CD134-allodepletion allows selective elimination of alloreactive human T cells without loss of virus-specific and leukemia-specific effectors.
Graft-versus-host disease (GVHD) remains a frequent and severe complication of allogeneic stem cell transplantation (SCT). One approach to reducing alloreactivity is to deplete the graft of alloreactive T cells. Global T cell depletion results in poor immune reconstitution with high mortality from viral infections and disease relapse. Therefore, an approach to selectively deplete alloreactive T cells without compromising other responses would be highly beneficial. We undertook studies to identify an inducible activation marker expressed on alloreactive effector T cells following culture with HLA-mismatched allostimulators. Compared to other markers, CD134 was superior because of its negative baseline expression and rapid upregulation after activation. Depletion of CD134(+) cells from responder populations dramatically reduced specific alloreactivity as determined by reduction of helper T cell precursor frequencies below the threshold predicting development of clinical GVHD while retaining responses to third-party alloantigens. CD134-allodepleted populations retained effectors specific for the Wilms' tumor (WT1) leukemia antigen as determined by WT1 specific pentamers, and CMV-specific effectors as determined by CMV-specific pentamers and CMV-specific ELISpot. Thus, use of CD134-allodepleted grafts may improve allogeneic SCT by reducing GVHD without loss of pathogen-specific and leukemia-specific immunity.
Ge
Xupeng
X
Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Brown
Julia
J
Sykes
Megan
M
Boussiotis
Vassiliki A
VA
D001773:Blood Cells; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D018920:Coculture Techniques; D003587:Cytomegalovirus / Q000276:immunology; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006801:Humans; D007109:Immunity; D008212:Lymphocyte Depletion / Q000379:methods*; D008954:Models, Biological; D053262:Receptors, OX40; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D025721:WT1 Proteins / Q000276:immunology
D053262:Receptors, OX40; C505716:TNFRSF4 protein, human; D025721:WT1 Proteins