title: Interleukin 5 immunotherapy depletes alloreactive plasma cells.
abstract: BACKGROUND
  Long-lived plasma cells (PCs) that form after alloantigen sensitization produce donor-specific alloantibodies that generate a positive serum crossmatch and preclude transplantation. New approaches for desensitization, including PC depletion with proteasome inhibition, show promise but carry considerable toxicity. Recently, eosinophils have been shown to govern PC persistence. Interleukin 5 (IL-5) depletion is known to reduce eosinophils in human asthmatics. We hypothesized that treatment with an anti-IL-5 antibody can deplete alloreactive PCs, reduce donor-specific alloantibodies, and serve as a less toxic alternative to proteasome inhibition.
  
  
  METHODS
  BALB/c mice were sensitized with B6 skin allografts. Starting at 8 wk after sensitization, control mice received injections of phosphate-buffered saline, whereas experimental mice received weekly injections of an anti-IL-5 antibody. PCs were enumerated by enzyme-linked immunosorbent spot after 8 wk.
  
  
  RESULTS
  All control and experimental recipients of skin allografts developed positive crossmatches when screened at 8 wk after sensitization. All experimental mice treated with anti-IL-5 showed a reduction in their total PC numbers. Also, in contrast to the known adverse effects of proteasome inhibition, experimental mice treated with anti-IL-5 exhibited negligible weight loss or lymphopenia.
  
  
  CONCLUSIONS
  Treatment with anti-IL-5 is sufficient to reduce, but not eliminate, alloreactive PCs in the bone marrow. This is because of the targeted reduction of eosinophils leading to a reduction in the PC survival factors a proliferation-inducing ligand and IL-6. Generalized toxicity was not observed in experimental mice. Overall, IL-5 directed immunotherapy can eliminate PC's but is unlikely to be a clinically significant desensitization strategy given the persistence of DSA.
authors.affiliation: Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: rrredfield@wisc.edu.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Redfield
authors.affiliation: Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rodriguez
authors.affiliation: Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Susan
authors.initials: S
authors.lastname: Rostami
authors.affiliation: Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Parsons
authors.affiliation: Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Hooman
authors.initials: H
authors.lastname: Noorchashm
authors.affiliation: Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Abt
authors.affiliation: Harrison Department of Surgical Research, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D003888:Desensitization, Immunologic / Q000379:methods*; D004804:Eosinophils / Q000166:cytology / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D015848:Interleukin-5 / Q000037:antagonists & inhibitors* / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007518:Isoantibodies / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology*; D016038:Skin Transplantation; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D015848:Interleukin-5; D015850:Interleukin-6; D007518:Isoantibodies; D007519:Isoantigens; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; C577686:interleukin-6, mouse
keywords: Desensitization; Donor-specific antibody; Eosinophils; Plasma cells; Solid organ transplantation