This new CPB mouse model will facilitate preclinical testing of therapeutic strategies in cardiovascular diseases and investigation of CPB in relation to different insults and pre-existing comorbidities. In combination with genetically modified mice, this model will be an important tool to dissect the molecular mechanisms involved in organ damage related to extracorporeal circulation.

Experimentally, regulatory T cells inhibit rejection. In clinical transplantations, however, it is not known whether T cell regulation is the cause for, or an epiphenomenon of, long-term allograft survival. Here, we study naïve and alloantigen-primed T cell responses of clinical lung transplant recipients in humanized mice. The pericardiophrenic artery procured from human lung grafts was implanted into the aorta of NODrag /IL-2rγc mice reconstituted with peripheral blood mononuclear cells (PBMCs) from the respective lung recipient. Naïve or primed allogeneic PBMCs procured 21 days post-lung transplantation with or without enriching for CD4 CD25 T cells were used. Transplant arteriosclerosis was assessed 28 days later by histology. Mice reconstituted with alloantigen-primed PBMCs showed significantly more severe transplant arteriosclerosis than did mice with naïve PBMCs (p = 0.005). Transplant arteriosclerosis was equally suppressed by enriching for autologous naïve (p = 0.012) or alloantigen-primed regulatory T cells (Tregs) (p = 0.009). Alloantigen priming in clinical lung recipients can be adoptively transferred into a humanized mouse model. Transplant arteriosclerosis elicited by naïve or alloantigen-primed PBMCs can be similarly controlled by potent autologous Tregs. Cellular therapy with expanded autologous Tregs in lung transplantation might be a promising future strategy.

Dendritic cell (DC)-based immunization is a potent strategy to direct prompt and durable immune responses against viral reactivations after transplantations. Here, we show that overnight lentiviral vector (LV) gene transfer into human monocytes co-expressing granulocyte-macrophage colony stimulating factor and interleukin (IL)-4 induced self-differentiated DCs (SMART-DCs) with stable DC immunophenotype over weeks in culture and secreted several inflammatory cytokines. SMART-DCs injected subcutaneously in immunodeficient NOD.Rag1-/ -.IL2rc -/ -(NRG) mice 1 day after LV transduction were stable for a month in vivo. ''Conventional'' DCs (cDCs) and SMART-DCs were compared with regard to their potency to accelerate the expansion, biodistribution, and antigenic stimulation of autologous human T cells. Peripheral blood cells obtained from human cytomegalovirus (hCMV)-reactive donors and full-length hCMV pp65 antigenic protein or peptides were used. DCs loaded with pp65 were administered subcutaneously into NRG mice as a preconditioning treatment a week prior to intravenous infusion with T cells. Optical imaging analyses demonstrated that in mice preconditioned with SMART-DC-pp65, T cells were directly recruited to the immunization site and subsequently spread to the spleen and other organs. A dramatic expansion of both human CD8 + and CD4 + T cells could be observed within a few days after infusion, and this was associated with consistent measurable CD8 + effector memory T-cell responses against different pp65 epitopes. Thus, this mouse model demonstrates the proof-ofprinciple for SMART-DCs to accelerate expansion of human lymphocytes, resulting in poly-functional and antigen-specific immune responses against hCMV-pp65.

The frequency of Treg cells was positively correlated with good lung function in the early period after lung transplantation.

Objective: Chronic lung allograft dysfunction (CLAD) is a severe complication of lung transplantation limiting long-term survival. We studied correlations between CLAD after clinical lung transplantation and leukocyte-mediated development of transplant arteriosclerosis (TA) in a humanized mouse model. The pericardiophrenic artery was procured from surplus tissue of donor lungs (n ¼ 22) transplanted in our clinical program and was implanted into the abdominal aorta of immune-deficient mice.Methods: Allogeneic human peripheral blood mononuclear cells (PBMCs) had been procured 1 day after lung transplantation from the respective recipients with or without enriching for CD4 þ CD25 high T cells were used. TA was assessed in mice 28 days later by histology. The respective clinical lung recipients were later divided into 2 groups. Eight patients (36.3%) had developed CLAD 23 AE 5 months after lung transplantation, whereas the remaining 14 (63.6%) did not develop CLAD within 25 AE 5 months.See Commentaries on pages 2538 and 2540.Long-term survival after lung transplantation is compromised by the development of chronic lung allograft dysfunction (CLAD), resulting from recurrent and compounding alloimmune infections and other insults and is characterized by neutrophil inflammation, fibrosis, respiratory failure, and death. Ten-year survival following From the a Division of Cardiac,