Attenuation of murine lysosomal storage disease by allogeneic neonatal bone marrow transplantation using costimulatory blockade and donor lymphocyte infusion without myeloablation.
Treatment of nonmalignant childhood disorders by bone marrow transplantation (BMT) is limited by toxicity from preparatory regimens and immune consequences associated with engraftment of allogeneic donor cells. Using costimulatory blockade (anti-CD40L mAb and CTLA-4Ig) combined with high-dose BMT in nonablated neonates, we obtained engraftment and established tolerance using both partially MHC mismatched (H2g7 into H2b) and fully mismatched BM (H2s into H2b). Recipients were mucopolysaccharidosis type VII (MPS VII) mice with lysosomal storage disease in order to assess therapeutic outcome. Recipients treated with donor lymphocyte infusion (DLI) amplified microchimerism to full donor. Recipients without DLI maintained long-term engraftment, tolerance, and had extended life spans. DLI increased donor cell mediated replacement of beta-glucuronidase (GUSB) activity in all tissues and maintained clearance of lysosomes better than in non-DLI-treated mice. DLI amplification of partially mismatched BM and fully mismatched BM caused late onset chronic GvHD in 56% and 100% of recipients, respectively.
Lessard
Mark D
MD
The Jackson Laboratory, Box 95, 600 Main Street, Bar Harbor, ME 04609, USA.
Alley
Travis L
TL
Proctor
Jennifer L
JL
Levy
Beth
B
Galvin
Nancy
N
Vogler
Carole A
CA
Soper
Brian W
BW
D000818:Animals; D016026:Bone Marrow Transplantation; D002678:Chimera; D006086:Graft vs Host Disease / Q000378:metabolism / Q000473:pathology; D006331:Heart Diseases / Q000628:therapy; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D017710:Lymphocyte Transfusion; D016464:Lysosomal Storage Diseases / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D019653:Myeloablative Agonists; D014184:Transplantation, Homologous
D019653:Myeloablative Agonists