Neonatal bone marrow transplantation of ADA-deficient SCID mice results in immunologic reconstitution despite low levels of engraftment and an absence of selective donor T lymphoid expansion.
Adenosine deaminase (ADA)-deficient severe combined immune deficiency (SCID) may be treated by allogeneic hematopoietic stem cell transplantation without prior cytoreductive conditioning, although the mechanism of immune reconstitution is unclear. We studied this process in a murine gene knockout model of ADA-deficient SCID. Newborn ADA-deficient pups received transplants of intravenous infusion of normal congenic bone marrow, without prior cytoreductive conditioning, which resulted in long-term survival, multisystem correction, and nearly normal lymphocyte numbers and mitogenic proliferative responses. Only 1% to 3% of lymphocytes and myeloid cells were of donor origin without a selective expansion of donor-derived lymphocytes; immune reconstitution was by endogenous, host-derived ADA-deficient lymphocytes. Preconditioning of neonates with 100 to 400 cGy of total body irradiation before normal donor marrow transplant increased the levels of engrafted donor cells in a radiation dose-dependent manner, but the chimerism levels were similar for lymphoid and myeloid cells. The absence of selective reconstitution by donor T lymphocytes in the ADA-deficient mice indicates that restoration of immune function occurred by rescue of endogenous ADA-deficient lymphocytes through cross-correction from the engrafted ADA-replete donor cells. Thus, ADA-deficient SCID is unique in its responses to nonmyeloablative bone marrow transplantation, which has implications for clinical bone marrow transplantation or gene therapy.
Carbonaro
Denise A
DA
Division of Research Immunology/Bone Marrow Transplantation, Childrens Hospital, Los Angeles, CA 90027, USA.
Jin
Xiangyang
X
Cotoi
Daniel
D
Mi
Tiejuan
T
Yu
Xiao-Jin
XJ
Skelton
Dianne C
DC
Dorey
Frederick
F
Kellems
Rodney E
RE
Blackburn
Michael R
MR
Kohn
Donald B
DB
D000243:Adenosine Deaminase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D016026:Bone Marrow Transplantation; D004789:Enzyme Activation; D006085:Graft Survival / Q000276:immunology; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016513:Mice, SCID; D020127:Recovery of Function / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D015996:Survival Rate; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D018183:Transplantation Chimera; D019172:Transplantation Conditioning
C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D000243:Adenosine Deaminase