after an i.p. injection of nanoparticles. Following the administration of nanoparticles by i.p. injection to mice, the urinary 8-hydroxy-2'-deoxyguanosine levels were analyzed by the HPLC-ECD method, to monitor the oxidative stress. The levels of 8-hydroxy-2'-deoxyguanosine in liver DNA were also measured. The results showed increases in the reticulocyte micronuclei formation in all nanoparticle-treated groups and in the urinary 8-hydroxy-2'-deoxyguanosine levels. The 8-hydroxy-2'-deoxyguanosine levels in the liver DNA of the CuO-treated group increased in a dose-dependent manner. In conclusion, the metal nanoparticles caused genotoxicity, and oxidative stress may be responsible for the toxicity of these metal nanoparticles.

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