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From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
1995 85: 580-587
Bone marrow transplantation in major histocompatibility complex
class II deficiency: a single-center study of 19 patients
C Klein, M Cavazzana-Calvo, F Le Deist, N Jabado, M Benkerrou, S Blanche, B
Lisowska-Grospierre, C Griscelli and A Fischer
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Bone Marrow Transplantation in Major Histocompatibility Complex Class I1
Deficiency: A Single-Center Study of 19 Patients
By Christoph Klein, Marina Cavazzana-Calvo, Frangoise Le Deist, Nada Jabado, Malika Benkerrou,
Stephane Blanche, Barbara Lisowska-Grospierre, Claude Griscelli, and Alain Fischer
Major histocompatibility complex (MHC) class II deficiency
(bare lymphocyte syndrome) is a rare inborn error of the
immune system characterized by impaired
antigen presentation and combined immunodeficiency. It causes severe and
unremitting infections leading t o progressive liver and lung
dysfunctions and death during childhood. As in other combined immunodeficiency disorders, bone marrow transplantation (BMT) is considered the treatment of choice for
MHC class II deficiency. We analyzed the filesof 19 patients
who have undergone BMT in our center. Of the 7 patients
who underwentHLA-identical BMT, 3 died in the immediate
posttransplant period of severe viral infections, whereas the
remaining 4 were cured, with recovery of normal immune
functions. Of the 12 patients who underwent HLA-haploidentical BMT, 3 were cured, 1 was improved by partialengraftment, 7 died of infectious complications due t o graft
failure or rejection, and 1 is still immunodeficient because
of engraftmentfailure. A favorable outcomein the HLA-nonidentical BMT group wasassociated with an age of less than
2 years at the timeof transplantation. All the patientswith
stable long-term engraftment had persistently low CD4
counts after transplantation (105 t o 650/pLat last follow
up), but no clear susceptibility t o opportunistic infections
despite persisting MHC class II deficiency on thymicepithelium and other nonhematopoietic cells. We conclude that
HLA-identical and -haploidentical BMT can cure MHC class
II deficiency, although the
success rate ofhaploidentical BMT
in other combined immunodeficiency synis lower than that
dromes. HLA-haploidentical BMT should preferrably be performed in the first 2 years of life, before the acquisition of
chronic virus carriage and sequelae of infections.
0 1995 by The American Society of Hematology.
M
Patients
AJOR HISTOCOMPATIBILITY complex (MHC)
class I1 deficiency is a rare combined immunodeficiency syndrome characterized by profoundly deficient HLA
class I1 expression, inconsistent and incomplete expression
of HLA class I molecules, and lack of cellular and humoral
immune responses to foreign antigens.' The underlying
pathophysiologic defect is impaired transcription of HLA
class 11-encodinggenes.*,' MHC class I1 deficiency is one
of the few diseases known to be caused by gene regulation
defects. At least three complementation groups seem to be
responsible for the immunodeficiency, suggesting that several distinct genes can be mutated in theMHC class IInegative phenotype. However, clinically, no corresponding
heterogeneity has been identified. Recently, one of the genes
involved in MHC class I1 deficiency has been c10ned.~Affected patients are prone to severe and recurrent bacterial,
viral, fungal, and protozoal infections, beginning in the first
year of life, owing to inefficient CD4 T-cell developmen?
and absent CD4 cell function. The natural history of MHC
class I1 deficiency is dismal, with patients dying at a mean
age of 4 years: often of overwhelming viral infections. Bone
marrow transplantation (BMT) is now a recognized treatment of primary immunodeficiency disorders' and can cure
the underlying genetic trait in MHC class I1 deficiency.','
We describe the outcome of BMT in 19 such children.
FromtheUnite' d'lmmunologie et d'H6matologie andINSERM
U132, Hipital Necker Enfants Malades, Paris, France.
Submitted April 21, 1994; accepted September 26, 1994.
Supported by grants from INSERM and ARC. C.K. is a recipient
of a Fritz Thyssen fellowship.
Address reprint requests to Alain Fischer, MD, Unite' 132 INSERM, Hipital Necker Enfants Malades,149, rue de Si.vres, F75743 Paris Ckdex, France.
The publication costsof this article were defrayedin part by page
chargepayment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section I734 solely to
indicate this fact.
0 1995 by The American Society of Hematology.
0006-4971/95/8502-0018$3.00/0
mn
PATIENTS, MATERIALS, AND METHODS
Nineteen children with MHC class 11 deficiency underwent BMT
atthe HGpital Necker-Enfants Malades from April1981through
June 1993. All received transplants from related donors, who were
HLA-matched in 7 cases. Extended specificity serotyping'" and genotyping" for HLA A, B, and DR antigens were applied to potential
transplant recipients and their family members. Age at BMT ranged
from 6 months to 6 years. Diagnosis was based on deficient HLA
class 11 expression on peripheral blood monocytes, B cells, and
phytohemagglutinin (PHA) activated T cells. The cut-off date for
the analysis was December I , 1993.
Treatment Regimen
The conditioning regimens are depicted in Table 1. In HLAcompatible BMT, graft-versus-host disease (GVHD) prophylaxis
consisted of methotrexate (10 mg/m*) on days l, 3, 6, and 11 and
cyclosporine for a total of 180 days, except for patient no. I , who
received only methotrexate. The mean number of infused mononuclear cells was 3 X 108ikg(range, 0.6 to 6.2 X 108/kg).
In HLA-mismatched BMT, the conditioning regimen was further
reinforced by the infusion of 0.2 mgikglday of a monoclonal antiLFA-I antibody (25-3 murine IgGl specific for the LFA-la subunit
[CDlla]) from day -3 to day +6 from 1987 onwards,2hexcept for
patient no. 7, who received 0.1 mg/kg/d of anti-LFA-l antibody on
S occasions.'2 From1991 onwards, a combination of anti-LFA-I
antibody (0.2 mg/kg/d on days -3 to + I O ) and a monoclonal antiCD2 antibody (murine BE2, isotype IgG2b; 0.2 rngkgld on days
-2 to + 11) was administered (patients no. 14, IS, 16, 18, and 19)."
GVHD prophylaxis wasbasedon graft T-cell depletion by Erosetting" or by treatment with Campath-LMantibody" (Dr G. Hale,
Cambridge, UK) plus human complement, according to the protocol.
The residual T-cell content of the infused marrow was always less
than 1.1 X I O 5 T cellsikg recipient body weight, based on limiting
dilution analysis after expansion in interleukin-2 (IL-2L"onditioned
medium. Patients no. 10 and 1 I received nondepleted donor marrow.
In the case of T-cell depletion by E-rosetting, cyclosporine was
administered intravenously (3 mg/kg/d) starting on day 0 before
marrow infusion until day 60. Doseswere adjusted according to
GVHD severity andrenal or other toxicity. Other treatments of
GVHD included corticosteroids and anti-IL-2 receptor monoclonal
antibodies.IG
Patients were infused with a mean of 3.6 X 10' (range, 0.5 to
Blood, Vol 85, No 2 (January 15). 1995: pp 580-587
From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
BMT IN MHC CLASS II DEFICIENCY
581
9.8 x 10') donor BM mononuclear cells/kg recipient body weight.
Depleted marrow was checked in the cases of patients no. 14 through
19 by determining hematopoietic precursor cell numbers. Mean colony-forming unit granulocyte-macrophage (Cm-GM) numbers
were 53 X 104/kg(range, 30 to 89.4 X 104/kg).
angitis occurred in 10 cases. Meningoencephalitis was diagnosed in 2 cases before BMT. Thirteen patients had persistent viral infections, a major cause of death in MHC class
I1 deficiency. Four patients had slight CD3 lymphopenia,
and 14 of 17 patients tested had reduced CD4' cell counts.
Most patients had elevated CD8+ cell counts, but 2 patients
had evidence of CD8 lymphopenia.*' HLA-DR expression
was, by definition, absent or low. Patients with residual DR
expression had no milder clinical presentation. All patients
had positive lymphocyte stimulation tests with PHA and
negative stimulation tests with antigens. Nine of 11 evaluable
patients had hypogammaglobulinemia and IgA levels were
reduced in 16 patients and normal in 3, whereas IgM levels
were reduced in 14 patients, normal in 4, and increased in
1. Three patients fell into complementation group A, 10
patients into group B, and 6 patients could not be classified.
However, neither residual DR expression nor clinical manifestation correlated strictly with the complementation group.
As shown in Table 3, 7 patients received HLA-identical
transplants and 12 patients received HLA-haploidentical
transplants. Six patients required more than one BMT procedure, owing to engraftment failure. The median age at the
time of the first transplant was 27 months in the HLA-identical group and 34 months in the HLA nonidentical group.
Eight patients are alive 6 months to 1 1 years post-BMT,
with a functional graft (median follow-up, 50 months).
Supportive Care
Engraftment
Patients were placed in a sterile isolator (Isoconcept, Paris, France)
or in isolation rooms with laminar airflow. All patients received gut
decontamination, and broad-spectrum antibacterial and antifungal
antibiotics were administered empirically for episodes of fever. Irradiated red blood cells and platelets were transfused as needed. If
evidence of cytomegalovirus (CMV) infection was found before
BMT in the donor (serology) or recipient (serology and/or culture
or polymerase chain reaction), acyclovir (1,500 mg/mz/d) was administered from day 0 to 60. Patients with no evidence of CMV
infection received blood components from CMV-negative donors.
Intravenous immune globulin was administered prophylactically
(200 mglkglwk) until reconstitution of endogenous immune globulin
production. Patient no. 18 also received intrathecal anti-enterovirusenriched immune globulin for chronic enterovirus meningitis.
Engraftment could be evaluated in 18 patients (Tables 3
and 4). Of the 7 patients who received HLA-identical BMT,
3 had initial signs of mixed hematopoietic chimerism but
died from infectious complications. Four patients had stable
long-term engraftment, with 3 showing full chimerism and
l (patient no. 2) showing partial engraftment with less than
50% of donor-derived B cells and monocytes. Stable longterm engraftment occurred in only 3 patients who underwent
nonidentical BMT. All 3 patients were less than 2 years old
at the time of transplantation. In this group, 1 patient (no.
10) had mixed and 2 (nos. 14 and 19) had full hematopoietic
chimerism. Another patient (no. 11) had full chimerism but
died 3 months post-BMT of severe GVHD and viral infections. One patient (no. 8) had partial T-cell and complete Bcell engraftment with normal production of specific antibodies. However, five years after BMT, she only has 2% of
donor B cells. One patient (no. 9) transiently achieved full
T-cell function, but gradually rejected the graft over 5 years.
Interestingly, full hematopoietic chimerism wasonly observed after introduction of a protocol using anti-LFA-l
and anti-CD2 antibodies to reduce engraftment failures. No
engraftment occurred in 6 patients, despite up to three transplantation attempts; only one of the five Campath-depleted
grafts (patient no. 9) resulted in engraftment, although the
transplant was gradually lost.
Two patients developed stage 3 GVHD, whereas mild to
moderate GVHD (sstage 2) occurred in 10 cases. No cases
of chronic GVHD occurred.
Tabla 1. Conditioning Regimens
I. HLA-compatible BMT
Cyclophosphamide (50mg/kg)
Antilymphocyte serum
2. Cyclophosphamide (50 mgikg)
CCNU (300mg/m*)
Procarbazine (280 mg/kg)
Antilymphocyte serum
3. Busulfan (20 mgkg)
Cyclophosphamide (200 mgikg)
II. HLA-mismatched BMT
4. Busulfan (20 mgkg; 16 mgkg if age >6 yr)
Cyclophosphamide (200 mgfkg)
5. Busulfan (20 mgkg; 16 mgkg if age >6 yr)
Cyclophosphamide (200 mg/kg)
Anti-LFA-l antibody
6. Busulfan (20 mglkg; 16 mg/kg if age >6 yr)
Cyclophosphamide (200 mg/kg)
Anti-LFA-l antibody
Anti-CD2 antibody
1.
Assessment of Engrafhnent and GVHD
Engraftment of donor cells was confirmed by testing for HLADR expression on peripheral B cells, monocytes, and PHA-activated
T cells. Karyotyping in case of sex mismatch, erythrocyte phenotyping, and chimerism analysis by means of restriction fragment length
polymorphism (RFLP)" on DNA extracted from peripheral mononuclear cells served as additional engraftment markers. The clinical
diagnosis of GVHD was confirmed by appropriate biopsies and
graded according to Glucksberg et al." Lymphocyte populations
were determined by immunofluorescence with T- and B-cell-specific monoclonal antibodies. Mitogen, antigen (Candida albicans,
tetanus toxoid, and CMV), and allogeneic cell-induced lymphocyte
proliferation tests were performed as previously described.19
RESULTS
Pretransplant clinical and immunologic characteristics of
the 19 patients are shown in Table 2. Chronic enteritis (16
cases) and respiratory tract infections (18 cases) were the
hallmarks of the clinical presentation. Hepatitis and/or chol-
Immunologic Reconstitution
T-cell reconstitution. T-cell reconstitution was confirmed in 6 patients by the presence of HLA-DR expression
From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
582
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BMT IN MHC CLASS II DEFICIENCY
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From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
KLEIN ET AL
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on activated T cells and normalization of antigen-specific
T-cell stimulation(Table4).Patients
with HLA-identical
transplants showed normal total lymphocyte counts andnormal CD3' cell counts 2 to 6 months after BMT. Patients with
nonidenticaltransplantationrequired
up to 2 yearsbefore
lymphocyte counts reached normal values for age. Patients
no. 14and 19 remain lymphopenic 2 yearsand 6 months
post-BMT, respectively.
With the exception of patient no. 2, who took 4 years to
develop normal lymphocyte stimulation tests, and patientno.
19, all patients with durable grafts responded positively to
specific antigens within 1 year after BMT. All the patients
had persistently low CD4' cell counts, ranging from 105 to
650/pL at last follow up (Fig 1 and Table 3 ) . This finding
is consistent with impairedthymicmaturation
caused by
defective HLA class I1 expression on thymic epithelia.
B-cell reconstitution. In the 7 patientswith durable engraftment, B-cell counts returned to normalwithin a few
weeks or months post-BMT. Ig levels normalized, with the
exception of 1 patient who had reduced IgA levelsand 2
patients with increased polyclonal IgM levels.
All 7 patients with durable engraftment had specific antibody production in response to immunization antigens (tetanus and diphtheriatoxoids, poliovirus). None of the patients
developed B-lymphoproliferative disorders.
Two patients (no. 2 and 10) have normal B-cell function
despite chimerism (10% to 46% B cells of host origin).
Clinical
course
and
infections. Seven patients died
within 3 months after BMT of infectious complications. All
of these early deaths were attributable to overwhelmingviral
infections leading to vital-organ failure, such as encephalitis
andpneumonia,or
lethalmultiorgan involvement.CMV,
enteroviruses,and
adenoviruswereresponsible
for the
deaths, as shown by viral culture of bodyfluids. All but
3 patients(no. 7, 10, and 18) receivedgrafts from CMVseropositive donors, which may have been responsible for
the CMV infection of 2 recipients. All other patients with
positive CMVculturespost-BMThadevidence
of CMV
infection before BMT. In 4 cases, the viruses incriminated
in lethal infections post-BMT had been identified before the
procedure (2 cases of CMV and 2 cases of enterovirus).
Three patients died morethan 1 year post-BMT of infectious
complications after graft failure. One patient (no. 1) who had
chronic CMV andenterovirus infection leading to intractable
diarrhea, chorioretinitis, and psychomotor regression died of
Pseudomonas sepsis.Patient no. 5 developedCryptosporidium-associated sclerosing cholangitis and liver failure and
died of Pseudomonas sepsis.Patient no. 9 hadrecurrent
bacterial and fungal infections, chronic enterovirus
infection,
pancreatitis,hepatitis, and oligoarthritis and died 5 years
post-BMT of meningoencephalitis and cardiac arrest.
One patient(no. 8) with partial engraftment is momentarily stable 5 years post-BMT. One patient was rescued by
autograftingafter two unsuccessfulhaploid BMT procedures. All the other patients are well, free of serious infections, and show normal physical and psychosocial development.Onepatient
(no. 10) developed typicalKawasaki
disease 3 years post-BMT thatresolvedwithoutsequelae.
At that time she was no longer
receiving intravenous Igs.
~There was no correlation of favorable or unfavorable outcome with assignment to complementation groups.
From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
585
BMT IN MHC CLASS II DEFICIENCY
0
0
patient
62
0
patient
#8
patient
#IO
0
patiem
#l2
patient
U13
o
patient
#l4
A
patient
#l7
A
patient
W19
i
Fig 1. CD4 T-cell count before
and after BMT.
p
po
r es-tB
- BMMT1
Of 12 comparable children seen in our institution who did
not undergo BMT, 5 died of overwhelming viral infections
within the first 2 years of life and 1 died at age 16 of liver
failure and gram-negative sepsis. The remaining 6 children
(aged 2 to 16 years) have severe sequelae from recurrent
infections and various autoimmune diseases.
DISCUSSION
BMT is now the treatment of choice for severe combined
immunodeficiency disorders and has been shown to reconstitute the immune system in MHC class I1 deficiency (bare
lymphocyte ~yndrome).~,’
However, preliminary analyses suggested that MHC class
11-deficient patients did less well after BMT than other patients with combined immunodeficiencies.” This finding is
apparently borne out by our series of 19 patients, although
no statistical analysis is possible. Four of seven children
who underwent HLA-identical BMT were cured (the other
3 children died early, possibly due to inadequate conditioning and/or infection control). In contrast, only 3 of 12 children who underwent HLA-nonidentical BMT were cured, a
rate lower than in other severe combined immunodeficiencies. One of the main obstacles to HLA-nonidentical BMT
is infectious complications.” Severe and persistent viral infections are a hallmark of MHC class I1 deficiency. Obviously, chronic viral carriage is a major danger in patients
with BM ablation. Although the prognosis of HLA-nonidentical BMT has improved, mainly through better control of
infections,23 the mortality rate among MHC-deficient patients, mainly due to overwhelming CMV, enterovirus, and
adenovirus infections, remains high.
The main cause of treatment failure in HLA-nonidentical
BMT is graft failure. This finding may be of particular importance in immunodeficiencies in which residual immune func-
tion inhibits engraftment, which include PNP-deficiency and
combined immunodeficiency syndromes.” In contrast to
other forms of SCID, MHC class 11-deficient patients develop a normal T-cell
and show inducible alloreactive T lymphocytes that can initiate immunologic rejection or hamper engraftn~ent.’~Over the last few years,
significant improvements have been made in promoting engraftment. A protocol including anti-LFA-l antibodies has
been shown to facilitate engraftment.26A subsequent protocol designed to further facilitate engraftment by addition of
anti-CD2 antibodies is now being tested. In our study, the
introduction of these protocols coincided with the development of full hematopoetic chimerism, without graft rejection,
in successfully transplanted children, although engraftment
failures still occurred. Other factors, such as the detrimental
influence of viral infections, may play a role in engraftment
failure.27
Age at the time of transplantation has been identified as
a risk factor in BMT for immunodeficiencies. Patients less
than 2 years of age do better than older patients.” This
difference seems to be especially true of MHC class IIdeficient patients, because only one child underwent successful HLA-identical BMT (no cases of successful haploidentical BMT) after 24 months of age. The kinetics of immune
reconstitution after BMT did not differ from that in other
primary immunodeficiency condition^.^*^^^
Before BMT, patients with MHC class I1 deficiency
showed low CD4” cell counts, with a compensatory increase
in CD8+ lymphocytes. This combination is reminiscent of
MHC class 11-knockout mi~e.~’.~’
However, in contrast to
MHC class 11-deficient mice, the proportion of CD4’ lymphocytes was higher in the patients, possibly due to residual
HLA class II expression in the thymus.32Interestingly, low
CD4+ cell counts persisted after BMT, possibly reflecting
From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
KLEIN ET AL
586
impaired thymic maturation of CD4’ cells due to decreased
MHC class I1 expression in the thymic epithelium. This also
provides indirect evidence that donor BM-derived cells are
not critical for positive thymic selection of CD4’ T cells.”
Clinically, CD4 lymphopenia was not associated with increased susceptibility to infections. In addition, despite a
lack of MHC class I1 reconstitution in nonhematopoietic
cells, infection control does occur. The antigen-presenting
function of activated endothelial and epithelial cells therefore
seemsto be dispensable when BM-derived antigen-presenting cells are functional.
Further studies to identify molecular defects are underway. There is some hope that, as in other primary immunodeficiency disorders,34gene therapy might improve the cure
rate in MHC class I1 deficiency in the future. Given the
dismal prognosis of patients with MHC class I1 deficiency,
BMT is, in our opinion, the treatment of choice today, provided it is performed early in life, before the onset of infection-related complications.
ACKNOWLEDGMENT
We are indebted to the medical and nursing staff taking care of
the patients, to the referring physicians, and to Dr Geoff Hale and
the staff of the Therapeutic Antibody Center (Cambridge, UK) for
providing the Campath-IM antibody.
REFERENCES
1. Griscelli C, Lisowska-Grospierre B, Mach B: Combined im-
munodeficiency with defective expression of MHC class I1 genes.
Immunodef Rev 1:135, 1989
2. De Pr6val C, Lisowska-Grospierre B, Loche M, Griscelli C,
Mach B: A transacting class I1 regulatory gene unlinked to the MHC
controls expression of HLA class I1 genes. Nature 318:291, 1985
3. Kara CJ, Glimcher LH: In vivo footprinting of MHC class I1
genes: Bare promoters in the bare lymphocyte syndrome. Science
252:709, 1991
4. Steimle V, Otten L, Zufferey M, MachB: Complementation
cloning ofan MHC class I1 transactivator mutated in hereditary
MHC class I1 deficiency (or bare lymphocyte syndrome). Cell
75:135, 1993
5. Van Eggermond MCJA, Rijkers GT, Kuis W, Zegers BJM,
Van den Elsen PJ: T cell development in a major histocompatibility
complex class I1 deficient patient. Eur J Immunol 23:2585, 1993
6. Klein C, Lisowska-Grospierre B, Le Deist F, Fischer A, Griscelli C: Major histocompatibility complex class I1 deficiency-Clinical manifestations, immunological features and outcome. J Pediatr
123:921, 1993
7. Lenarsky C, Parkman R: Bone marrow transplantation for the
treatment of immune deficiency states. Bone Marrow Transplant
6:361, 1990
8. Fischer A, Durandy A, Vilmer E, Griscelli C: Bone marrow
transplantation in a patient with HLA defective combined immunodeficiency, in Griscelli C, Vossen J (eds): Progress in Immunodeficiency Research and Therapy I. Amsterdam, The Netherlands, Excerpta Medical 1984, p 262
9. Casper JT, Ash RA, Kirchner P, Hunter JB, Havens PL, Chusid
MJ: Successful treatment with an unrelated donor bonemarrow
transplant in an HLA-deficient patient with severe combined immunodeficiency (“bare lymphocyte syndrome”). J Pediatr 116:262,
1990
10. Terasaki PI, Bemoco D, Park MS, Ozturk G, Iwaki Y: Microdroplet testing for HLA-A, -B, -C and -D antigens. Am J Clin Pathol
69: 103, 1978
11. Marcadet A, Cohen D, Dausset J, Fischer A, Durandy A,
Griscelli C: Genotyping with DNA probes in combined immunodeficiency syndrome with defective expression of HLA. N Engl J Med
312:1287, 1985
12. Fischer A, Griscelli C, Blanche S, Le Deist F, Veber F, Lopez
M, Delaage M, Olive D, Maseur C, Janossy: Prevention of graft
failure by anti-HLFAI monoclonal antibody inHLA mismatched
bone marrow transplantation. Lancet 2:1058, 1986
13. Jabado N, Thomas C, Cavazzano-Calvo M, Morgan G, Bujan
W, Cant A, De Graeff-Meeders, Hale G, Benkerrou M, Fischer A:
The useof two monoclonal antibodies (anti-LFA-l CD1 la, antiCD2) in HLA non identical bone marrow transplantation in children
with inherited disorders. 20th Annual Meeting of theEuropean
Group for Bone Marrow Transplantation (EBMT). Harrogate, London, March 1994 (abstr)
14. Fischer A, Durandy A, De Villartay JP, Vilmer E, Le Deist
F, Gerota I, Griscelli C: HLA haploidentical bonemarrow transplantation for severe combined immunodeficiency using E rosette
fractionation and cyclosporine A. Blood 67:444, 1986
15. Hale G, Cobbold S, Waldmann H: T cell depletion with Campath-l in allogeneic bonemarrow transplantation. Transplantation
45:753, 1988
16. Herbelin C, Stephan JL, Donadieu J, Le Deist F, Racadot E.
Wijdenes J, Fischer A: Treatment of steroid-resistant acute graftversus-host disease with an anti-11-2-receptor monoclonal antibody
(5BT 563) in children who received T cell-depleted, partially
matched, related bone marrow transplants. Bone Marrow Transplant
13563, I994
17. Yam PJY, Petz LD, Knowlton RG, Wallace LB, Stock AD,
de Lange G, Brown VA, Donis-Keller H, Blume KG: Use of DNA
restriction fragment length polymorphism to document marrow engraftment and mixed hematopoietic chimerism following bone marrow transplantation. Transplantation 43:399, 1987
18. Glucksberg H, Storb R, Fefer A: Clinical manifestations of
GVHD in human recipients of marrow from HLA matched sibling
donors. Transplantation 18:295, 1974
19. Le Deist F, Thoenes G, Grospierre B, Fischer A: Immunodeficiency with low expression of T cell receptor-CD3 complex. Eur
J Immunol 21:1641, 1991
20. Erkeller-Yuksel FM, Deneys V, Yuksel B, Hannet I, Hulstaart
F, Hamilton C, Mackinnon H, Tumor-Stoker L, Munkyerhuli V,
Vanlangendonck F, De Brujere M, Bach BA, Lydaard PM: Agerelated changes in human blood lymphocyte subpopulations. J Pediatr 120:216, 1992
21. Fischer A, Friedrich W, Levinsky R, et al: Bone marrow
transplantation for immunodeficiencies and osteopetrosis: European
survey 1968-1985. Lancet 2:1080, 1986
22. O’Reilly RY, Keever CA, Small TN, Brochstein S: The use
of HLA non identical T-cell depleted marrow transplants for correction of SCID. Immunodef Rev 1:273, 1990
23. Fischer A, Landais P, Friedrich W, Gerritsen B, Fasth A,
Porta F, Vellodi A, Benkenou M, Cavazzano-Calvo M, Souillet G,
Bordigoni P, Morgan G, Van Dijken P, Vossen J, Locatelli F, Di
Bartolomeo P: Bone marrow transplantation in Europe for primary
immunodeficiencies other than severe combined immunodeficiency.
An EBMTEGID report. Blood 83:1149, 1994
24. Rieux-Laucat F, Le Deist F, Selz F, Fischer A, de Villartay
JP: Normal T cell Vbeta usage in a primary immunodeficiency associated with HLA class II deficiency. Eur J Immunol 23:928, 1993
25. Knobloch C, Ballas M, Wolpl A, Friedrich W: Allorecognitionand T cell repertoire selection in severe combined immunodeficiency lacking HLA class 11 antigens. Transplantation 53:1295,
I992
26. Fischer A, Friedrich W, Fasth A, Blanche S, Le Deist F,
Girault D, Veber F, Vossen J, Lopez M, Griscelli C, Him M: Reduction of graft failure by a monoclonal antibody (anti-FLA-l CD1 I )
From www.bloodjournal.org by guest on October 15, 2014. For personal use only.
BMT IN MHC CLASS II DEFICIENCY
after HLA nonidentical bone marrow transplantation in children with
immunodeficiencies, osteopetrosis, and Fanconi’s anemia: A European Group for ImmunodeficiencyEuropean Group for Bone Marrow Transplantation report. Blood 77:249, 1991
27. Drobyski W R , Dunne W M , Burd EM, Knox KK, Ash RC,
Horowitz MM, Flomenberg N, Carrigan DR: Human herpesvirus-6
(HHV-6) infection in allogeneic bone marrow transplant recipients:
Evidence of a marrow-suppressive role for HHV in vivo. J Infect
Dis 167:735, 1993
28. Buckley RH, Schiff SE, Sampson HA, Schiff RI, Markert
ML, Knutsen AP, Hershfield MS, Huang AT, Mickey GH, Ward FE:
Development of immunity in human severe primary T cell deficiency
following haploidentical bone marrow stem cell transplantation. J
Immunol 136:2398, 1986
29. Dror Y,Gallagher R, Wara DW, Colombe BW, Merino A,
Benkerrou M, Cowan MJ: Immune reconstitution in severe combined immunodeficiency disease after lectin-treated, T-cell-depleted
587
haplocompatible bone marrow transplantation. Blood 8 1:2021,
1993
30. Grusby MJ, Johnson RS, Papaioannou VE, Glimcher LH:
Deletion of CD4+ T cells in major histocompatibility complex class
I1 deficient mice. Science 253:1417, 1991
31. Cosgrove D, Gray D, Dierich A, Kaufman J, Lemeur M,
Benoist C, Mathis D: Mice lacking MHC class I1 molecules. Cell
66:1061, 1991
32. Schuurman HJ, van de Wijngaert FP, Huber J, Schuurman RKB,
Zegers BJM, Rood JJ, Kater L The thymus in “bare lymphocyte syndrome.’’ Significance of expression of MHC antigens on thymic epithelial
cells in intrathymic T cell maturation. Hum Immunol 13:69, 1985
33. Kisielow P, Teh HS, Bluthmann H, von Boehmer H: Positive
selection of antigen-specific T cells in thymus by restricting MHC
molecules. Nature 335:730, 1988
34. Blaese RM, Culver KW: Gene therapy for primary immunodeficiency disease. Immunodef Rev 3:329, 1992