Prolongation of allograft survival by passenger donor regulatory T cells.

Tissue resident lymphocytes are present within many organs, and are presumably transferred at transplantation, but their impact on host immunity is unclear. Here, we examine whether transferred donor natural regulatory CD4 T cells (nT-regs) inhibit host alloimmunity and prolong allograft survival. Transfer of donor-strain lymphocytes was first assessed by identifying circulating donor-derived CD4 T cells in 21 consecutive human lung transplant recipients, with 3 patterns of chimerism apparent: transient, intermediate, and persistent (detectable for up to 6 weeks, 6 months, and beyond 1 year, respectively). The potential for transfer of donor nT-regs was then confirmed by analysis of leukocyte filters recovered from ex vivo normothermic perfusion circuits of human kidneys retrieved for transplantation. Finally, in a murine model of cardiac allograft vasculopathy, depletion of donor CD4 nT-regs before organ recovery resulted in markedly accelerated heart allograft rejection and augmented host effector antibody responses. Conversely, adoptive transfer or purified donor-strain nT-regs inhibited host humoral immunity and prolonged allograft survival, and more effectively so than following administration of recipient nT-regs. In summary, following transplantation, passenger donor-strain nT-regs can inhibit host adaptive immune responses and prolong allograft survival. Isolated donor-derived nT-regs may hold potential as a cellular therapy to improve transplant outcomes.

Comparison between cellular and acellular perfusates for ex vivo lung perfusion in a porcine model.

BACKGROUND: Ex vivo lung perfusion with acellular solutions is an established technique for assessing marginal donor lungs. We evaluated the utility of a blood-based lung preservation fluid as an alternative perfusate. METHODS: Donor lungs from 50-kg donation after cardiac death pigs (n = 24) were randomized into 3 groups: acellular, commercial blood-based, and Papworth-Blood. Physiologic function was evaluated using conventional markers of pulmonary vascular resistance, pulmonary compliance, lactate excretion, partial pressure of oxygen/fraction of inspired oxygen, and wet-to-dry ratios. The immunologic profile was assessed by fluorescence-activated cell sorting analysis of bronchoalveolar lavage and cells entrapped in the leucocyte filter. Cytokines were quantified using a commercial platform. RESULTS: No significant difference was noted in pulmonary vascular resistance (p = 0.26), compliance (p = 0.12), partial pressure of oxygen/fraction of inspired oxygen (p = 0.06) and wet-to-dry ratios (p = 0.26) between groups. There was no difference between the percentages of lymphocytes (p = 0.51), macrophages (p = 0.87), monocytes (p = 0.68), and dendritic cells (p = 0.65) in the leukocyte filters. Interleukin (IL)-1ß (p = 0.36), IL-6 (p = 0.08), IL-8 (p = 0.64), and IL-18 (p = 0.14) were elevated in all groups. In bronchoalveolar lavage, IL-8 was significantly higher in the acellular group (p = 0.04). Electron microscopy cell characteristics were similar among the groups. CONCLUSIONS: This study demonstrated no significant difference in the physiologic, immunologic, or ultrastructural parameters between lungs perfused with cellular or acellular solutions. The Papworth-Blood solution is a potential alternative perfusate for ex vivo lung perfusion.

Impact of donor mismatches at individual HLA-A, -B, -C, -DR, and -DQ loci on the development of HLA-specific antibodies in patients listed for repeat renal transplantation.

We have analyzed the relationship between donor mismatches at each HLA locus and development of HLA locus-specific antibodies in patients listed for repeat transplantation. HLA antibody screening was undertaken using single-antigen beads in 131 kidney transplant recipients returning to the transplant waiting list following first graft failure. The number of HLA mismatches and the calculated reaction frequency of antibody reactivity against 10,000 consecutive deceased organ donors were determined for each HLA locus. Two-thirds of patients awaiting repeat transplantation were sensitized (calculated reaction frequency over 15%) and half were highly sensitized (calculated reaction frequency of 85% and greater). Antibody levels peaked after re-listing for repeat transplantation, were independent of graft nephrectomy and were associated with length of time on the waiting list (odds ratio 8.4) and with maintenance on dual immunosuppression (odds ratio 0.2). Sensitization was independently associated with increasing number of donor HLA mismatches (odds ratio 1.4). All mismatched HLA loci contributed to the development of HLA locus-specific antibodies (HLA-A: odds ratio 3.2, HLA-B: odds ratio 3.4, HLA-C: odds ratio 2.5, HLA-DRB1: odds ratio 3.5, HLA-DRB3/4/5: odds ratio 3.9, and HLA-DQ: odds ratio 3.0 (all significant)). Thus, the risk of allosensitization following failure of a first renal transplant increases incrementally with the number of mismatches at all HLA loci assessed. Maintenance of re-listed patients on dual immunosuppression was associated with a reduced risk of sensitization.