The Use of Post-Transplantation Cyclophosphamide after Myeloablative, HLA-Matched Allogeneic Bone Marrow Transplantation Minimizes the Need for Additional Immunosuppression
Year: 2016
Type: article
Abstract: Graft-vs-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT).Acute (a) GVHD results from direct donor T cell (TC) damage of organs.In contrast, the biology of chronic (c) GVHD with various autoimmune-like manifestations remains poorly understood.We studied the pathophysiology of cGVHD in an MHCmatched mouse model (C57BL/6 à BALB.B) using lethal irradiation and HCT of pure hematopoietic stem cells (HSC; cKIT+Thy1.1loSca1+Lin-)or HSC + TC.Recipients of HSC remained healthy; mice given HSC+TC developed aGVHD with a mortality of w30%.Survivors stabilized around d+45, but developed chronic GVHD after 6-12m with sclerodermatous skin excoriations, cataracts, and liver fibrosis/ cirrhosis.Thymuses were a major target of aGVHD resulting in severe hypocellularity and disrupted organ architecture.During the months of lymphoid reconstitution thymuses of HSC+TCrecipients showed markedly lower expression of cytokeratin 5 (CK5) than HSC recipients.CK5 marks medullary thymic epithelial cells (mTEC) that provide a specialized microenvironment for survival, proliferation, and differentiation of immature TC.Expression of AIRE, a transcription factor in the thymic medulla that controls negative selection during TC maturation was low in all transplanted groups.During aGVHD only TH1-donor TC, but not CD4+IL17+ (TH17)-cells were detectable.Starting at 2m TH17 cells emerged, first in intestines then liver and skin (all typical GVHD target organs) increasing until 6-12 months post-HCT.Of note, TH17 cells originated from donor-HSC, not adaptively transferred mature TC.Even recipients of pure HSC showed increasing proportions of TH17 cells over time, and could manifest discrete signs of cGVHD.From our model we hypothesize the thymus is damaged by conditioning regimen and alloreactive donor TC.Disruption of mTEC may compromise negative selection of nascent HSCderived donor TC, thereby misguide TC maturation and ultimately result in the emergence of TH17 donor-TC in target organs of chronic GVHD.
Authors: Christopher G. Kanakry, Javier Bolaños-Meade, Yvette L. Kasamon, Marianna Zahurak, Nadira Durakovic, Terry Furlong, Marta Medeot, Marco Mielcarek, Ivan M. Borrello, Robert A. Brodsky, Douglas E. Gladstone, Carol Ann Huff, William H. Matsui, Lode J. Swinnen, Richard F. Ambinder, Ephraim J. Fuchs, Marcos de Lima, Borje S. Andersson, Ravi Varadhan, Paul V. O'Donnell, Richard J. Jones, Leo Luznik
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2275952114