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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-04-1093.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1422-1429
IMMUNOBIOLOGY
Differential CD52 expression by distinct myeloid dendritic cell
subsets: implications for alemtuzumab activity at the level of antigen
presentation in allogeneic graft-host interactions in
transplantation
Gudrun Ratzinger,
John L. Reagan,
Glenn Heller,
Klaus J. Busam, and
James W. Young
From the Laboratory of Cellular Immunobiology,
Department of Medicine; Department of Epidemiology and Biostatistics;
Surgical Pathology Service, Department of Pathology; Allogeneic
Transplantation and Clinical Immunology Services, Division of
Hematologic Oncology, Department of Medicine; Memorial Sloan-Kettering
Cancer Center, New York, NY; and Weill Medical College of Cornell
University, New York, NY.
Alemtuzumab (anti-CD52; Campath 1-H) depletes both host and donor T
cells when used in preparative regimens for allogeneic transplantation.
This promotes engraftment even after nonmyeloablative conditioning and
limits graft-versus-host disease (GVHD) even after unrelated or major
histocompatibility complex (MHC) disparate allografts. We asked whether
anti-CD52 differentially targets antigen-presenting cells (APCs), in
addition to depleting T cells. Monocyte-derived dendritic cells (moDCs)
expressed abundant CD52 as expected. Langerhans cells (LCs) and
dermal-interstitial DCs (DDC-IDCs), however, never expressed CD52.
Immunostaining of skin and gut confirmed the absence of CD52 on these
resident DC populations under both steady-state and inflammatory
conditions. Although anti-CD52 functions primarily by
antibody-dependent cellular cytotoxicity (ADCC) in vivo, assessment of
its activity in vitro included complement-dependent lysis of
CD52+ cells. Anti-CD52 did not impair DC-T-cell adhesion,
diminish DC-stimulated T-cell proliferation, or alter moDC development in vitro. We propose that anti-CD52 abrogates GVHD not only by T-cell
depletion, but also by removing moDCs and their precursors. This would
mitigate moDC phagocytosis and presentation of host-derived antigens to
donor T cells in the inflammatory peritransplantation environment,
thereby limiting GVHD. The sparing of LCs and DDC-IDCs by anti-CD52, as
well as the recovery of donor-derived moDCs in a less inflammatory
environment later after transplantation, may allow all these DCs to
exert formative roles in graft-versus-tumor (GVT) reactions and immune
reconstitution. Whether these results support a separation of
deleterious from beneficial graft-host interactions at the level of
antigen presentation, rather than solely at the level of T cells, will
require further evaluation.
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