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Prepublished online as a Blood First Edition Paper on August 22, 2002; DOI 10.1182/blood-2002-05-1452.
Submitted May 22, 2002
Accepted August 19, 2002
IN VITRO ADHERENCE OF LYMPHOCYTES TO DERMAL ENDOTHELIUM UNDER SHEAR STRESS: IMPLICATIONS IN PATHOBIOLOGY AND STEROID THERAPY OF ACUTE CUTANEOUS GVHD
Robert Sackstein*, Jane L Messina, and Gerald J Elfenbein
Dermatology and Medicine, Harvard Medical School, Brigham & Women's Hospital and Massachusetts General Hospital, Boston, MA, USA
Pathology and Laboratory Medicine, University of South Florida College of Medicine, Tampa, FL, USA
Oncology, Roger Williams Hospital, Providence, RI, USA
* Corresponding author; email: rsackstein{at}rics.bwh.harvard.edu.
The extravasation of leukocytes at sites of inflammation critically depends on initial shear-resistant adhesive interactions between leukocytes in blood flow and target tissue endothelium. Dermal lymphocytic infiltrates are a hallmark feature of acute cutaneous graft-versus-host disease (acGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). These infiltrates occur commonly during periods of profound lymphopenia, suggesting that the dermal endothelial adhesive mechanism(s) promoting lymphocyte emigration in acGVHD are highly efficient. To examine this issue, we performed Stamper-Woodruff assays on frozen sections of biopsy specimens of cutaneous lesions occurring within 100 days of HSCT in 22 autologous (auto-HSCT) and 25 allo-HSCT recipients. Using this shear-based assay, we observed lymphocyte adherence to papillary dermal vascular structures in all punch biopsy specimens of allo-HSCT recipients who had clinicohistologic evidence of acGVHD and who were not receiving steroids, whereas no lymphocyte adherence was observed within skin specimens from allo-HSCT recipients who did not develop acGVHD. Within the group of auto-HSCT recipients, 2 of 22 skin biopsies demonstrated lymphocyte binding to dermal vessels. Among allo-HSCT patients receiving steroid therapy for acGVHD, lymphocyte binding to dermal endothelium was abrogated prior to resolution of rash in those who responded, yet binding was persistent in skin from one patient whose rash did not respond to steroid therapy. Collectively, these data indicate that the papillary endothelium of skin in acGVHD displays heightened capacity to support lymphocyte adhesion under shear stress conditions and suggest that down-modulation of this endothelial adhesive capability may be one mechanism by which steroids abrogate acGVHD reactions.
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