It is the prevailing view that adaptive immune responses are initiated in secondary lymphoid organs. Studies using alymphoplastic mice have shown that secondary lymphoid organs are essential to initiate allograft rejection of skin, heart, and small bowel. The high immunogenicity of lungs is well recognized and allograft rejection remains a major contributing factor to poor outcomes after lung transplantation. We show in this study that alloreactive T cells are initially primed within lung allografts and not in secondary lymphoid organs following transplantation. In contrast to other organs, lungs are acutely rejected in the absence of secondary lymphoid organs. Two-photon microscopy revealed that recipient T cells cluster predominantly around lung-resident, donor-derived CD11c+ cells early after engraftment. These findings demonstrate for the first time that alloimmune responses following lung transplantation are initiated in the graft itself and therefore identify a novel, potentially clinically relevant mechanism of lung allograft rejection.

Granulocytes are pivotal regulators of tissue injury. However, the transcriptional mechanisms that regulate granulopoiesis under inflammatory conditions are poorly understood. Here we show that the transcriptional coregulator B cell leukemia/lymphoma 3 (Bcl3) limits granulopoiesis under emergency (i.e., inflammatory) conditions, but not homeostatic conditions. Treatment of mouse myeloid progenitors with G-CSF -serum concentrations of which rise under inflammatory conditions -rapidly increased Bcl3 transcript accumulation in a STAT3-dependent manner. Bcl3-deficient myeloid progenitors demonstrated an enhanced capacity to proliferate and differentiate into granulocytes following G-CSF stimulation, whereas the accumulation of Bcl3 protein attenuated granulopoiesis in an NF-κB p50-dependent manner. In a clinically relevant model of transplant-mediated lung ischemia reperfusion injury, expression of Bcl3 in recipients inhibited emergency granulopoiesis and limited acute graft damage. These data demonstrate a critical role for Bcl3 in regulating emergency granulopoiesis and suggest that targeting the differentiation of myeloid progenitors may be a therapeutic strategy for preventing inflammatory lung injury.

Objective-This study examines the potential role of candidate genes in moderating treatment effects of methylphenidate (MPH) in Attention-Deficit/Hyperactivity Disorder (ADHD).Method-Eighty two subjects with ADHD aged 6 to 17 participated in a prospective, doubleblind, placebo-controlled, multiple-dose, crossover titration trial of immediate release MPH three times daily. Subjects were assessed on a variety of parent and clinician ratings, and a laboratory math test. Data reduction based on principal components analysis identified statistically derived efficacy and side effect outcomes.Results-ADHD symptom response was predicted by polymorphisms at the serotonin transporter (SLC6A4) intron 2 VNTR (p=.01), with a suggested trend for catechol-Omethyltransferase (COMT) (p=.04). Gene × dose interactions were noted on math test outcomes for the dopamine D4 receptor (DRD4) promoter (p=.008), DRD4 exon 3 VNTR (p=.006), and SLC6A4 promoter insertion/deletion polymorphism (5HTTLPR) (p=.02). Irritability was predicted by COMT (p=.02). Vegetative symptoms were predicted by 5HTTLPR (p=.003). No significance effects were noted for the dopamine transporter (SLC6A3) or synaptosomal-associated protein 25 (SNAP25).