C1-inhibitor treatment in patients with severe complement-mediated autoimmune hemolytic anemia.

Complement-mediated (CM) autoimmune hemolytic anemia (AIHA) is characterized by the destruction of red blood cells (RBCs) by autoantibodies that activate the classical complement pathway. These antibodies also reduce transfusion efficacy via the lysis of donor RBCs. Because C1-inhibitor (C1-INH) is an endogenous regulator of the classical complement pathway, we hypothesized that peritransfusional C1-INH in patients with severe CM-AIHA reduces complement activation and hemolysis, and thus enhances RBC transfusion efficacy. We conducted a prospective, single-center, phase 2, open-label trial (EudraCT2012-003710-13). Patients with confirmed CM-AIHA and indication for the transfusion of 2 RBC units were eligible for inclusion. Four IV C1-INH doses (6000, 3000, 2000, and 1000 U) were administered with 12-hour intervals around RBC transfusion. Serial blood samples were analyzed for hemolytic activity, RBC opsonization, complement activation, and inflammation markers. Ten patients were included in the study. C1-INH administration increased plasma C1-INH antigen and activity, peaking at 48 hours after the first dose and accompanied by a significant reduction of RBC C3d deposition. Hemoglobin levels increased briefly after transfusion but returned to baseline within 48 hours. Overall, markers of hemolysis, inflammation, and complement activation remained unchanged. Five grade 3 and 1 grade 4 adverse event occurred but were considered unrelated to the study medication. In conclusion, peritransfusional C1-INH temporarily reduced complement activation. However, C1-INH failed to halt hemolytic activity in severe transfusion-dependent-CM-AIHA. We cannot exclude that posttransfusional hemolytic activity would have been even higher without C1-INH. The potential of complement inhibition on transfusion efficacy in severe CM-AIHA remains to be determined.

Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease.

The complement system is an important part of the innate immune system, providing a strong defense against pathogens and removing apoptotic cells and immune complexes. Due to its strength, it is important that healthy human cells are protected against damage induced by the complement system. To be protected from complement, each cell type relies on a specific combination of both soluble and membrane-bound regulators. Their importance is indicated by the amount of pathologies associated with abnormalities in these complement regulators. Here, we will discuss the current knowledge on complement regulatory protein polymorphisms and expression levels together with their link to disease. These diseases often result in red blood cell destruction or occur in the eye, kidney or brain, which are tissues known for aberrant complement activity or regulation. In addition, complement regulators have also been associated with different types of cancer, although their mechanisms here have not been elucidated yet. In most of these pathologies, treatments are limited and do not prevent the complement system from attacking host cells, but rather fight the consequences of the complement-mediated damage, using for example blood transfusions in anemic patients. Currently only few drugs targeting the complement system are used in the clinic. With further demand for therapeutics rising linked to the wide range of complement-mediated disease we should broaden our horizon towards treatments that can actually protect the host cells against complement. Here, we will discuss the latest insights on how complement regulators can benefit therapeutics. Such therapeutics are currently being developed extensively, and can be categorized into full-length complement regulators, engineered complement system regulators and antibodies targeting complement regulators. In conclusion, this review provides an overview of the complement regulatory proteins and their links to disease, together with their potential in the development of novel therapeutics.

Ephrin-Eph signaling usage by a variety of viruses.

Ephrin-Eph signaling is a receptor tyrosine kinase signaling pathway involved in a variety of cellular mechanisms, of which many are related to the adhesion or migration of cells. Both the Eph receptor and ephrin ligand are abundantly present on a wide variety of cell types, and strongly evolutionary conserved. This review provides an overview of how 18 genetically diverse viruses utilize the Eph receptor (Eph), ephrin ligand (ephrin) or ephrin-Eph signaling to their advantage in their viral life cycle. Both Ephs and ephrins have been shown to serve as entry receptors for a variety of viruses, via both membrane fusion and endocytosis. Ephs and ephrins are also involved in viral transmission by vectors, associated with viral replication or persistence and lastly to neurological damage caused by viral infection. Although therapeutic opportunities targeting Ephs or ephrins do not seem feasible yet, the current research does propose two models for the viral usage of ephrin-Eph signaling. Firstly, the viral entry model, in which membrane molecules are used for viral entry, leading to cells being used for replication or as a transporter. Secondly, the advantageous expression ephrin-Eph signaling model, where viruses adapt the expression of Ephs or ephrins to change cell-cell interaction to their advantage. These models can guide future research questions on the usage of Ephs or ephrins by viruses and therapeutic opportunities.