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Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2923-2930
Long-Term Chimerism and B-Cell Function After Bone Marrow
Transplantation in Patients With Severe Combined Immunodeficiency With
B Cells: A Single-Center Study of 22 Patients
By
Elie Haddad,
Françoise Le Deist,
Pierre Aucouturier,
Marina Cavazzana-Calvo,
Stephane Blanche,
Geneviève De Saint Basile, and
Alain Fischer
From the Unité d'Immunologie et d'Hématologie
Pédiatriques, Unité INSERM U429, and Laboratoire
d'Immunologie Clinique, INSERM U25, Hôpital Necker-Enfants
Malades, Paris, France.
 |
ABSTRACT |
We retrospectively analyzed the B-cell function and leukocyte
chimerism of 22 patients with severe combined immunodeficiency with B
cells (B+ SCID) who survived more than 2 years after bone
marrow transplantation (BMT) to determine the possible consequences of
BMT procedures, leukocyte chimerism, and SCID molecular deficit on
B-cell function outcome. Circulating T cells were of donor origin in
all patients. In recipients of HLA-identical BMT (n = 5), monocytes
were of host origin in 5 and B cells were of host origin in 4 and of
mixed origin in 1. In recipients of HLA haploidentical T-cell-depleted BMT (n = 17), B cells and monocytes were of host origin in 14 and of
donor origin in 3. Engraftment of B cells was found to be associated
with normal B-cell function. In contrast, 10 of 18 patients with host B
cells still require Ig substitution. Conditioning regimen (ie, 8 mg/kg
busulfan and 200 mg/kg cyclophosphamide) was shown neither to promote
B-cell and monocyte engraftment nor to affect B-cell function. Eight
patients with B cells of host origin had normal B-cell function.
Evidence for functional host B cells was further provided in 3 informative cases by Ig allotype determination and by the detection, in
5 studied cases, of host CD27+ memory B cells as in
age-matched controls. These results strongly suggest that, in some
transplanted patients, host B cells can cooperate with donor T cells to
fully mature in Ig-producing cells.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
SEVERE COMBINED immunodeficiencies (SCID)
is a heterogeneous group of inherited disorders characterized by a
severe impairment of both cellular and humoral immunity that leads to death during infancy in the absence of treatment.1-4 The
most common SCID phenotype results from a selective block in T-cell and, usually, natural killer (NK) cell differentiation while there is a
normal B-cell differentiation. It is thereafter called B+
SCID. It is caused by mutation of either the  c5,6 or the JAK-3 genes.7,8 Recently, IL7R gene mutations have been shown to cause a SCID with a T B+
NK+ phenotype.9 The molecular basis of a small
subset (5%) of B+ SCID cases so far remains
unknown.1 Bone marrow transplantation (BMT) has been shown
to be the treatment of choice for patients with SCID. Various studies
have reported excellent results for HLA-identical BMT, with full
restoration of T- and B-cell function in most
patients.10-14 HLA-identical related donors are not
available for most patients; therefore, HLA-nonidentical BMT have been
performed since 1981, when it became feasible to deplete marrow
specimen from T cells.15-21 However, the prospects of
survival with long-term immune reconstitution are poorer, because
HLA-nonidentical BMT led to 52% to 78% survival rates in different
series.14,20-23 It has been recently demonstrated that SCID
phenotype has an influence on the outcome of HLA-nonidentical
T-cell-depleted BMT.24 In the latter study, the survival
rate was 60% for B+ SCID patients, whereas it was only
35% for patients with SCID characterized by an absence of both T and B
cells (B SCID). Immune functions develop more
rapidly and are more often of higher quality both for T-cell and B-cell
immunity in transplanted B+ SCID than B
SCID patients.25 However, despite normal T-cell immunity
development, normal humoral immune function is observed in only 50% to
60% of B+ SCID patients several years after HLA
haploidentical T-cell-depleted BMT.14,25-28 In contrast,
full T- and B-cell functions do develop in most recipients of
histocompatible BMT.14,21,23,27
It has been suggested that the inconstant development of antibody
responses after HLA haploidentical T-cell-depleted BMT in B+ SCID patients is a consequence of defective B-cell
engraftment,20,23,26,27,29-31 thus reflecting an intrinsic
B-cell deficiency. Involvement of c and JAK-3 in interleukin-4
(IL-4) signaling supports this hypothesis.32,33 We
therefore retrospectively studied the B-cell immune function of 22 B+ SCID patients who survived more than 2 years after
HLA-identical or HLA-mismatched T-cell-depleted BMT to determine the
effects of the underlying molecular deficiency together with BMT
procedure factors and leukocyte chimerism on B-cell function outcome.
| |
PATIENTS AND METHODS |
Patients
Patients with SCID with B cells (B+ SCID) alive at least 2 years after BMT were enrolled in this study. BMTs were performed between 1976 and 1995 at the Hopital Necker-Enfants Malades (Paris, France). Twenty-two patients fulfilled the inclusion criteria. Median
age at diagnosis was 5 months (range, 1 to 7 months). Fourteen patients
had c deficiency, 4 had JAK-3 deficiency, and 4 had a yet unknown
molecular deficiency as defined by normal c gene sequence and
protein detection as well as of JAK-3 protein detection and normal
phosphorylation after stimulation with IL-2 of Epstein-Barr virus
(EBV)-transformed B cells.34
BMT characteristics.
Median age at BMT was 6.5 months (range, 1 to 93 months). Two patients
required a second transplantation at 29 and 93 months of age,
respectively, because of poor T-cell development. Data were analyzed
from the last BMT in these 2 patients. The median length of follow-up
was 5 years (range, 2 to 23 years). The end point for analysis was
December 31, 1998.
Three patients received a BMT from an HLA-identical sibling and 2 received a BMT from a phenotypically HLA-identical aunt (n = 1) or
mother (n = 1). These patients did not receive a conditioning regimen
(CR). The marrow inoculum was not T-cell-depleted. No prophylaxis
against graft-versus-host disease (GVHD) was used except for the
patient who received a marrow transplant from his phenotypically
HLA-identical mother. He received a 60-day course of intravenous
cyclosporin A.
Seventeen patients underwent related HLA-nonidentical T-cell-depleted
BMT. All the donors were parents. They were 2 HLA antigens (4 cases) or
full haplotype (13 cases) mismatched. Eight of the 17 did not receive a
CR, because they had a severe infection at the time of BMT. The CR
administered to the other 9 patients consisted of busulfan (8 mg/kg
total dose) and cyclophosphamide (200 mg/kg total dose). Twelve
patients were also treated intravenously with a monoclonal anti-LFA1
antibody to prevent graft rejection.35 All marrow
transplants were T-cell-depleted to prevent GVHD. E-rosetting was used
to achieve depletion in 8 patients transplanted between 1983 and
1990,18 Campath 1-M Ab plus human complement was used in 6 patients transplanted between 1990 and 1994,36 and
monoclonal anti-CD2 and anti-CD7 antibodies with complement lysis was
used in 3 patients transplanted in 1994 and 1995. Post-BMT GVHD
prophylaxis was administered to patients who received bone marrow
depleted by E-rosetting (60-day course of cyclosporin A).18
All patients were placed in a protective environment (sterile isolator)
and received prophylactic antimicrobial medication to eliminate the intestinal microflora and intravenous immune globulin (IVIG) therapy weekly for 3 months after BMT and then every 3 weeks for at least 3 months. Acute and chronic GVHD was assessed in all patients according
to standard criteria.37
Methods
Blood samples were collected and analyzed in 1998, which was 2 to 23 years after BMT.
B-cell function.
We studied B-cell function by determining serum concentrations of IgG,
IgG isotypes, IgA, IgM, IgE, and serum antibodies to polioviruses,
tetanus, and diphtheria toxoids in all patients except for those
undergoing treatment with IVIG. In all cases, the last booster
immunization had been administered 3 to 6 months (n = 19) or 6 months
to 3 years (n = 3) before analysis. Serum Ig concentrations were
measured by nephelometry. IgG isotypes were determined by an
immunoenzymatic method using monoclonal antibodies (MoAbs). Serum
antibodies directed against polioviruses, tetanus, and diphtheria
toxoids were determined by enzyme-linked immunosorbent assays. The
determination of Ig allotypes was performed by an hemagglutination assay.
Antibodies.
The following MoAbs were used in immunofluorescence studies: anti-CD3:
Leu 4 (IgG2a; Becton Dickinson, San Diego, CA); anti-CD4: Leu 3a (IgG1;
Becton Dickinson); anti-CD8: Leu 2a (IgG1; Becton Dickinson);
anti-CD19: J4 119 (IgG1; Immunotech, Marseille, France); anti-CD27: 1A4
(IgG1; Immunotech); anti-CD14: Leu M3 (Becton Dickinson); anti-CD16:
3G8 (IgG1; Immunotech); and anti-CD56: MY31 (IgG1; Becton Dickinson).
Cells were fluorescence stained with phycoerythrin (PE)- or fluorescein
isothiocyanate (FITC)-conjugated MoAbs. Cell fluorescence was measured
with a FACScan flow cytometer (Becton Dickinson).
Cell isolation.
Leukocytes were isolated from fresh heparin-treated blood by Plasmagel
(Roger Bellon Laboratories, Paris, France) sedimentation and separation
by Lymphoprep (Nicomed Pharma, Oslo, Norway). Polymorphonuclear (PMN)
cells sedimented in the pellet and peripheral mononuclear cells (PBMC)
at the interface. E+ (rosette forming) and
E (no rosette) cells were obtained by treatment of
PBMC with neuraminidase-treated (Berhing Werke, Marburg Lahn, Germany)
red blood cells from sheep.
Monocytes (CD14+) and B lymphocytes (CD19+) on
the one hand and T lymphocytes (CD3+) and NK cells
(CD56+CD16+CD3) on the other
hand were sorted, respectively, from E and
E+ cells using a FACStar plus cell sorter (Becton
Dickinson) after staining with the appropriate MoAb.
Chimerism studies.
DNA chimerism was studied using the patients' sorted cells. Cells (0.1 mol/L) were lysed by incubation with 50 µL lysis buffer (10×
Taq buffer [ATGC, Noisy le Grand, France], 0.5% Tween-20, and 0.1 mg/mL proteinase K at 56°C for 45 minutes, followed by heat
inactivation of the enzyme at 94°C for 5 minutes). Polymerase chain
reaction (PCR) was performed using 1 µL of the DNA preparation and
primers specific for the dinucleotide, trinucleotide, or
tetranucleotide repeat polymorphism at the D10S 206,38
DXS101,39 or HPRT40 loci, respectively. All of
the patient studies were informative for at least 1 of these 3 loci.
One tenth of each reaction mixture was subjected to electrophoresis in
a 5% polyacrylamide, 8 mol/L urea sequencing gel. The sensitivity of
chimerism detection was 5%.
| |
RESULTS |
Chimerism Analysis
HLA-identical BMT.
Five patients received an HLA-identical BMT. Chimerism studies
(Table 1) showed that, in all cases, T
cells originated from the donor, whereas monocytes originated from the
host. Four of these 5 patients exhibited B cells of host origin and 1 patient had B-cell mosaicism (50% donor cells). NK-cell chimerism was studied in 4 cases: NK cells were of donor origin in 2 cases, of host
origin in 1 case, and undetectable in 1 case. T- and B-cell chimerism
was previously studied in 2 patients during the first 2 years after BMT
by using HLA typing in 1 case and by karyotyping in the other. These 2 patients with donor T cells and host B cells 5 and 6 months,
respectively, after BMT exhibited the same chimerism pattern at last
follow-up 14 and 21 years, respectively, after BMT.
HLA-nonidentical T-cell-depleted BMT.
Seventeen patients received an HLA-nonidentical T-cell-depleted BMT. T
cells originated from the donor in all patients. In 3 patients, both B
cells and monocytes were exclusively of donor origin, whereas neither
donor B cells nor donor monocytes were detected in 14 patients (Table 1
and Fig 1). NK-cell chimerism was studied
in 10 of these 17 patients.
CD16+CD56+CD3 NK cells were
of donor origin in 8, whereas no CD16+ cells were detected
in the blood of 2 patients. Among the 8 patients with NK cells of donor
origin, B cells and monocytes were of host origin in 7 and of donor
origin in 1 (Table 1). T- and B-cell chimerism was previously studied
in 3 patients during the first 2 years after BMT by using HLA typing.
In all 3 cases, T and B cells were found to be of donor origin 6, 14, and 15 months, respectively, after BMT, whereas host B cells only were
detected at the last follow-up 3, 9, and 2 years, respectively, after
BMT.
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| Fig 1.
Leukocyte chimerism of B+ SCID patients
after BMT. Microsatellite typing of polymorphonuclear cells (PN), T
lymphocytes (T), natural killer cells (NK), B lymphocytes (B), and
monocytes (M) from recipients (R) or from donor cells (D) was performed
at the D10S206 (A), DXS101 (B), or HPRT (C) loci, depending on how
informative the locus was for each subject. (A) UPN 299; (B) UPN 272b;
(C) UPN 223.
|
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Conditioning regimen treatment did not affect long-term chimerism of
monocytes and B cells, because B cells and monocytes were of donor
origin in 2 of 8 patients who did not receive any CR, whereas B cells
and monocytes were of donor origin in 1 of 9 patients who did receive a
CR. In contrast, all tested patients who received a CR treatment had NK
cells of donor origin (n = 6), whereas NK cells were either of donor
origin (n = 2) or undetectable (n = 2) in patients who did not receive
any CR. Other characteristics of the BMT procedure, such as the method
of T-cell depletion used, anti-LFA1 antibody treatment, and the number
of nucleated cells and T cells infused, did not affect chimerism status
(data not shown, P = not significant [NS]).
B-Cell Function Analysis
HLA-identical BMT.
All 5 patients exhibited normal blood B-cell counts (range, 150 to
672/µL; median, 505/µL). As shown in
Table 2, at last follow-up, 3 patients were
considered to have a normal B-cell function, because they had normal
IgG concentrations, exhibited a normal antibody production, and did not
require IVIG treatment. One of these 3 patients exhibited a low level
of IgG2 and an absence of IgA and IgE. One patient (UPN 17) is
considered to have a B-cell deficiency, because he never achieved a
normal IgG concentration and attempts to stop IVIG treatment led to a
much lower serum IgG concentration and to the recurrence of infections.
One patient (UPN 50) had an isolated IgG2 deficiency with recurrent
pulmonary infections and therefore required IVIG treatment despite
antibody production to poliovirus and tetanus toxoid. In this patient, the B-cell deficiency could be the consequence of a low T-cell count
and function.41
HLA-nonidentical T-cell-depleted BMT.
Sixteen of the 17 patients exhibited normal to elevated blood B-cell
counts (range, 140 to 2,280/µL; median, 550/µL). One patient had
very low B-cell counts (40/µL) and low T-cell counts. At last
follow-up, 9 patients were considered to have deficiencies in B-cell
function, because they still required IVIG treatment and attempts to
stop IVIG treatment led to a much lower serum IgG concentration and to
the recurrence of infections (except for UPN 303). Eight patients were
considered to have functional B-cell immunity, because they had normal
IgG concentrations, produced antibodies, and did not require IVIG
treatment. No recurrent infections occurred in these patients. However,
in 3 of these patients, an IgA deficiency was found.
Analysis of the Factors Influencing B-Cell Function
B-cell chimerism status exerts an influence on B-cell function, because
all 4 patients whose B cells were of donor origin (3 patients after an
HLA-nonidentical BMT and 1 after an HLA identical BMT) had normal or
close to normal B-cell function. Conversely, 10 of the 18 patients
whose peripheral B cells were found exclusively of host origin (9 patients after an HLA-nonidentical BMT and 1 after an HLA-identical
BMT) required IVIG treatment. These results confirm that engraftment of
donor B cells offers the best chance to achieve development of normal
B-cell function.
However, it was found that the exclusive detection of host peripheral B
cells was associated with normal B-cell function in 8 other patients (5 after HLA-nonidentical BMT and 3 after HLA-identical BMT; Table 2).
These results suggest that c( ), JAK3(), or other
genetically deficient B cells could function once T-cell function is
restored. However, a B-cell microchimerism cannot be strictly excluded
and could account for development of in vivo B-cell function. We
therefore studied the origin of serum Igs by determining several Ig
heavy chain and  -associated allotypes in 4 of these cases.
Polymorphism for 3 (3m21 and 3m28) was found in 2 families,
enabling us to determine that, in these 2 patients (UPN 261 and 158),
IgG3 were of host origin. It was similarly found that IgG2 (2m23)
were of host origin in patient UPN 365. It was also possible to assess
whether host B cells, in patients with and without B-cell immunity,
respectively, express the membrane marker CD27 that is associated with
memory.42 It was found that, in 5 patients studied who had
normal B-cell function, the percentage of
CD27+CD19+ B cells was close to age-matched
controls (range in patients, 8% to 29%; range in controls, 12% to
67%). In contrast, in the 3 patients studied who had no B-cell
function, the fraction of CD27+ CD19 B cells was less than
4%. In 1 patient still under IVIG, a high fraction of
CD27+CD19+ B cells was found (ie, 23%). It is
noteworthy that IgA and IgM are detectable within the normal range in
the serum of this patient (UPN 303; Table 2). His B-cell immunity
is thus not absent. Overall, these results show that host memory B
cells are detectable in patients who developed B-cell immunity
after BMT.
After HLA-nonidentical BMT, the conditioning regimen used was found not
to affect B-cell chimerism and therefore B-cell function outcome,
because 4 of the 8 patients who did not receive any CR treatment and 4 of the 9 patients who did receive a CR treatment do not require IVIG
treatment. Other factors, including age at BMT, occurrence and outcome
of acute and chronic GVHD, method of T-cell depletion used, anti-LFA1
antibody treatment, and duration of follow-up, had no effect on B-cell
function (data not shown, P = NS).
It is difficult to assess in this series of patients whether SCID
diagnosis and possible intrinsic B-cell functional defects had an
influence on B-cell function outcome after BMT because of the small
number of JAK-3-deficient patients in this study. However, it was
found that B cells from patients with SCID of unknown etiology and
JAK-3 deficiency were functional
(Table 3).
It is worth noting that patients UPN 51 and 116, who are first cousins
and carry the same c mutation, had a different B-cell function
outcome after BMT, although T-cell function was found normal and B
cells were of host origin in both cases. The only observed difference
is that patient UPN 51 received an HLA-identical BMT whereas patient
UPN 116 received an HLA-nonidentical BMT.
| |
DISCUSSION |
We report in this retrospective study the chimerism status and B-cell
function of 22 patients with B+ SCID treated by a BMT at a
single center who are still alive more than 2 years after BMT. All
studies were performed in 1997 and 1998 in long-term survivors. The
survival rate (data not shown) is similar to those reported in other
studies.19-21,23,29,30,43
Chimerism studies showed that there was an engraftment of T cells in
all of the patients, consistent with previous
reports.20,21,23,26,27,44 However, circulating B cells and
monocytes from 18 of the 22 patients were found to be of host origin.
It is worth noting that repeated chimerism analysis performed in 5 patients from this study showed an apparent loss of donor B cells found
in 3 patients in the first 2 years post-BMT. An initial myeloid
engraftment followed by the gradual loss of the engrafted B cells may
account for this finding. However, monocyte chimerism was not
previously studied in any of these patients. Therefore, a transient
peripheral expansion of the donor B-cell population in the initial
months after BMT in the absence of myeloid engraftment cannot be
entirely excluded. Whatever the case of this observation, it shows that
lymphoid chimerism status can not be considered as stable before a long period of time after BMT performed in B+ SCID patients has elapsed.
The fact that T cells and NK cells were found to be of donor origin in
most patients, whereas B cells and monocytes were of host origin,
suggests that donor pluripotent stem cells do not develop into all cell
lineages in these patients. This split chimerism may be due to the
transfer of mature T cells from the marrow inoculum, producing a
long-lived expansion in the pool of memory cells. This may partially
account for the pattern of T-cell immunity development after
HLA-identical BMT, but it cannot account for the chimerism status
observed after HLA-nonidentical T-cell-depleted BMT. Indeed, the
depletion of mature T cells from the marrow inoculum results in a delay
of 3 to 6 months in the generation of peripheral blood T
cells.17,25,28 This delay, consistent with the
recapitulation of fetal thymopoiesis,45,46 suggests that T
cells develop from transplanted hematopoietic stem cells
rather than being transferred as mature T cells directly from the
transplanted marrow. Similarly, naive CD45RA(+) T cells develop in X
SCID dogs transplanted with a T-cell-depleted marrow
inoculum.47 It is nevertheless possible that pluripotent
stem cells can engraft in these patients. These donor-derived stem
cells could result in the development of donor T cells and NK cells,
given the selective advantage conferred to c or JAK-3(+) T/NK
lymphoid precursor cells, whereas normal monocytes and B-cell
precursors that are less likely to benefit from selective advantage
would be diluted out in the host population. Another possibility is
that potential donor self-renewing progenitor cells migrate directly to
the thymus without colonization of the marrow.
It has been suggested that conditioning regimen use could increase
donor B-cell engraftment after HLA-nonidentical BMT and thereby
increase the likelihood of humoral immune function
development.20,21,23,26,27,44 However, we found that
busulfan (8 mg/kg) and cyclophosphamide (200 mg/kg total dose)
treatment did neither result in higher frequency of B-cell engraftment
nor of B-cell function. This apparent discrepancy may be related to the
fact that, in the above-mentioned studies, all types of SCID were
considered rather than B+ SCID only. A detailed analysis of
chimerism after BMT in B+ SCID patients has been reported
in 2 studies. Dror et al26 have reported that B cells were
of host origin in 5 of 6 cases and of unknown origin in 1. In van
Leeuwen et al,23 B cells were found to be of host origin in
3 of 11, of donor origin in 3, and of mixed origin in 5. Because use of
a CR consisting of 8 mg/kg busulfan and 200 mg/kg cyclophosphamide
total doses does not improve survival,17,21,24,25 we
propose that it should not be used any longer in B+ SCID
patients receiving haploidentical BMT. However, we show here that
B-cell engraftment is the best setting to observe B-cell immunity
development. Because in most reported studies, including this one, the
CR used was not myeloablative, the possibility remains that fully
myeloblative CR would be of clinical benefit. In the European registry,
10 of 16 patients to whom 16 mg/kg busulfan was administered are alive,
9 of them with functional B cells.25 Unfortunately,
chimerism data are not currently available for these patients. This
strategy therefore remains a possible option, at least in patients who
are not severely infected at the time of BMT.
In this study, autologous B cells and monocytes were detected together
with donor T cells in 18 cases. Because T cells were functional in all
but 1, it provides a unique opportunity to determine host B-cell
function in these patients. B-cell function was found normal in 8 of
these 18 patients. From these data, it cannot be fully excluded that a
B-cell microchimerism accounts for antibody production in these
patients. This hypothesis appears unlikely because, when tested and
informative, Ig allotype determination showed that IgG isotypes were of
host origin. In addition, memory B cells (CD27+ B
cells)42 were detected among host B cells of patients with normal B-cell function but not among host B cells of patients with
persisting B-cell immunodeficiency. Although not definitive, these data
strongly argue in favor of the in vivo ability of
c-deficient or JAK-3-deficient B cells to produce
antibodies in the presence of competent T cells. Cooperation via the
shared HLA antigens or even T-cell education by host major
histocompatibility complex (MHC) antigens expressed in the thymus can
probably account for these results.48-52 B-cell function
may rely on c-independent cytokine pathways such as IL4/IL4RII or
IL13/IL13R.31,32 However, 4 of these 8 patients do not make
IgA, consistent with the results of Buckley et al17 and van
Leeuwen et al,23 who found that half of the B+
SCID patients with B cells of host origin did not synthesize IgA after
BMT. Determining whether the molecular defect had a subtle influence on
B-cell function would require a more thorough analysis of B-cell
function in a larger group of patients.
However, B-cell function was deficient in 10 other patients with
autologous c() B cells. These results are consistent with some form of intrinsic B-cell defect, as also suggested by the subtle
anomalies found in vitro in X-linked SCID B-cell
activation53 and by the nonrandom X inactivation pattern of
mature B lymphocytes from obligate XSCID carriers.54 There
could be 2 possible reasons to explain why c() B cells of
some patients function normally, whereas others do not. First, the
nature and severity of the c mutation may affect B-cell function.
However, this is ruled out by the fact that B cells from 2 related
patients (first cousins) with the same c gene mutation had different
functional abilities in vivo. Alternatively, because patients receiving
T-cell-depleted marrow from an HLA-identical donor develop more
frequently normal B-cell function than those receiving T-cell-depleted
nonidentical marrow, the expansion of a pool of mature T cells could
exert an indirect effect on B-cell function. Mebius et al55
have shown that the normal lymph node architecture of mice depends on a
fraction of T-cell precursors (CD4+CD3
cells) that colonize lymph nodes during the last weeks of fetal development and during the first 3 or 4 days after birth that are
c-dependent in their growth. After HLA-identical BMT, the infusion
of full marrow may lead to the rapid colonization of lymph nodes by
similar cells, rescuing lymph nodes from involution. In
HLA-nonidentical T-cell-depleted BMT, the maturation of the T cells
could take too long to prevent at least some lymph node involution,
preventing germinal center formation. Histology analysis of lymph node
from transplanted B+ SCID patients would be useful to
assess this hypothesis.
This retrospective analysis of B-cell function and chimerism
demonstrates that BMT in B+ SCID patients is a reliable
tool for studying in vivo the function of genetically deficient B cells
and the mechanism of engraftment and hematopoiesis after BMT in the
absence of a myeloablative conditioning regimen.
| |
ACKNOWLEDGMENT |
The authors thank the clinical staff for taking care of patients and Dr
M. Daveau (Bois-Guillaume, France) for Ig allotype determination.
| |
FOOTNOTES |
Submitted October 1, 1998; accepted June 16, 1999.
Supported by an institutional INSERM grant.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Elie Haddad, MD, Unité d'Immunologie
et d'Hématologie Pédiatriques, Hôpital
Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France; e-mail: ehaddad{at}igr.fr.
| |
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ABSTRACT
INTRODUCTION