Prevention of graft-versus-host disease by anti IL-7Ralpha antibody.
Graft-versus-host disease (GVHD) continues to be a serious complication that limits the success of allogeneic bone marrow transplantation (BMT). Using IL-7-deficient murine models, we have previously shown that IL-7 is necessary for the pathogenesis of GVHD. In the present study, we determined whether GVHD could be prevented by antibody-mediated blockade of IL-7 receptor alpha (IL-7Ralpha) signaling. C57/BL6 (H2K(b)) recipient mice were lethally irradiated and underwent cotransplantation with T-cell-depleted (TCD) BM and lymph node (LN) cells from allogeneic BALB/c (H2K(d)) donor mice. Following transplantation, the allogeneic BMT recipients were injected weekly with either anti-IL-7Ralpha antibody (100 mug per mouse per week) or PBS for 4 weeks. Anti-IL-7Ralpha antibody treatment significantly decreased GVHD-related morbidity and mortality compared with placebo (30% to 80%). IL-7Ralpha blockade resulted in the reduction of donor CD4(+) or CD8(+) T cells in the periphery by day 30 after transplantation. Paradoxically, the inhibition of GVHD by anti-IL-7Ralpha antibody treatment resulted in improved long-term thymic and immune function. Blockade of IL-7R by anti-IL-7Ralpha antibody resulted in elimination of alloreactive T cells, prevention of GVHD, and improvement of donor T-cell reconstitution.
Chung
Brile
B
Division of Stem Cell Transplantation, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
Dudl
Eric P
EP
Min
Dullei
D
Barsky
Lora
L
Smiley
Nancy
N
Weinberg
Kenneth I
KI
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000917:Antibody Formation / Q000187:drug effects; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects; D013950:Thymus Gland / Q000187:drug effects; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain