title: Depletion of T regulatory cells promotes natural killer cell-mediated cardiac allograft vasculopathy.
abstract: BACKGROUND
  A role for natural killer (NK) cells in cardiac allograft vasculopathy (CAV) was suggested by our earlier observation that CAV arises even in the absence of detectable antidonor T-cell or B-cell reactivity in parental to F1 mouse heart grafts. However, prevention of CAV in this setting required the depletion of both NK and CD4 T cells.
  
  
  METHODS
  To clarify the interrelationship between NK and CD4 cells, we analyzed early events and selective depletion of T regulatory cells (Tregs). Hearts from C57BL/6 (B6) donors were transplanted heterotopically into BALB/c x C57BL/6 (CB6F1) recipients and NK cells, CD4 T cells, and Tregs were depleted with anti-NK1.1 (PK136), anti-CD4 (GK1.5), or anti-CD25 (PC61), respectively.
  
  
  RESULTS
  In contrast to prior studies in which the prevention of CAV at 8 weeks required the codepletion of NK and CD4 T cells, NK cells depletion alone eliminated CAV at 3 weeks. Furthermore, depletion of CD25 cells accelerated the onset and maturation of CAV at both 2 and 3 weeks (P<0.02 and P<0.001, respectively). However, anti-NK1.1 treatment prevented lesions in CD25-depleted recipients. Finally, CD4 T cell depletion alone did not prevent or accelerate development of CAV but inhibited the effect of CD25 T cell depletion.
  
  
  CONCLUSIONS
  These data suggest that NK cells can play an important role in the early pathogenesis of CAV but that their ability to mediate early CAV can be modulated by Tregs.
authors.affiliation: 1 Transplantation Center and Department of Surgery, Massachusetts General Hospital, Boston, MA. 2 Department of Pathology, Massachusetts General Hospital, Boston, MA. 3 Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA. 4 Address correspondence to Joren C. Madsen, M.D., D.Phil., White 510a, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hirohashi
authors.forename: Catharine M
authors.initials: CM
authors.lastname: Chase
authors.forename: Patricia
authors.initials: P
authors.lastname: DellaPelle
authors.forename: Divya
authors.initials: D
authors.lastname: Sebastian
authors.forename: Evan
authors.initials: E
authors.lastname: Farkesh
authors.forename: Robert B
authors.initials: RB
authors.lastname: Colvin
authors.forename: Paul S
authors.initials: PS
authors.lastname: Russell
authors.forename: Alessandro
authors.initials: A
authors.lastname: Alessandrini
authors.forename: Joren C
authors.initials: JC
authors.lastname: Madsen
mesh_terms: D000818:Animals; D016027:Heart Transplantation / Q000009:adverse effects*; D007694:Killer Cells, Natural / Q000276:immunology*; D008212:Lymphocyte Depletion; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D058426:Neointima / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D014184:Transplantation, Homologous; D014652:Vascular Diseases / Q000209:etiology*