Pretransplant Recipient Blood CD14+ preDC Levels Correlate with Increased Acute GVHD after Allogeneic PBSC Transplantation.
Authors: Arpinati Mario , Giannoullia Panagiota , Chirumbolo Gabriella , Perrone Giulia , Bonifazi Francesca , Sanuthararajah Yogen , Palandri Francesca , Giannini Maria Benedetta , Bandini Giuseppe , Martelli Valeria , Sanchini Sara , Baccarani Michele , Rondelli Damiano 
Published: April 2020

Host dendritic cells (DC) are thought to be essential in the induction of acute GVHD after allogeneic HSCT. Human peripheral blood contains various circulating DC precursors including CD11c+ myeloid preDC (mDC), CD14+ monocytic DC precursors (CD14+ preDC) and plasmacytoid preDC (pDC). In this study we employed flow cytometry to enumerate both mDC (lin-, HLA-DR+ and CD11c+), mono-DC (CD14+, CD45 bright) and pDC (lin-, HLA-DR+ and CD123+) numbers in the blood of patients receiving an allogeneic HSCT. Fifty consecutive patients undergoing HSCT from HLA-matched either related (n=28) or unrelated (n=22) donors were enrolled in the study. The stem cell source was bone marrow in all unrelated donors, and G-CSF mobilized PBSC in related donors. Indications to transplant were AML (n=12), ALL (n=11), MM (n=10), CML (n=7), NHL (n=6) and HD (n=4). 13 patients (26%) received reduced dose conditioning regimens (RIC). All patients received CsA and MTX as GVHD prophylaxis. Moreover, 26 patients (52%) received ATG before transplant. mDC and pDC PB counts were significantly lower in patients as compared to 28 age-matched healthy controls [8.8 cells/microL (25th to 75th percentile 3.5–14.5) mDC, and 2.8 (1.3–5.5) pDC, vs 15.5 (12.1–25.1) and 8.6 (5.6–13.1), respectively] (p&lt;0.001). However the mDC/pDC ratio was significantly higher in the patient group [3.5 (1.6–6.2) vs 1.7 (1.3–2.6), p=0.002], indicating a preferential decrease of pDC. CD14+ preDC counts were not significantly different. Among 46 patients evaluable, 12 (26%) developed acute GVHD grade II–IV. Risk factors significantly associated with acute GVHD were older age (p=0.01), PBSC transplants (p=0.02) and the absence of ATG in the conditioning regimen (p=0.01). Patients with acute GVHD had significantly higher pre-transplant mDC:pDC ratio [5.7 (3.3–16.4) vs 3.1 (1.6–5.5)] (p=0.03) and CD14+ preDC counts [395 (326–625) vs 284 (187–395] (p=0.02). A subset analysis was performed in PBSC patients, only 3 of whom had received ATG before transplant. Among 26 evaluable patients, 10 (38%) developed acute GVHD grade II–IV. Besides older age (p=0.02), the only risk factors significantly associated with acute GVHD in PBSC patients were the pre-transplant mDC:pDC ratio [5.7 (4.1–13.1) vs 1.7 (1.2–2.9)](p=0.008) and CD14+ preDC counts [395 (352–710) vs 259 (199–314)](p=0.004). In multivariate analysis, only older age (p=0.04) and pretransplant circulating CD14+ preDC numbers (p=0.04) were significantly associated with acute GVHD in PBSC transplants. Patients with pretransplant CD14+ preDC counts &gt; 310/mL (median value) had a higher actuarial probability of developing acute GVHD grade II–IV than patients with lower CD14+ preDC counts (61% vs 15%). No correlation was observed between pretransplant recipient PB mDC, pDC or CD14+ preDC counts and chronic GVHD. These findings demonstrate that blood levels of DC precursors may represent an important biomarker correlating with a higher risk of developing aGVHD. Based on these results, future studies will exploit clinical strategies aimed at depleting or inactivating host preDC before allotransplant as a means of GVHD prophylaxis.