Expression of Activation Marker, CMRF-44, on Blood CD11c+ Dendritic Cells Is Closely Associated with the Severity of Acute GVHD after Allogeneic Haematopoietic Stem Cell Transplant.

Abstract

AIM: Dendritic cells (DC) are considered central to the development of graft versus host disease (GVHD) following allogeneic haematopoietic stem cell transplantation (alloHSCT). Both donor and host DC are thought to initiate allogeneic immune responses by presenting host antigens to donor T lymphocytes. We studied the potential of CMRF-44, a novel monoclonal antibody identifying activated circulating blood DC, as a predictive marker of acute GVHD.METHODS: In a prospective study, peripheral blood was taken from 40 patients twice weekly up to 100 days post-alloHSCT. Circulating myeloid (CD11chi) and plasmacytoid (CD123hi) DCs were enumerated and the expression of CMRF-44 was assessed on CD11chi DC by four colour flow cytometry. Multivariate analyses were performed using a non-parametric Mann-Whitney U-test and Receiver Operating Characteristic (ROC) curves.RESULTS: Following alloHSCT, the severity of acute GVHD correlated with the number of total DC in the blood (p=0.035). Furthermore, low myeloid and plasmacytoid DC numbers were significantly associated with grade 2-4 acute GVHD (p=0.046 and 0.017 respectively). In 40 alloHSCT patients, 27 developed acute GVHD. CMRF-44 was expressed on CD11c+ DC in all cases prior to the onset of acute GVHD. Of the 13 patients without GVHD, 8 had no circulating CMRF-44+ CD11c+ DC. CMRF-44 expression was independent of the reconstitution of myeloid DC (p=0.73). Patients who had CMRF-44+ CD11c+ DC in more than 20% of their post-transplant monitoring samples were more likely to develop acute GVHD (p=0.001, OR=37.1). In addition, patients with more severe grade 2–4 GVHD had significantly higher percentages of CMRF-44+ CD11c+ DCs (p=0.001). CMRF-44 expression at greater than or equal to 12% of CD11chi DCs had a sensitivity of 87.5 for prediction of grade 2–4 acute GVHD, and a specificity of 91.7.CONCLUSION: CMRF-44 expression on blood CD11c+ DC is highly associated with the onset of acute GVHD. These results suggest that CMFR-44 may be used as a predictive tool to identify patients at risk of severe GVHD and to direct therapy. Furthermore, it reinforces the potential application of suitably engineered CMRF-44 antibodies for the prevention or treatment of graft versus host disease.