Treatment of autoimmune and inflammatory diseases typically involves immune suppression. In an opposite strategy, we show that administration of the highly inflammatory erythrocyte-specific antibody Ter119 into mice remodels the monocyte cellular landscape, leading to resolution of inflammatory disease. Ter119 with intact Fc function was unexpectedly therapeutic in the K/BxN serum transfer model of arthritis. Similarly, it rapidly reversed clinical disease progression in collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis and completely corrected CAIA-induced increase in monocyte Fcγ receptor II/III expression. Ter119 dose-dependently induced plasma chemokines CCL2, CCL5, CXCL9, CXCL10, and CCL11 with corresponding alterations in monocyte percentages in the blood and liver within 24 hours. Ter119 attenuated chemokine production from the synovial fluid and prevented the accumulation of inflammatory cells and complement components in the synovium. Ter119 could also accelerate the resolution of hypothermia and pulmonary edema in an acute lung injury model. We conclude that this inflammatory anti-erythrocyte antibody simultaneously triggers a highly efficient anti-inflammatory effect with broad therapeutic potential.
Monoclonal IgG antibodies to CD44 (anti-CD44) are anti-inflammatory in numerous murine autoimmune models but the mechanisms are poorly understood. Anti-CD44 anti-inflammatory activity shows complete therapeutic concordance with intravenous immunoglobulin (IVIg) in treating autoimmune disease models, making anti-CD44 a potential IVIg alternative. In murine immune thrombocytopenia (ITP), there is currently no mechanistic explanation for anti-CD44 activity although anti-CD44 ameliorates disease similarly to IVIg. Here we demonstrate a novel anti-inflammatory mechanism of anti-CD44 that explains disease amelioration by anti-CD44 in murine ITP. Macrophages treated with anti-CD44 in vitro had dramatically suppressed phagocytosis through FcγRs in two separate systems of IgG-opsonized platelets and erythrocytes. Phagocytosis inhibition by anti-CD44 was mediated by blockade of the FcγR IgG binding site without changing surface FcγR expression. Anti-CD44 of different subclasses revealed that FcγR blockade was specific to receptors that could be engaged by the respective anti-CD44 subclass, and Fc-deactivated anti-CD44 variants lost all FcγR-inhibiting activity. In vivo, anti-CD44 functioned analogously in the murine passive ITP model and protected mice from ITP when thrombocytopenia was induced through an FcγR that could be engaged by the CD44 antibody's subclass. Consistent with FcγR blockade, Fc-deactivated variants of anti-CD44 were completely unable to ameliorate ITP. Together, anti-CD44 inhibits macrophage FcγR function and ameliorates ITP consistent with an FcγR blockade mechanism. Anti-CD44 is a potential IVIg alternative and may be of particular benefit in ITP due to the significant role of FcγRs in human ITP pathophysiology.
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare neonatal disorder that is caused by alloimmunization against platelet antigens during pregnancy. Although rare, affecting only 1 in 1000 live births, it can cause intracranial hemorrhage and other bleeding complications that can lead to miscarriage, stillbirth and lifelong neurological complications. One of the gold-standard therapies for at risk pregnancies is the administration of IVIg. Although IVIg has been used in a variety of different disorders for over 40 years, its exact mechanism of action is still unknown. In FNAIT, the majority of its therapeutic effect is thought the be mediated through the neonatal Fc receptor, however other mechanisms cannot be excluded. Due to safety, supply and other concerns that are associated with IVIg use, alternative therapies that could replace IVIg are additionally being investigated. This includes the possibility of a prophylaxis regimen for FNAIT, similarly to what has been successfully used in hemolytic disease of the fetus and newborn for over 50 years.
Polyclonal anti-D is a first-line therapy for immune thrombocytopenia (ITP). Monoclonal antibodies are desirable alternatives, but none have yet proven successful despite their ability to opsonize erythrocytes (or red blood cells, RBCs) and cause anemia. Here, we examined 12 murine erythrocyte–specific antibodies of different specificity and subtypes and found that 8 of these antibodies could induce anemia in antigen-positive mice. Of these 8 antibodies, only 5 ameliorated ITP. All antibodies were examined for their in vitro ability to support macrophage-mediated phagocytosis of erythrocytes. Antibodies which supported erythrocyte phagocytosis in vitro successfully ameliorated ITP in vivo. To examine the ability of each antibody to inhibit phagocytosis of platelets, the antibodies were used to sensitize erythrocytes in vitro and these were added to a platelet phagocytosis assay. Antibodies that inhibited platelet phagocytosis in vitro also all ameliorated ITP in vivo. We conclude that inducing anemia is not a sufficient condition for amelioration of ITP but that the antibody’s ability to prevent platelet phagocytosis in vitro predicted its ability to ameliorate ITP. We suggest that inhibition of in vitro platelet phagocytosis may prove to be a valuable tool for determining which erythrocyte antibodies would likely be candidates for clinical use in ITP.
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