Selective growth advantage of wild-type lymphocytes in X-linked SCID recipients.
The cytokine receptor common gamma chain (gamma c) plays a pivotal role in multiple interleukin signaling, and gamma c gene mutations cause an X-linked form of SCID (X-SCID). Recently, gamma c gene transfer into the autologous X-SCID BM achieved appreciable lymphocyte reconstitution, contrasting with the limited success in previous gene therapy trials targeting hematopoietic stem cells. To understand the mechanisms underlying this success, we examined the repopulating potential of the wild-type (WT) BM cells using an X-SCID mouse model. Limited numbers of WT cells were infused into non-ablated WT and X-SCID hosts. Whereas no appreciable engraftment was observed in WT recipients, donor-derived lymphocytes repopulated well in X-SCID, reaching 37% (10(6)cells given) and 53% (10(7) cells given) of the normal control value 5 months post BMT. A lineage analysis showed a predominance of the donor-derived lymphocytes (CD4(+) T, CD8(+) T, B and NK cells) in X-SCID while the donor-derived granulocytes and monocytes engrafted poorly. These results showed a selective advantage of WT cells in X-SCID, and that the advantage was restricted to lymphocytes. In human gene therapy for X-SCID, an analogous growth advantage would greatly enhance the repopulation of lymphocytes derived from a very small number of gamma c gene-supplemented precursors.
Kume
A
A
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, Minamika-wachi, Tochigi 329-0498, Japan.
Koremoto
M
M
Mizukami
H
H
Okada
T
T
Hanazono
Y
Y
Sugamura
K
K
Ozawa
K
K
D000818:Animals; D016026:Bone Marrow Transplantation; D002455:Cell Division; D019070:Cell Lineage; D004195:Disease Models, Animal; D040181:Genetic Diseases, X-Linked / Q000628:therapy; D006085:Graft Survival; D053631:Interleukin Receptor Common gamma Subunit; D008214:Lymphocytes / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D020395:Receptors, Interleukin-7 / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000628:therapy*; D013997:Time Factors; D018183:Transplantation Chimera
C507941:IL2RG protein, human; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D020395:Receptors, Interleukin-7