Remodeling specific immunity by use of MHC tetramers: demonstration in a graft-versus-host disease model.
Major histocompatibility complex (MHC) molecules carrying selected peptides will bind specifically to their cognate T-cell receptor on individual clones of reactive T cells. Fluorescently labeled, tetrameric MHC-peptide complexes have been widely used to detect and quantitate antigen-specific T-cell populations via flow cytometry. We hypothesized that such MHC-peptide tetramers could also be used to selectively deplete unique reactive T-cell populations, while leaving the remaining T-cell repertoire and immune response intact. In this report, we successfully demonstrate that a tetramer-based depletion of T cells can be achieved in a murine model of allogeneic bone marrow transplantation. Depletion of a specific alloreactive population of donor splenocytes (< 0.5% of CD8+ T cells) prior to transplantation significantly decreased morbidity and mortality from graft-versus-host disease. There was no early regrowth of the antigen-specific T cells in the recipient and in vivo T-cell proliferation was greatly reduced as well. Survival was increased more than 3-fold over controls, yet the inherent antitumor activity of the transplant was retained. This method also provides the proof-of-concept for similar strategies to selectively remove other unwanted T-cell clones, which could result in novel therapies for certain autoimmune disorders, T-cell malignancies, and solid organ graft rejection.
Kappel
Barry J
BJ
Department of Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, Howard 719, Mailbox 531, 1275 York Ave, New York, NY 10021, USA.
Pinilla-Ibarz
Javier
J
Kochman
Adam A
AA
Eng
Jeffrey M
JM
Hubbard
Vanessa M
VM
Leiner
Ingrid
I
Pamer
Eric G
EG
Heller
Glen
G
van den Brink
Marcel R M
MR
Scheinberg
David A
DA
D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods; D008285:Major Histocompatibility Complex / Q000276:immunology; D008297:Male; D051379:Mice; D010455:Peptides / Q000008:administration & dosage* / Q000276:immunology; D014184:Transplantation, Homologous
D010455:Peptides