Anti-CD14 monoclonal antibody, clone cjH 68

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by tissue accumulation of CD1a(+)CD207(+) LCH cells. In LCH, somatic mutations of the BRAF(V600E) gene have been detected in tissue LCH cells, bone marrow CD34(+) hematopoietic stem cells, circulating CD14+ monocytes, and BDCA1(+) myeloid dendritic cells (DC). Targeting BRAF(V600E) in clonal Langerhans cells (LC) and their precursors is a potential treatment option for patients whose tumors have the mutation. The development of mouse macrophages and LCs is regulated by the CSF1 receptor (CSF1R). In patients with diffuse-type tenosynovial giant cell tumors, CSF1R inhibition depletes tumor-associated macrophages (TAM) with therapeutic efficacy; however, CSF1R signaling in LCs and LCH has not been investigated. We found through IHC and flow cytometry that CSF1R is normally expressed on human CD1a(+)CD207(+) LCs in the epidermis and stratified epithelia. LCs that were differentiated from CD14(+) monocytes, BDCA1(+) DCs, and CD34(+) cord blood progenitors expressed CSF1R that was downregulated upon maturation. Immature LCs migrated toward CSF1, but not IL34. Administration of the c-FMS/CSF1R kinase inhibitors GW2580 and BLZ945 significantly reduced human LC migration. In LCH clinical samples, LCH cells (including BRAF(V600E) cells) and TAMs retained high expression of CSF1R. We also detected the presence of transcripts for its ligand, CSF1, but not IL34, in all tested LCH cases. CSF1R and CSF1 expression in LCH, and their role in LC migration and differentiation, suggests CSF1R signaling blockade as a candidate rational approach for treatment of LCH, including the BRAF(V600E) and wild-type forms of the disease.

The CXCR3 chemokine CXCL10 or IFN-gamma inducible protein 10 (IP-10) has been identified as an important biomarker of cerebral malaria (CM) mortality in children. Studies in mouse malaria infection models have shown that CXCL10 blockade alleviates brain intravascular inflammation and protects infected mice from CM. Despite the key role that CXCL10 plays in the development of CM, the leucocytic sources of CXCL10 in response to human malaria are not known. Here we investigated CXCL10 responses to Plasmodium falciparum in peripheral blood mononuclear cells (PBMCs). We found that PBMCs from malaria-unexposed donors produce CXCL10 in response to P. falciparum and that this response is IFN-gamma-dependent. Moreover, CD14(+) monocytes were identified as the main leucocytic sources of CXCL10 in peripheral blood, suggesting an important role for innate immune responses in the activation of this pathway involved in the development of symptomatic malaria.