Background:

Infection with Epstein-Barr virus (EBV) manifests as a spectrum of disease ranging from asymptomatic viremia to PTLD. Innate immune cells such as monocytes/macrophages, dendritic cells (DCs), and natural killer (NK) cells contribute to EBV clearance and priming of adaptive immunity against EBV. We performed detailed innate immune profiling of patients with controlled low-level and chronic high-level EBV viremia.

Methods:

We prospectively enrolled consecutive adult organ transplant recipients with EBV viremia. Patients were classified into two phenotypes according to peak viral loads: chronic high viremia (≥10⁴ IU/mL) and low level viremia (<10⁴ IU/mL). PBMCs were collected during active EBV viremia and innate cell populations were identified using mass cytometry with the following cell-surface markers: CD3, CD19, CD56, CD16, CD14, CD11c, CD11b, CD141, BDCA-2, TCRVα24 and γδTCR.

Results:

We enrolled 30 patients with median age 57.5 (range 20-74). Median peak viral load among the high (n=15) and low (n=15) viremia groups was 3×10⁵ and 4×10³ IU/mL, respectively. Types of transplants included kidney (33%), heart (30%), liver (20%), lung (10%), combined kidney and pancreas (3%) and small bowel (3%). Time post-transplant to testing was median 1.7 years (range 0.1-28). Patients were EBV seronegative at transplant (n=12) or seropositive (n=17). Use of anti-thymocyte globulin, prednisone, calcineurin-inhibitors or mycophenolate, as well as recipient EBV serostatus were similar between groups. Patients with low level EBV viremia expressed significantly greater proportions of classic monocytes/macrophages (CD14⁺CD16^–) (24% vs 12%; p=0.03). In addition, low level viremia patients also had significantly greater proportions of CD141⁺ DCs (1.5% vs 0.21%; p=0.04), which have been postulated to be cross-presenting antigen presenting cells. Although the proportion of CD11c⁺ DCs was also greater in the low viremia group (45% vs 34%), this difference was not statistically significant (p=0.15). There was a trend to greater PD-1 expression on intermediate monocytes in the high viremia group (CD14⁺CD16⁺)(p=0.056) suggestive of an exhaustion phenotype. No differences were measured with regard to γδ T-cells, invariant NKT cells, plasmacytoid DCs, non-classical monocytes/macrophages or NK cells.

Conclusions:

These results suggest that innate immune cells play an important role in the control of EBV viremia and provide novel insight into the immunobiology of patients who develop a chronic high viral load phenotype.

CITATION INFORMATION: Ferreira V, Batist J, Kumar D, Husain S, Humar A. In Depth Characterization of the Innate Immune Response in Transplant Recipients with EBV Viremia. Am J Transplant. 2017;17 (suppl 3).

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