Classical meets malignant hematology: a case of acquired εγδß-thalassemia in clonal hematopoiesis.

Hemoglobinopathies including thalassemias are among the most frequent genetic disorders worldwide. Primarily, these entities result from germline variants in the globin gene clusters and their cis-acting regulatory elements, and thus the WHO classifies thalassemias as inherited diseases. Non-inherited disorders of globin chain synthesis mimicking the phenotype of thalassemias have also been described and are referred to as acquired thalassemias. These forms mainly affect the alpha-globin genes and are observed at much lower frequencies...

SIRPα-antibody fusion proteins stimulate phagocytosis and promote elimination of acute myeloid leukemia cells.

CD47, expressed on a variety of tumor cells, confers immune resistance by delivering an inhibitory "don't eat me" signal to phagocytic cells via its myeloid-specific receptor SIRPα. Recent studies have shown that blocking the CD47-SIRPα axis with CD47-directed antibodies or antibody-derivatives enhances phagocytosis and increases antitumor immune effects. However, CD47 expression on healthy cells creates an antigen sink and potential sites of toxicity, limiting the efficacy of CD47-directed therapies. In this study, we first characterized CD47 expression in Acute Myeloid Leukemia (AML) patients (n = 213) and found that CD47 is highly expressed on both AML bulk and stem cells irrespective of the disease state. Furthermore, to inhibit the CD47-SIRPα signaling pathway at the tumor site, we developed a so-called local inhibitory checkpoint monoclonal antibody (licMAB) by grafting the endogenous SIRPα domain to the N-terminus of the light chain of an antibody targeting CD33, a surface antigen expressed in AML. LicMABs selectively bind CD33-expressing cells even in the presence of a large CD33-negative CD47-positive antigen sink, stimulate phagocytosis of AML cells and eliminate AML cell lines and primary, patient-derived AML cells. Our findings qualify licMABs as a promising therapeutic approach to confine the benefit of disrupting the CD47-SIRPα axis to tumor antigen-expressing cells.

Attenuated viral hepatitis in Trem1-/- mice is associated with reduced inflammatory activity of neutrophils.

TREM1 (Triggering Receptor Expressed on Myeloid Cells 1) is a pro-inflammatory receptor expressed by phagocytes, which can also be released as a soluble molecule (sTREM1). The roles of TREM1 and sTREM1 in liver infection and inflammation are not clear. Here we show that patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection manifest elevated serum levels of sTREM1. In mice, experimental viral hepatitis induced by infection with Lymphocytic Choriomeningitis Virus (LCMV)-WE was likewise associated with increased sTREM1 in serum and urine, and with increased TREM1 and its associated adapter molecule DAP12 in the liver. Trem1-/- mice showed accelerated clearance of LCMV-WE and manifested attenuated liver inflammation and injury. TREM1 expression in the liver of wild-type mice was mostly confined to infiltrating neutrophils, which responded to LCMV by secretion of CCL2 and TNF-α, and release of sTREM1. Accordingly, the production of CCL2 and TNF-α was decreased in the livers of LCMV-infected Trem1-/- mice, as compared to LCMV-infected wildtype mice. These findings indicate that TREM1 plays a role in viral hepatitis, in which it seems to aggravate the immunopathology associated with viral clearance, mainly by increasing the inflammatory activity of neutrophils.

CD4+ T-cell help is required for effective CD8+ T cell-mediated resolution of acute viral hepatitis in mice.

Cytotoxic CD8+ T cells are essential for the control of viral liver infections, such as those caused by HBV or HCV. It is not entirely clear whether CD4+ T-cell help is necessary for establishing anti-viral CD8+ T cell responses that successfully control liver infection. To address the role of CD4+ T cells in acute viral hepatitis, we infected mice with Lymphocytic Choriomeningitis Virus (LCMV) of the strain WE; LCMV-WE causes acute hepatitis in mice and is cleared from the liver by CD8+ T cells within about two weeks. The role of CD4+ T-cell help was studied in CD4+ T cell-lymphopenic mice, which were either induced by genetic deficiency of the major histocompatibility (MHC) class II transactivator (CIITA) in CIITA-/- mice, or by antibody-mediated CD4+ cell depletion. We found that CD4+ T cell-lymphopenic mice developed protracted viral liver infection, which seemed to be a consequence of reduced virus-specific CD8+ T-cell numbers in the liver. Moreover, the anti-viral effector functions of the liver-infiltrating CD8+ T cells in response to stimulation with LCMV peptide, notably the IFN-γ production and degranulation capacity were impaired in CIITA-/- mice. The impaired CD8+ T-cell function in CIITA-/- mice was not associated with increased expression of the exhaustion marker PD-1. Our findings indicate that CD4+ T-cell help is required to establish an effective antiviral CD8+ T-cell response in the liver during acute viral infection. Insufficient virus control and protracted viral hepatitis may be consequences of impaired initial CD4+ T-cell help.