title: Hemin controls T cell polarization in sickle cell alloimmunization.
abstract: Patients with sickle cell disease (SCD) often require transfusions to treat and prevent worsening anemia and other SCD complications. However, transfusions can trigger alloimmunization against transfused RBCs with serious clinical sequelae. Risk factors for alloimmunization in SCD remain poorly understood. We recently reported altered regulatory T cell (Treg) and Th responses with higher circulating Th1 (IFN-γ(+)) cytokines in chronically transfused SCD patients with alloantibodies as compared with those without alloantibodies. Because monocytes play a critical role in polarization of T cell subsets and participate in clearance of transfused RBCs, we tested the hypothesis that in response to the RBC breakdown product hemin, monocyte control of T cell polarization will differ between alloimmunized and non-alloimmunized SCD patients. Exogenous hemin induced Treg polarization in purified T cell/monocyte cocultures from healthy volunteers through the monocyte anti-inflammatory heme-degrading enzyme heme oxygenase-1. Importantly, hemin primarily through its effect on CD16+ monocytes induced an anti-inflammatory (higher Treg/lower Th1) polarization state in the non-alloimmunized SCD group, whereas it had little effect in the alloimmunized group. Non-alloimmunized SCD CD16+ monocytes expressed higher basal levels of heme oxygenase-1. Furthermore, IL-12, which contributed to a proinflammatory polarization state (low Treg/high Th1) in SCD, was dampened in hemin-treated stimulated monocytes from non-alloimmunized SCD patients, but not in the alloimmunized group. These data suggest that unlike alloimmunized patients, non-alloimmunized SCD CD16+ monocytes in response to transfused RBC breakdown products promote an anti-inflammatory state that is less conducive to alloimmunization.
authors.affiliation: Laboratory of Complement Biology, New York Blood Center, New York, NY 10065;
authors.forename: Hui
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Laboratory of Complement Biology, New York Blood Center, New York, NY 10065;
authors.forename: Weili
authors.initials: W
authors.lastname: Bao
authors.affiliation: Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
authors.forename: David
authors.initials: D
authors.lastname: Friedman
authors.affiliation: Laboratory of Complement Biology, New York Blood Center, New York, NY 10065; kyazdanbakhsh@nybloodcenter.org.
authors.forename: Karina
authors.initials: K
authors.lastname: Yazdanbakhsh
mesh_terms: D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000276:immunology* / Q000473:pathology; D004912:Erythrocytes / Q000276:immunology* / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology; D051547:Heme Oxygenase-1 / Q000276:immunology; D006427:Hemin; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology; D007518:Isoantibodies / Q000276:immunology*; D008297:Male; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D017452:Receptors, IgG / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D007518:Isoantibodies; D017452:Receptors, IgG; D018664:Interleukin-12; D006427:Hemin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1