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Published in final edited form as: Pediatrics. 2009 Mar;123(3):836–840. doi: 10.1542/peds.2008-1191

Allogeneic hematopoietic stem cell transplantation for Leukocyte Adhesion Deficiency

Waseem Qasim 1, Marina Cavazzana-Calvo 2, EGraham Davies 1, Jeffery Davis 3, Michel Duval 4, Gretchen Eames 5, Nuno Farinha 6, Alexandra Filopovich 7, Alain Fischer 2, Wilhelm Friedrich 8, Andrew Gennery 9, Carsten Heilmann 10, Paul Landais 2, Mitchell Horwitz 11, Fulvio Porta 12, Petr Sedlacek 13, Reinhard Seger 14, Mary Slatter 9, Lochie Teague 15, Mary Eapen 16, Paul Veys 1
PMCID: PMC3380632  NIHMSID: NIHMS373897  PMID: 19255011

Abstract

OBJECTIVES

Leukocyte Adhesion Deficiency (LAD) is a rare primary immune disorder caused by defects of the CD18 β-integrin molecule on immune cells. The condition usually presents in early infancy and is characterised by deep tissue infections, leukocytosis with impaired formation of pus and delayed wound healing. Allogeneic haematopoietic stem cell transplantation (HSCT) offers the possibility of curative therapy, and with patient numbers at any individual centre being limited, we surveyed the transplant experience at 14 centres worldwide.

PATIENTS & METHODS

The course of 36 children with a confirmed diagnosis of LAD who underwent HSCT between 1993 and 2007 was retrospectively analysed. Data was collected by the registries of the European Society for Immunodeficiencies (ESID)/European Group for Blood and Marrow Transplantation (EBMT), and the Center for International Blood and Marrow Transplant Research (CIBMTR)

RESULTS

At median followup of 62 months (extending to 14 years) overall survival was 75%. Myeloablative conditioning regimens were used in 28 patients, and reduced intensity conditioning (RIC) in 8 patients, with no deaths in this subgroup. Survival after matched family donor and unrelated donor transplants was similar, with 11/14 matched family donor and 12/14 unrelated donor recipients alive; mortality was greatest following haplo-identical transplants, where 4/8 children did not survive. Twenty seven transplant recipients are alive, with full donor engraftment in 17 cases, mixed multi-lineage chimerism in 7 patients, and mononuclear cell restricted chimerism in a further 3 cases.

CONCLUSIONS

HSCT offers long term benefit in LAD and should be considered as an early therapeutic option if a suitable HLA-matched stem cell donation is available. Reduced intensity conditioning was particularly safe, and mixed donor chimersim appears sufficient to prevent significant symptoms, although careful long term monitoring will be required for these patients.

Keywords: Leukocyte adhesion deficiency, Stem cell transplantation, Reduced Intensity Conditioning

INTRODUCTION

Leukocyte adhesion deficiency (LAD) type 1 is a rare autosomal recessive immunodeficiency documented in approximately 300 patients worldwide. Defective expression of the beta-2 integrin, CD18, on immune cells results in impaired leukocyte adhesion, egression and migration. CD18 forms the dimeric complexes LFA-1 (lymphocyte function associated antigen-1) in association with CD11a, Mac-1 in combination with CD11b and p150-95 with CD11c. These molecular complexes are essential for effective migration and homing of immune cells, including neutrophils, dendritic cells and T lymphocytes.1;2 Defective neutrophil migration can result omphalitis and delayed separation of the umbilical cord, a characteristic and early presenting hallmark of LAD1.3 Other features include recurrent deep tissue bacterial infections affecting the skin and mucosa. Leukocytosis in peripheral blood and the absence of pus formation at sites of infection is characteristic. Poor post-operative wound healing may be a presenting feature. Patients with less than 1% CD18 expression are considered to have the most severe phenotype, with serious infections leading to life-threatening complications in early infancy. Allogeneic haematopoietic stem cell transplantation (HSCT) offers the possibility of curative therapy for LAD, but as the condition is extremely rare, experience at any particular centre is limited.4;5 A two centre study has previously reported the outcomes of 14 matched family and haploidentical donor transplants, undertaken between 1982-1993. Their findings noted particular difficulties associated with transplantation for LAD, including graft rejection and graft versus host disease (GVHD). In some patients, additional chemotherapy with agents such as Etoposide was used to supplement conventional myeloablative conditioning with Busulphan and Cyclophosphamide.6 There was an overall mortality rate of 28%, but interestingly no difference in survival following HLA-identical or non-identical procedures was detected, and the study has broadly influenced the subsequent approach to stem cell transplantation for LAD. We have surveyed the results of transplantation undertaken in the subsequent period, between 1993 and 2007, of children who were treated at 14 centres worldwide and have compiled a series of 36 patients. Our findings provide the most comprehensive picture of outcomes following transplantation and highlight an increased use of alternative stem cell sources and reduced intensity regimens.

PATIENTS AND METHODS

Data Sources

Patient data, transplant characteristics and outcomes were reported to the European Society for Immunodeficiencies (ESID)/European Group for Blood and Marrow Transplantation (EBMT) registry and the Center for International Blood and Marrow Transplant Research (CIBMTR). Forteen centres treated between 1-9 patients each (median 1.5/centre). Included are patients documented as having reduced or absent expression of CD18 by flow cytometric analysis and transplanted after 1993. Excluded are patients with a clinical suspicion of LAD, but without proven reduction in CD18 expression. Although this is the largest series to date, patients treated under any one particular transplant regimen were small, limiting the power of any statistical analysis.

Transplantation

Thirty six patients underwent their first transplant for LAD between 1993 and 2007. Patients received bone marrow (n=27), peripheral blood progenitor cells (n=4) or umbilical cord blood grafts (n=5) from 14 HLA-matched family donors, 8 haploidentical donors and 14 unrelated donors (Table 1A, 1B). The median age at SCT was 9 months (range 2 months – 14 years). Most (n=28) patients received fully myeloablative regimens which combinations of Busulphan (16-20mg/kg), Cyclophosphamide (100-200mg/kg) and Etoposide (VP16, 900mg/m2). Additional serotherapy included Campath 1G, anti-leukocyte function antigen-1 (LFA-1), anti-CD2 antibody, anti-CD3 antibody, or anti-thymocyte globulin (ATG). The remaining 8 patients received reduced intensity conditioning (RIC) with combinations of Fludarabine (150mg/m2), Melphalan (140mg/m2), Treosulphan (42mg/m2), Campath 1H (1mg/kg) and rabbit ATG (10mg/kg). In the haploidentical setting T cell depletion was achieved by E-Rosetting or CD34+ stem cell selection form marrow or mobilised PBSC. Most patients received Cyclosporine either alone or in combination with Mycophenolate, Methotrexate and/or Prednisolone for graft-versus-host disease (GVHD) prophylaxis. Chimerism post-SCT was monitored by a variety of techniques including fluorescent in situ hybridisation (FISH) for sex mismatched grafts, PCR analysis using micro-satellite probes, and flow cytometry for CD18.7,8 Six patients received a second SCT for graft failure (n=5) or secondary malignancy (EBV lymphoma, n=1) and 2 patients underwent a third procedure for graft failure or low level donor chimerism. All but one of these multiple grafts was in the haploidentical setting.

Table 1.

Patients surviving after allogeneic transplantation for LAD

Donor Age mths Year BMT Follow-up (mths) Conditioning Graft Prophyl-axis Gvhd Infections Chimerism
1 MFD 14 1996 156 Bu CY VP16 BM CyA Mtx III/IV Full
2 MFD 18 2006 14 *Flu Mel Cam1H BM CyA MMF II CMV MNC 30
3 MFD 3 2007 5 *Flu Treo Cam1H BM CyA MMF Full
4 MSD 78 1994 156 Bu VP16 UCB Pneumonit is PMN 44 MNC 64
5 MSD 10 1995 147 Bu CY VP16 BM CyA EBV Full
6 MSD 6 1997 120 Bu CY BM CyA II MNC 100
7 MSD 2 2000 36 Bu Cy BM CyA Mtx Prd Full
8 MSD 5 2003 36 Bu CY BM CyA Full
9 MSD 4 2003 36 Bu CY ATG BM CyA Full
10 MSD 16 2005 30 Bu Cy ATG BM CyA Mtx Prd CMV PMN 25 MNC 77
11 MSD 11 2006 24 Bu CY BM CyA I Full
12 MUD 8 1993 168 Bu CY Cam1G BM CyA Mtx Full
13 MUD 150 1998 71 Bu CY VP16 BM CyA Mtx VZV PMN 63 MNC75
14 MUD 60 2000 72 *Flu Mel Cam1H BM CyA CMV, EBV PMN100 MNC92
15 MUD 24 2001 72 *Flu Mel Cam1H BM CyA II/III ADV Full
16 MUD 36 2001 74 *Flu Mel Cam1H BM CyA Crypto PMN 87 MNC 93
17 MUD 24 2003 62 *Flu Mel Cam1H BM CyA Full
18 MUD 8 2006 24 Bu CY ATG BM/CD34 II MNC 30
19 MUD 1AMM 9 2006 14 *Flu Treo Cam1H BM CyA MMF III/IV CMV Fungal Full
20 MUD 1AMM 27 1999 96 Bu CY ATG UCB CyA Prd Full
21 MUD 1AMM 4 1999 50 Bu CY ATG UCB CyA Prd I/II Full
22 MUD 3AMM 7 2007 12 *Flu Treo ATG UCB CyA Prdd PMN 3 MNC 5
23 MUD 3AMM 7 1997 93 Bu CY ATG UCB CyA Prd I Candida Full
24

  1. HAPL

  2. HAPL

 7 1999 96

  1. Bu CY TP

  2. Flu Mel ATG

  1. BM/CD34

  2. BM/CD34

 I Full
25

  1. HAPL(P)

  2. HAPL(M)

  3. HAPL(M)

 2 2000 19

  1. Bu CY ATG

  2. Flu aCD3

  3. None

  1. PBSC/CD34

  2. PBSC/CD34

  3. PBSC/CD34

 Full
26

  1. HAPL

  2. HAPL

 22 2003 48

  1. Bu CY ATG

  2. Flu Mel TP Cam1G

  1. PBSC/CD34

  2. PBSC/CD34

 III Full
27

  1. HAPL

  2. MMFD

 4 1993 147

  1. Bu CY ATG

  2. TBI CY ARA-C

  1. BM T dep

  2. BM T dep

 CyA Candida PMN 24, MNC10
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RESULTS

In general, outcomes following HSCT for primary immunodeficiencies have improved over time.7 We found long term survival following transplantation for LAD undertaken between 1993-2007 was around 75%, little changed to that reported for the period 1982-1993.6 Previous transplant experience had suggested that non-identical, T cell depleted grafts, could be as successful as HLA-identical procedures in LAD, but our survey has found a high levels of primary graft failure, which resulted in secondary (or tertiary) grafting in all 8 haploidentical transplants. Consequently, only 4/8 (50%) children in this subgroup survived. The increased availability of matched unrelated adult and cord blood stem cell grafts has been an important change in recent years and survival following either matched family donor or unrelated donor transplantation was notably better. Thus 12/14 (86%) recipients of unrelated donor HSCT survived, and this was comparable to 11/14 (79%) of the matched family donor recipients.

Nine patients (4 haploidentical, 3 sibling donor and 2 matched unrelated donor) did not survive following transplantation (Table 2). All had received myeloablative conditioning and donor engraftment was established in seven patients, albeit after repeat procedures in five cases. Infection related deaths occurred in 5 cases, with 3 deaths linked to veno-occlusive disease and one case of secondary malignancy (EBV lymphoma). We noted that six deaths occurred in the first seven-year period of this analysis (1993-2000) compared to three deaths in the subsequent period (2001-2007). This probably reflects the reduced use of haploidentical donors in the second period, rather than any generalised improvements in transplantation procedures or supportive care in recent years.

Table 2.

Patients not surviving after allogeneic transplantation for LAD

Donor Age (months) Year BMT Conditioning Graft GVHD Prophylaxis GVHD Grade Engraftment Cause of death
1 MSD 15 1995 BU VP16 BM Mtx Yes Pneumonitis
2 MSD 3 2001 BU CY BM CyA Yes VOD
3 MSD 8 2001 BU CY BM CyA Mtx Pred Yes VOD
4 MUD 168 1996 BU CY Cam1G BM CyA Mtx Yes Infection
5

  1. MUD

  2. MUD

 13 1998

  1. BU CY ATG

  2. BU CY VP16 ATG

  1. BM

  2. BM

 CyA Mtx II Yes Infection
6

  1. HAPL

  2. MUD

 19 1993

  1. BU CY VP16

  2. TBI CY ATG

  1. BM T dep

  2. BM

 CyA I No Infection, Malignancy
7

  1. HAPL(P)

  2. HAPL(M)

 5 1994

  1. BU CY VP16 αLFA-1 αCD2

  2. BU CY VP16 Cam1G

  1. BM T dep

  2. BM T dep

 Yes Infection VOD
8

  1. HAPL(P)

  2. HAPL(M)

  3. HAPL(M)

 3 1997

  1. BU CY αCD2

  2. BU CY αCD2 ATG

  3. CY ATG

  1. BM T dep

  2. BM T dep

  3. BM T dep

 CyA Yes Infection
9

  1. HAPL(M)

  2. HAPL(P)

 4 2004

  1. BU CY ATG

  2. BU CY ATG

  1. BM T dep

  2. PBSC/CD34

 No ARDS
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*

Indicates Reduced Intensity Conditioning (RIC). Other abbreviations for Tables 1 & 2: ARA-C, Cytarabine; ARDS, Acute respiratory distress syndrome; ATG, Antithymocyte gobulin; BM, Bone Marrow; Bu, Busulphan; Cam1G, Campath 1G; Cam1H, Campath 1H; CMV, Cytomegalovirus; CY Cyclophosphamide; CyA, Cyclosporin; EBV, Epstein Barr Virus; HAPL, Haloidentical donor (P-paternal, M-maternal); MFD, Matched family donor; MSD, Matched sibling donor; MUD, Matched unrelated donor; MMUD, Mismatched unrelated donor (1-3 antigens); PBSC, Peripheral blood stem cell collection (CD34 selected where indicated); MNC, mononuclear cells; Mtx, Methotrexate; MMF, Mycophenolate mofetil; PMN, Polymorphonuclear cells; Prd, prednisolone; T dep, T cell depleted; TP, Thiopeta; UCB, Umbilical cord blood; VP16, Etoposide; VOD, Veno-occlusive disease; VZV, Varicella zoster virus

Complications that may be anticipated following allogeneic stem cell transplantation include GVHD, infections and the toxic side effects of chemotherapy. Nine patients developed GVHD at grade II or greater, including two cases of severe grade IV skin and gut GVHD (one MFD and the other a 1-antigen mismatched MUD). Viral reactivations of CMV, EBV, Adenovirus and Varicella Zoster were detected, and there were at least two significant cases of unexplained pneumonitis. Veno-occlusive disease in three cases followed Busulphan based conditioning, and contributed to the cause of death in these cases. Overall the use of RIC regimens appeared to be associated with reduced toxicity, with all 8 patients in this subgroup surviving, although two (patients no 2 and 22) have low level donor chimerism. With twenty seven surviving patients followed-up for a median of 62 months, full chimerism has been recorded in 17, with stable mixed chimerism in granulocytes and mononuclear cells being achieved in 7 patients (Table 1). The latter included an umbilical cord blood graft recipient mismatched at 3-loci who has very low levels of chimerism in both lineages (~5%) but remains symptom-free. The remaining three patients have lymphoid engraftment (one full, two mixed) but no documented engraftment of donor granulocytes, and these patients also remain well but continue to receive close monitoring.

DISCUSSION

We report the transplant experience for LAD for procedures undertaken at 14 centres worldwide over a 14 year period. There is general agreement that infants presenting with significant infections in the first weeks or months of life who have a diagnosis of LAD confirmed on the basis of CD18 expression should undergo early HSCT if a suitable HLA-matched family donor can be identified. In the absence of a HLA matched family donor, the ready availability of a parental haploidentical donor has obvious attractions and the previous experience of successful haploidentical transplantation in LAD had suggested that T cell depleted family mismatched grafts could be as successful as HLA-identical (T cell replete) procedures in LAD. It was postulated that this may relate to the reduced ability of the LAD host to mediate graft rejection.5;6 This observation has not been borne out in the current series, where all the haploidentical grafts were initially rejected despite full myeloablative conditioning. Secondary procedures were performed using either the same (2 cases) or alternative donors (6 cases), resulting in successful reconstitution in 4 patients. This experience is in line with that seen for other primary immune deficiencies treated using HLA mismatched donors.7 In such settings the depletion of donor T cells necessary for preventing GVHD results in reduced graft potency, and increases the risk of graft failure and infective complications.9

In more recent years, there has been increased availability of unrelated volunteer donors and umbilical cord stem cell donations, and this is reflected in our series which included 14 such procedures. Until now there have been only isolated reports describing the successful transplantation for LAD using matched unrelated adult donors10-14 and umbilical cord blood grafts.15 As unrelated donor transplants undertaken with conventional myeloablative conditioning can be associated with significant toxicity, especially in the context of pre-existing organ dysfunction, a number of these procedures were performed using modified, reduced intensity regimens. We have previously documented improved survival in children with primary immune deficiencies who underwent RIC procedures.8 These transplants are generally less toxic and rely on intense immunosuppression to engineer host:donor tolerance sufficient for reliable donor engraftment. In the LAD setting the RIC regimens were well tolerated, and although a number of children have mixed chimerism, all remain alive and free of significant symptoms. The long term consequences of RIC pre-conditioning in these patients will be of particular interest considering that intact fertility and uncomplicated pregnancies have been reported in dogs with canine LAD (CLAD) following non-myeloablative SCT.16

Interestingly, low levels of donor neutrophil engraftment as measured in peripheral blood appear sufficient for patients to remain symptom-free. The minimum level of functional CD18 expression on leukocytes required to prevent complications is not known. Somatic reversion events, leading to normal CD18 expression on a small fraction of peripheral blood T cells, have been reported in a LAD.17;18 Somatic mosaicism in patients with other inherited immunodeficiencies has been linked to milder phenotypes,19;20 but in LAD the reversion phenomena have been limited to CD8+ T cells, and it is unclear if small populations of CD18+ T cells played a role in patient survival into adulthood or if they arose as a consequence of longer term survival.17 In addition, observations from animal studies are encouraging and suggest that low levels of functional, CD18 expressing, leucocytes can prevent disease.21 Transplant studies in CLAD have indicated that less than 500 CD18+ donor neutrophils/microL in peripheral blood can reverse disease phenotype.22 It should be noted that in LAD the levels of circulating donor neutrophils may not accurately reflect levels of true engraftment, as functional CD18+ cells may preferentially egress the circulation and mediate important beneficial effects at target sites such as the oral mucosa. Thus, in dogs selective accumulation of donor neutrophils was demonstrated in the oral mucosa resulting in significantly higher levels of donor chimerism in the saliva of animals compared to peripheral blood after transplantation.22 Evidence from gene therapy studies in the CLAD model also supports the notion that low numbers of functional cells can prevent disease. The infusion of autologous haematopoietic stem cells transduced to express canine CD18 corrected 5-10% of circulating leukocytes and this was sufficient to mediate durable reversal of the disease.23 Presently, a number of patients with mixed donor chimerism, including those with only mononuclear lineage engraftment remain free of significant disease. Further investigation of these patients may be warranted, including detailed lineage specific chimaerism in tissues (in the bone marrow and gingival tissues) and the exclusion of host mediated cellular or autoantibody responses against donor derived cells.

CONCLUSION

LAD1 is a serious primary immune disorder that can be corrected by allogeneic HSCT. Matched family donor and unrelated donor procedures were equally successful and mixed chimerism in peripheral blood appears sufficient to keep patients free of significant symptoms. The study has highlighted the impressive safety profile of RIC regimens, and the greater availability of suitable unrelated donors in combination with tailored conditioning regimens should improve outcomes further.

Acknowledgments

WQ is supported by the Leukaemia Research Fund. Support from Public Health Service grant U24-CA76518-10 from the National Cancer Institute, National Institute of Allergy and Infectious Diseases and the National heart Lung and Blood Institute is acknowledged.

Abbreviations

ARA-C

Cytarabine

ARDS

Acute respiratory distress syndrome

ATG

Antithymocyte globulin

BM

Bone Marrow

Bu

Busulphan

Cam1G

Campath 1G

Cam1H

Campath 1H

CLAD

Canine leukocyte adhesion deficiency

CMV

Cytomegalovirus

CY

Cyclophosphamide

CyA

Cyclosporin

EBV

Epstein Barr Virus

FISH

fluorescent in situ hybridization

GVHD

Graft versus host disease

HAPL

Haloidentical donor (P-paternal, M-maternal)

HSCT

Haematopoietic stem cell transplantation

LAD

Leukocyte adhesion deficiency

MFD

Matched family donor

MMUD

Mismatched unrelated donor

MSD

Matched sibling donor

MUD

Matched unrelated donor

PBSC

Peripheral blood stem cell collection

MNC

mononuclear cells

Mtx

Methotrexate

MMF

Mycophenolate mofetil

PMN

Polymorphonuclear cells

Prd

prednisolone

RIC

reduced intensity conditioning

T dep

T cell depleted

TP

Thiopeta

UCB

Umbilical cord blood

VP16

Etoposide

VOD

Veno-occlusive disease

VZV

Varicella zoster virus

Footnotes

Contributions: WQ,PV,ME designed study, provided data, collected data, and wrote the manuscript; MCC,EGD,JD,MD,GE,AF,WF,AG,CH,PL,MH,FP,PS,RS,MS,LT provided data; NF, AF contributed to study design.

There were no financial conflicts of interest.

Reference List

  • 1.Fischer A, Lisowska-Grospierre B, Anderson DC, Springer TA. Leukocyte adhesion deficiency: molecular basis and functional consequences. Immunodefic Rev. 1988;1:39–54. [PubMed] [Google Scholar]
  • 2.Malech HL, Hickstein DD. Genetics, biology and clinical management of myeloid cell primary immune deficiencies: chronic granulomatous disease and leukocyte adhesion deficiency. Curr Opin Hematol. 2007;14:29–36. doi: 10.1097/00062752-200701000-00007. [DOI] [PubMed] [Google Scholar]
  • 3.Movahedi M, Entezari N, Pourpak Z, et al. Clinical and laboratory findings in Iranian patients with leukocyte adhesion deficiency (study of 15 cases) J Clin Immunol. 2007;27:302–7. doi: 10.1007/s10875-006-9069-4. [DOI] [PubMed] [Google Scholar]
  • 4.Fischer A, Trung PH, Descamps-Latscha B, et al. Bone-marrow transplantation for inborn error of phagocytic cells associated with defective adherence, chemotaxis, and oxidative response during opsonised particle phagocytosis. Lancet. 1983;2:473–6. doi: 10.1016/s0140-6736(83)90509-3. [DOI] [PubMed] [Google Scholar]
  • 5.Le Deist F, Blanche S, Keable H, et al. Successful HLA nonidentical bone marrow transplantation in three patients with the leukocyte adhesion deficiency. Blood. 1989;74:512–6. [PubMed] [Google Scholar]
  • 6.Thomas C, Le Deist F, Cavazzana-Calvo M, et al. Results of allogeneic bone marrow transplantation in patients with leukocyte adhesion deficiency. Blood. 1995;86:1629–35. [PubMed] [Google Scholar]
  • 7.Antoine C, Muller S, Cant A, et al. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99. Lancet. 2003;361:553–60. doi: 10.1016/s0140-6736(03)12513-5. [DOI] [PubMed] [Google Scholar]
  • 8.Rao K, Amrolia PJ, Jones A, et al. Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen. Blood. 2005;105:879–85. doi: 10.1182/blood-2004-03-0960. [DOI] [PubMed] [Google Scholar]
  • 9.Ho VT, Soiffer RJ. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood. 2001;98:3192–204. doi: 10.1182/blood.v98.12.3192. [DOI] [PubMed] [Google Scholar]
  • 10.Engel ME, Hickstein DD, Bauer TR, Jr, Calder C, Manes B, Frangoul H. Matched unrelated bone marrow transplantation with reduced-intensity conditioning for leukocyte adhesion deficiency. Bone Marrow Transplant. 2006;37:717–8. doi: 10.1038/sj.bmt.1705301. [DOI] [PubMed] [Google Scholar]
  • 11.Takahashi D, Nagatoshi Y, Saito Y, et al. Unrelated bone marrow transplantation using a reduced intensity-conditioning regimen in leukocyte adhesion deficiency. Bone Marrow Transplant. 2006;37:807–8. doi: 10.1038/sj.bmt.1705336. [DOI] [PubMed] [Google Scholar]
  • 12.Tokunaga M, Miyamura K, Ohashi H, et al. Successful nonmyeloablative bone marrow transplantation for leukocyte adhesion deficiency type I from an unrelated donor. Int J Hematol. 2007;86:91–5. doi: 10.1532/IJH97.06209. [DOI] [PubMed] [Google Scholar]
  • 13.Farinha NJ, Duval M, Wagner E, et al. Unrelated bone marrow transplantation for leukocyte adhesion deficiency. Bone Marrow Transplant. 2002;30:979–81. doi: 10.1038/sj.bmt.1703719. [DOI] [PubMed] [Google Scholar]
  • 14.Hattori H, Tsuruta S, Horikoshi Y, et al. Successful human leukocyte antigen one antigen-mismatched related bone marrow transplantation in a 6-year-old boy with leukocyte adhesion deficiency syndrome. Pediatr Int. 2001;43:306–9. doi: 10.1046/j.1442-200x.2001.01381.x. [DOI] [PubMed] [Google Scholar]
  • 15.Stary J, Bartunkova J, Kobylka P, et al. Successful HLA-identical sibling cord blood transplantation in a 6-year-old boy with leukocyte adhesion deficiency syndrome. Bone Marrow Transplant. 1996;18:249–52. [PubMed] [Google Scholar]
  • 16.Burkholder TH, Colenda L, Tuschong LM, Starost MF, Bauer TR, Jr, Hickstein DD. Reproductive capability in dogs with canine leukocyte adhesion deficiency treated with nonmyeloablative conditioning prior to allogeneic hematopoietic stem cell transplantation. Blood. 2006;108:1767–9. doi: 10.1182/blood-2006-02-005645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Uzel G, Tng E, Rosenzweig SD, et al. Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1) Blood. 2008;111:209–18. doi: 10.1182/blood-2007-04-082552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Tone Y, Wada T, Shibata F, et al. Somatic revertant mosaicism in a patient with leukocyte adhesion deficiency type 1. Blood. 2007;109:1182–4. doi: 10.1182/blood-2007-08-039057. [DOI] [PubMed] [Google Scholar]
  • 19.Stephan V, Wahn V, Le Deist F, et al. Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N Engl J Med. 1996;335:1563–7. doi: 10.1056/NEJM199611213352104. [DOI] [PubMed] [Google Scholar]
  • 20.Ariga T, Kondoh T, Yamaguchi K, et al. Spontaneous in vivo reversion of an inherited mutation in the Wiskott-Aldrich syndrome. J Immunol. 2001;166:5245–9. doi: 10.4049/jimmunol.166.8.5245. [DOI] [PubMed] [Google Scholar]
  • 21.Creevy KE, Bauer TR, Jr, Tuschong LM, et al. Mixed chimeric hematopoietic stem cell transplant reverses the disease phenotype in canine leukocyte adhesion deficiency. Vet Immunol Immunopathol. 2003;95:113–21. doi: 10.1016/s0165-2427(03)00108-9. [DOI] [PubMed] [Google Scholar]
  • 22.Bauer TR, Jr, Creevy KE, Gu YC, Tuschong LM, et al. Very low levels of donor CD18+ neutrophils following allogeneic hematopoietic stem cell transplantation reverse the disease phenotype in canine leukocyte adhesion deficiency. Blood. 2004;103:3582–9. doi: 10.1182/blood-2003-11-4008. [DOI] [PubMed] [Google Scholar]
  • 23.Bauer TR, Jr, Allen JM, Hai M, et al. Successful treatment of canine leukocyte adhesion deficiency by foamy virus vectors. Nat Med. 2008;14:93–7. doi: 10.1038/nm1695. [DOI] [PMC free article] [PubMed] [Google Scholar]

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