Publications

Chronic lung allograft dysfunction (CLAD) is linked to rejection and limits survival following lung transplantation. HLA-Bw4 recipients of HLA-Bw6 grafts have enhanced host-versus-graft (HVG) natural killer (NK) cell activity mediated by killer cell immunoglobulin-like receptor (KIR)3DL1 ligand. Because NK cells may promote tolerance by depleting antigen-presenting cells, we hypothesized improved outcomes for HLA-Bw4 recipients of HLA-Bw6 grafts. We evaluated differences in acute cellular rejection and CLAD-free survival across 252 KIR3DL1+ recipients from University of California, San Francisco (UCSF). For validation, we assessed survival and freedom from bronchiolitis obliterans syndrome (BOS), retransplantation, or death in 12 845 non-KIR typed recipients from the United Network for Organ Sharing (UNOS) registry. Cox proportional hazards models were adjusted for age, gender, ethnicity, transplant type, and HLA mismatching. HVG-capable subjects in the UCSF cohort had a decreased risk of CLAD or death (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.36-0.88) and decreased early lymphocytic bronchitis. The HVG effect was not significant in subjects with genotypes predicting low KIR3DL1 expression. In the UNOS cohort, HVG-capable subjects had a decreased risk of BOS, retransplant, or death (HR 0.95, 95% CI 0.91-0.99). Survival improved with the higher-affinity Bw4-80I ligand and in Bw4 homozygotes. Improved outcomes in HVG-capable recipients are consistent with a protective NK cell role. Augmentation of NK activity could supplement current immunosuppression techniques.

To investigate the role of immune cells in lung regeneration, we used a unilateral pneumonectomy model that promotes the formation of new alveoli in the remaining lobes. Immunofluorescence and single-cell RNA sequencing found CD115+ and CCR2+ monocytes and M2-like macrophages accumulating in the lung during the peak of type 2 alveolar epithelial stem cell (AEC2) proliferation. Genetic loss of function in mice and adoptive transfer studies revealed that bone marrow-derived macrophages (BMDMs) traffic to the lung through a CCL2-CCR2 chemokine axis and are required for optimal lung regeneration, along with Il4ra-expressing leukocytes. Our data suggest that these cells modulate AEC2 proliferation and differentiation. Finally, we provide evidence that group 2 innate lymphoid cells are a source of IL-13, which promotes lung regeneration. Together, our data highlight the potential for immunomodulatory therapies to stimulate alveologenesis in adults.

The 25-hydroxylated metabolite of vitamin D is the best clinical indicator of vitamin D status. For many years, emphasis has been on measuring total levels of 25-hydroxyvitamin D [25(OH)D], but recently, interest in measuring free 25(OH)D as a potentially better marker of vitamin D status has arisen. Since the 1980s when the first measurements of free 25(OH)D were made, little progress has been made in the development of rapid, reliable methods to determine the levels of free 25(OH)D. For many years, assessment of free 25(OH)D relied on calculations using levels of total 25(OH)D, albumin, and vitamin D binding protein (VDBP), for which many assays exist. However, because of vagaries in the measurement of VDBP in particular and the assumption of a constant affinity of VDBP for the vitamin D metabolites (which has been shown to be problematic), calculated values have proved suspect. This changed a few years ago when a new immunoassay was developed to measure free 25(OH)D directly. This review examines methods for determining free 25(OH)D, the different methods used in clinical studies, and the relationships between free 25(OH)D and other vitamin D metabolites and the physiologic functions affected by vitamin D metabolites, such as bone cell activity and turnover. The review also comments on the value of assessing free 25(OH)D and the efforts to standardize the assays.

Here we address the potential difference in rosuvastatin pharmacokinetics in Asians vs. whites. Our prospective study, reported in this issue, shows no ethnic difference when all subjects are wild-type for OATP1B1 and BCRP. We argue that although our study may be under powered to prove no ethnic difference, and that further confirmatory study is required, the virtual clinical study analysis, also reported in this issue, does not contradict the results of our prospective clinical study and that previous retrospective analysis of clinical studies does not include enough relevant subjects to conclude that wild-type OATP1B1 and BCRP do still demonstrate ethnic differences.