Attenuation of murine lysosomal storage disease by allogeneic neonatal bone marrow transplantation using costimulatory blockade and donor lymphocyte infusion without myeloablation

• Published in: Clinical Immunology Vol. 119; no. 2; pp. 166 - 179
• Main Authors: Lessard, Mark D., Alley, Travis L., Proctor, Jennifer L., Levy, Beth, Galvin, Nancy, Vogler, Carole A., Soper, Brian W.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.05.2006; Elsevier
• Subjects: Animals; Biological and medical sciences; Bone Marrow Transplantation; CD40L; Chimera; Chronic GvHD; Costimulatory blockade; CTLA-4Ig; Donor lymphocyte infusion (DLI); Fundamental and applied biological sciences. Psychology; Fundamental immunology; Graft vs Host Disease - metabolism; Graft vs Host Disease - pathology; Heart Diseases - therapy; Immunohistochemistry; Immunopathology; Kidney - pathology; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Lymphocyte Transfusion; Lysosomal storage disease; Lysosomal Storage Diseases - therapy; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mucopolysaccharidosis type VII (MPS VII); Myeloablative Agonists; Neonate; Tolerance; Transplantation, Homologous; CD40L; Neonate; Donor lymphocyte infusion (DLI); Costimulatory blockade; Bone marrow transplantation; Tolerance; CTLA-4Ig; Lysosomal storage disease; Mucopolysaccharidosis type VII (MPS VII); Chronic GvHD; Neonatal; Stem cell; Hematopoietic cell; Homograft; Immunology; Immunotherapy; Bone marrow; Graft; Myelosuppression; Adoptive immunization; Human; Immunopathology; Donor lymphocyte infusion; Rodentia; Vertebrata; Mammalia; Newborn; Treatment; Donor; Mouse; Animal; Lymphocyte
• ISSN: 1521-6616; 1521-7035; 1365-2567
• DOI: 10.1016/j.clim.2005.12.015

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 ( H2 g7 into H2 b ) and fully mismatched BM ( H2 s into H2 b ). 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 β-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.