title: The Influence of Timing and Frequency of Adipose-Derived Mesenchymal Stem Cell Therapy on Immunomodulation Outcomes After Vascularized Composite Allotransplantation.
abstract: BACKGROUND
  Cellular therapies for immunomodulation in vascularized composite allotransplantation (VCA) have gained importance due to their potential for minimization of immunosuppression. Adipose-derived (AD) mesenchymal stem cells (MSCs) especially have shown encouraging potential. We investigated the influence of timing and frequency of AD-MSC treatment on immunologic and graft survival as well as graft vasculopathy outcomes after VCA.
  
  
  METHODS
  Lewis rats received full-mismatched Brown Norway rat hindlimb transplants. Recipient animals were assigned to groups receiving donor-derived AD-MSCs (10 cells/animal) either on postoperative day (POD) 1, POD 4, or repeatedly on POD 4, 8, and 15, and compared to untreated controls.
  
  
  RESULTS
  Although AD-MSC administration on POD 1 or POD 4, 8, and 15 resulted in 50% long-term graft acceptance, recipients treated on POD 4, and controls rejected before POD 50. All treated animals revealed peripheral blood chimerism (4 weeks), most pronounced after repetitive cell administration (12.92% vs 5.03% [POD 1] vs 6.31% [POD 4]; P < 0.05; all P < 0.01 vs control 1.45%). Chimerism was associated with the generation of regulatory T cells (CD4CD25FoxP3). In vitro mixed lymphocyte reactions revealed modulation of the recipient immune response after AD-MSC treatment. Graft arteries at end point revealed significant differences of arterial intimal thickness between rejecting and AD-MSC-treated animals (P < 0.01).
  
  
  CONCLUSIONS
  Taken together, our results point to the potential for repetitive AD-MSC administration in improving outcomes after VCA. Future studies are warranted into optimization of the dosing and frequency of AD-MSC therapy, either alone or used in, combination with other cell therapies (such as hematopoietic stem cells or bone marrow-derived MSC or dendritic cells) for optimization of appropriate conditioning or maintenance regimens.
authors.affiliation: 1 Department of Plastic Surgery, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA. 2 McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA. 3 Department of Plastic Surgery and Hand Surgery, University Hospital Zurich (USZ), Zurich, Switzerland. 4 Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Plock
authors.forename: Jonas T
authors.initials: JT
authors.lastname: Schnider
authors.forename: Riccardo
authors.initials: R
authors.lastname: Schweizer
authors.forename: Wensheng
authors.initials: W
authors.lastname: Zhang
authors.forename: Wakako
authors.initials: W
authors.lastname: Tsuji
authors.forename: Matthias
authors.initials: M
authors.lastname: Waldner
authors.forename: Mario G
authors.initials: MG
authors.lastname: Solari
authors.forename: Kacey G
authors.initials: KG
authors.lastname: Marra
authors.forename: J Peter
authors.initials: JP
authors.lastname: Rubin
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Gorantla
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D064595:Composite Tissue Allografts / Q000098:blood supply* / Q000276:immunology / Q000637:transplantation*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival; D006614:Hindlimb / Q000098:blood supply* / Q000276:immunology / Q000637:transplantation*; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D008213:Lymphocyte Activation; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D023421:Models, Animal; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors; D018183:Transplantation Chimera; D023001:Transplantation Tolerance; D014652:Vascular Diseases / Q000276:immunology / Q000517:prevention & control; D063986:Vascularized Composite Allotransplantation / Q000009:adverse effects / Q000379:methods*