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Regulatory T cells (Treg) can regulate alloantigens and may counteract chronic lung allograft dysfunction (CLAD) in lung transplantation. We analyzed Treg in peripheral blood prospectively and correlated percentages of subpopulations with the incidence of CLADat 2 years. Among lung‐transplanted patients between January 2009 and July 2011, only patients with sufficient Treg measurements were included into the study. Tregs were measured immediately before lung transplantation, at 3 weeks and 3, 6, 12, and 24 months after transplantation and were defined as CD4+CD25highT cells and further analyzed for CTLA4, CD127, FoxP3, and IL‐2 expressions. Between January 2009 and July 2011, 264 patients were transplanted at our institution. Among the 138 (52%) patients included into the study, 31 (22%) developed CLADwithin 2 years after transplantation. As soon as 3 weeks after lung transplantation, a statistically significant positive association was detected between Treg frequencies and later absence of CLAD. At the multivariate analysis, increasing frequencies of CD4+CD25highCD127low, CD4+CD25highFoxP3+and CD4+CD25highIL‐2+T cells at 3 weeks after lung transplantation emerged as protective factors against development of CLADat 2 years. In conclusion, higher frequencies of specific Treg subpopulations early after lung transplantation are protective against CLADdevelopment. Salman and colleagues explore the relationship between the frequencies of T regulatory cell subpopulations and the development of chronic lung allograft dysfunction after lung transplantation and demonstrate an association between higher CD4+CD25highCD127low, FoxP3+, and IL‐2+T cell frequencies early after lung transplantation and less chronic lung allograft dysfunction at two years.

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 PBMCsprocured 21 days post–lung transplantation with or without enriching for CD4+CD25highT cells were used. Transplant arteriosclerosis was assessed 28 days later by histology. Mice reconstituted with alloantigen‐primed PBMCsshowed 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 PBMCscan be similarly controlled by potent autologous Tregs. Cellular therapy with expanded autologous Tregs in lung transplantation might be a promising future strategy. Naïve leukocytes from lung transplant recipients carry a strong alloreactive function that further increases following three weeks posttransplant in vivopriming, but this alloreactivity could be fully suppressed by higher autologous regulatory T cell numbers.

The role of mammalian target of rapamycin (mTOR)inhibitors in de novoimmunosuppression after lung transplantation is not well defined. We compared Everolimus versus mycophenolate mofetil in an investigator‐initiated single‐center trial in Hannover, Germany. A total of 190 patients were randomly assigned 1:1 on day 28 posttransplantation to mycophenolate mofetil (MMF)or Everolimus combined with cyclosporine A (CsA) and steroids. Patients were followed up for 2 years. The primary endpoint was freedom from bronchiolitis obliterans syndrome (BOS). The secondary endpoints were incidence of acute rejections, infections, treatment failure and kidney function. BOS‐free survival in intention‐to‐treat (ITT)analysis was similar in both groups (p = 0.174). The study protocol was completed by 51% of enrolled patients. The per‐protocol analysis shows incidence of bronchiolitis obliterans syndrome (BOS): 1/43 in the Everolimus group and 8/54 in the MMFgroup (p = 0.041). Less biopsy‐proven acute rejection (AR)(p = 0.005), cytomegalovirus (CMV)antigenemia (p = 0.005) and lower respiratory tract infection (p = 0.003) and no leucopenia were seen in the Everolimus group. The glomerular filtration rate (GFR)decreased in both groups about 50% within 6 months. Due to a high withdrawal rate, the study was underpowered to prove a difference in BOS‐free survival. The dropout rate was more pronounced in the Everolimus group. Secondary endpoints indicate potential advantages of Everolimus‐based protocols but also a potentially higher rate of drug‐related serious adverse events. Everolimus and mycophenolate mofetil have different adverse event profiles when used in de novolung transplantation.

We report on the use of veno‐arterial extracorporeal membrane oxygenation (ECMO) as a bridging strategy to lung transplantation in awake and spontaneously breathing patients. All five patients described in this series presented with cardiopulmonary failure due to pulmonary hypertension with or without concomitant lung disease. ECMO insertion was performed under local anesthesia without sedation and resulted in immediate stabilization of hemodynamics and gas exchange as well as recovery from secondary organ dysfunction. Two patients later required endotracheal intubation because of bleeding complications and both of them eventually died. The other three patients remained awake on ECMO support for 18–35 days until the time of transplantation. These patients were able to breathe spontaneously, to eat and drink, and they received passive and active physiotherapy as well as psychological support. All of them made a full recovery after transplantation, which demonstrates the feasibility of using ECMO support in nonintubated patients with cardiopulmonary failure as a bridging strategy to lung transplantation.