Hematopoietic Stem-Cell Transplantation for the Treatment of Severe Combined Immunodeficiency

Buckley, Rebecca H.; Schiff, Sherrie E.; Schiff, Richard I.; Markert, M. Louise; Williams, Larry W.; Roberts, Joseph L.; Myers, Lawrence E.; Ward, Frances E.

doi:10.1056/nejm199902183400703

Cited by 663 publications

(531 citation statements)

References 35 publications

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“…23,24 Survival of SCID patients undergoing MMRD BMT has been reported to vary between 12.5 and 78% in single centers, while multicenter trials showed approximately 50% survival rate over the past two decades. 3,18,24,25 The survival of T þ CID in these cohorts have been estimated to be even lower.…”

Section: Discussionmentioning

confidence: 99%

Matched unrelated bone marrow transplant for T+ combined immunodeficiency

Roifman

Somech

Grunebaum

2008

Bone Marrow Transplant

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Little information is currently available on the outcome and the long-term restoration of immune function in infants with combined immunodeficiency and residual T cells (T þ CID) treated by BMT. We prospectively followed patients with T þ CID who received matched unrelated donor BMT at our center. Engraftment, immune reconstitution and transplant-related complications were recorded. Humoral and cellular immunity were evaluated. Ten patients with combined immune deficiency who had more than 1000 circulating T cells/ll were designated as having T þ CID. They were diagnosed at a mean age of 9.7 months and received a matched unrelated donor BMT at the mean age of 17.4 months. All 10 patients are alive and well at a mean of 110 months after transplant. All patients have evidence of full hemopoietic engraftment and robust immune function. We have shown here that matched unrelated donor BMT is highly effective in curing patients with T þ CID. This mode of treatment should be preferred for patients with T þ CID when a related identical donor is not available.

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Section: Discussionmentioning

confidence: 99%

Matched unrelated bone marrow transplant for T+ combined immunodeficiency

Roifman

Somech

Grunebaum

2008

Bone Marrow Transplant

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“…(12) In humans, allogeneic SCT without any prior myeloablation is used for treatment of children with SCID owing to deficiency of both ADA and the common interleukin receptor g chain (X-linked SCID). (1) A selective expansion of T-lymphocytes has been observed in the recipients, explaining the curative effect despite lack of conditioning to open up stem cell niches. However, somewhat surprisingly, Kohn and colleagues found in a mouse-model of ADA-SCID that there was no evidence of selective expansion after nonablative SCT.…”

Section: Discussionmentioning

confidence: 99%

“…(25) This was therefore in contrast to the human situation and also to the mouse model of X-linked SCID, in which a clear expansion of T-lymphocytes was seen. (1,25) With this background, we wanted to determine if there was any evidence of selective expansion of the osteoclast lineage in the oc/oc mouse model after nonablative SCT. However, when comparing the frequency of donor-derived cells in the dynamic 18-to 20-day period after transplantation, there was no difference between oc/oc and control mice in the frequency of GFP þ cells in the preosteoclast CD11b/Gr1 low cell population in peripheral blood, spleen, or bone marrow, indicating that increased recruitment of cells to the osteoclast lineage is not the driving force behind the rapid reversal of osteopetrosis.…”

Section: Discussionmentioning

confidence: 99%

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Nonablative neonatal bone marrow transplantation rapidly reverses severe murine osteopetrosis despite low-level engraftment and lack of selective expansion of the osteoclastic lineage

Flores

Vries

Moscatelli

et al. 2010

Journal of Bone and Mineral Research

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Infantile malignant osteopetrosis (IMO) is caused by lack of functional osteoclasts leading to skeletal abnormalities, blindness owing to compression of the optic nerves, bone marrow (BM) failure, and early death. In most patients, TCIRG1, a proton pump subunit essential for bone resorption, is mutated. oc/oc mice represent a model for IMO owing to a deletion in Tcirg1 and die around 4 weeks of age. To determine if hematopoietic stem cell transplantation without prior conditioning can reverse osteopetrosis, neonatal mice were transplanted intravenously with lineage-depleted BM cells. More than 85% of oc/oc mice transplanted with 5 Â 10 6 cells survived long term with an engraftment of 3% to 5% in peripheral blood (PB). At 3 weeks, engraftment in the BM was 1% to 2%, but the cellularity had increased 60-fold compared with untreated oc/oc mice, and RANKL and macrophage colony-stimulating factor (M-CSF) expression in the BM was normalized. Histopathology and micro-computed tomography revealed almost complete reversal of osteopetrosis after 4 weeks. In vitro studies showed that bone resorption by osteoclasts from transplanted oc/oc mice was 14% of transplanted controls, and immunofluorescence microscopy revealed that resorption was mainly associated with osteoclasts of donor origin. Lineage analysis of BM, PB, and spleen did not provide any evidence for selective recruitment of cells to the osteoclastic lineage. The vision also was preserved in transplanted oc/oc mice, as determined by a visual tracking drum test. In summary, nonablative neonatal transplantation leading to engraftment of only a small fraction of normal cells rapidly reverses severe osteopetrosis in the oc/oc mouse model. ß

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“…Transplantation can be performed within the first 3 months of life and offers a 95% survival rate (Buckley et al, 1999). Children with untreated SCID rarely live past the age of two.…”

Section: Flow Cytometric Assays For Treatment Monitoringmentioning

confidence: 99%