title: Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity.
abstract: OBJECTIVE
  GVHD after allogeneic hematopoietic stem cell transplantation (alloSCT) has been associated with low numbers of circulating CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs). Because Tregs express high levels of the interleukin (IL)-2 receptor, they may selectively expand in vivo in response to doses of IL-2 insufficient to stimulate T effector T-cell populations, thereby preventing GVHD.
  
  
  METHODS
  We prospectively evaluated the effects of ultra low-dose (ULD) IL-2 injections on Treg recovery in pediatric patients after alloSCT and compared this recovery with Treg reconstitution post alloSCT in patients without IL-2. Sixteen recipients of related (n = 12) or unrelated (n = 4) donor grafts received ULD IL-2 post hematopoietic stem cell transplantation (HSCT; 100,000-200,000 IU/m(2) ×3 per week), starting <day 30 and continuing for 6 to 12 weeks.
  
  
  RESULTS
  No grade 3/4 toxicities were associated with ULD IL-2. CD4(+)CD25(+)FoxP3(+) Tregs increased from a mean of 4.8% (range, 0%-11.0%) pre IL-2 to 11.1% (range, 1.2%-31.1%) following therapy, with the greatest change occurring in the recipients of matched related donor (MRD) transplants. No IL-2 patients developed grade 2-4 acute GVHD (aGVHD), compared with 4 of 33 (12%) of the comparator group who did not receive IL-2. IL-2 recipients retained T cells reactive to viral and leukemia antigens, and in the MRD recipients, only 2 of 13 (15%) of the IL-2 patients developed viral infections versus 63% of the comparator group (P = 0.022).
  
  
  CONCLUSIONS
  Hence, ULD IL-2 is well tolerated, expands a Treg population in vivo, and may be associated with a lower incidence of viral infections and GVHD.
authors.affiliation: Authors' Affiliations: Center for Cell and Gene Therapy, Dan L. Duncan Cancer Center, Baylor College of Medicine; The Methodist Hospital, Houston, Texas; and National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Alana A
authors.initials: AA
authors.lastname: Kennedy-Nasser
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ku
authors.forename: Paul
authors.initials: P
authors.lastname: Castillo-Caro
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Hazrat
authors.forename: Meng-Fen
authors.initials: MF
authors.lastname: Wu
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Jos
authors.initials: J
authors.lastname: Melenhorst
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
authors.forename: Sawa
authors.initials: S
authors.lastname: Ito
authors.forename: Aaron
authors.initials: A
authors.lastname: Foster
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.forename: Eric
authors.initials: E
authors.lastname: Yvon
authors.forename: George
authors.initials: G
authors.lastname: Carrum
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Ramos
authors.forename: Robert A
authors.initials: RA
authors.lastname: Krance
authors.forename: Kathryn
authors.initials: K
authors.lastname: Leung
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bollard
mesh_terms: D000293:Adolescent; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D007938:Leukemia / Q000097:blood / Q000517:prevention & control*; D018655:Lymphocyte Count; D008297:Male; D011446:Prospective Studies; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects*; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D007376:Interleukin-2