Moen RC, Horowitz SD, Sondel PM, Borcherding WR, Trigg ME ...

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1987 70: 664-669
Immunologic reconstitution after haploidentical bone marrow
transplantation for immune deficiency disorders: treatment of bone marrow
cells with monoclonal antibody CT-2 and complement
RC Moen, SD Horowitz, PM Sondel, WR Borcherding, ME Trigg, R Billing and R Hong
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Immunologic Reconstitution After Haploidentical Bone Marrow Transplantation
for Immune Deficiency Disorders: Treatment of Bone Marrow Cells
With Monoclonal Antibody CT-2 and Complement
By R.C. Moon, S.D. Horowitz, P.M. Sondel, W.R. Borcherding, M.E. Trigg, R. Billing, and R. Hong
Patients with congenital T lymphocyte deficiency disorders
received transplants with parental bone marrow depleted
of mature T cells by the use of an anti-T cell monoclonal
antibody (CT-2) and complement. Our results with 16
consecutive patients (20 transplants) showed rapid
engraftment of donor cells; cytoreduction (busulfan. cytosine
arabinoside [ara-CJ. cyclophosphamide) was used in
six transplants. and marrow ablation was used in six
(ara-C. cyclophosphamide. 1 .365-cGy total body irradiation).
No patient received prophylactic anti-graft-v-host
disease (GVHD) therapy posttransplant, and only one
patient developed significant GVHD. which involved the
skin. liver. and gastrointestinal tract. Seven others showed
some manifestations of GVHD. but these were of minimal
clinical significance and required only occasional steroid
therapy. Overall. eight patients are alive and well; eight did
not survive. Polyclonal immunoglobulin synthesis by donor
memory B cells was seen shortly after transplantation.
with peak donor-derived serum levels seen approximately
2 months after transplantation. After this initial immuneglobulin
synthesis waned. another wave of B cell responses
developed. This immunoglobulin response appears to be
permanent. T cell functions appeared as soon as 3 weeks
after transplantation. This experience in a variety of
patients with combined immunodeficiency who received
transplants with monoclonal antibody T cell-depleted marrow
shows gratifying results with a consistent T and B cell
benefit.
a 1987 by Grune & Stratton, Inc.
S EVERE COMBINED IMMUNE DEFICIENCY
(SCID) can be successfully treated with transplantation
of bone marrow from HLA-identical siblings. Unfortunately,
the majority of affected individuals will lack an
HLA-identical bone marrow transplant (BMT) donor. To
offer BMT therapy to patients without suitably matched
stem cell donors, immunocompetent T cells have been
removed from bone marrow by antibodies to T cells’ or by
agglutination with soybean lectin or sheep erythrocytes.58
We report our results in I 6 consecutive patients with immunodeficiency
syndromes receiving parental marrow depleted
of T lymphocytes by the use of the monoclonal antibody
CT-2 and complement. This procedure has resulted in marrow
engraftment and reconstitution of both B and T cell
functions with minimal graft-v-host disease (GVHD).
MATERIALS AND METHODS
Donor and recipient characteristics. The diagnoses of the
patients included SCID (adenosine deaminase [ADA]-positive and
-negative), Wiskott-Aldrich syndrome (WAS), and cartilage-hair
hypoplasia (CHH) (Tables 1 and 2). Of the I I ADA-positive SCID
From the Department of Pediatrics, University of Wisconsin,
Madison.
Submitted September 12, 1986; accepted April 30, 1987.
Supported in part by Grant No. A! 10404 from National Institutes
of Health.
Presented in part at the Keystone UCLA conference. April 1986.
ME. T. is now affiliated with the Department of Pediatrics,
University of Iowa, Iowa City. RB. is now affiliated with the
Conejo Valley Cancer Center. Westlake Village. CA.
Address reprint requests to R. Hong. MD. Department of Pediatrics.
University of Wisconsin Clinical Science Center, 600 Highland
Ave K4/434, Madison, WI 53792.
The publication costs ofthis article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. §1734 solely to
indicate this fact.
© I 987 by Grune & Stratton, Inc.
0006-4971/87/7003-0009$3.OO/O
patients, eight had disproportionate amounts of B cells, the most
common variety. Three patients had normal to elevated Ig responses
but had had prior thymus transplants. Three (patient nos. 34, 86,
and 87) had, before therapy, levels of immunoglobulins consistent
with the diagnosis ofSCID with immunoglobulins. Informed written
consent for bone marrow transplantation with donor bone marrow
depleted of T lymphocytes was obtained. All protocols for transplantation
were approved by the Human Subjects Committee of the
University of Wisconsin.
BMT preparation regimens. Busulfan (4 mg/kg/d orally for
four days) was used for patients under 2 years of age to avoid the
CNS toxicity of total body irradiation (TBI) (Table 1 ). Otherwise,
fractionated TBI was administered at a dose of 1,320 cOy (165
cGy x 8) with only the eyes shielded (patient no. 80) or both eyes
and lungs shielded (patient nos. 87 and 100). Cyclophosphamide was
used in all patients receiving myeloablative therapy. Cytosine arabinoside
(six doses of 3 g/m2 or 2 g/m2 [transplant 105]) was added to
the preparative regimen to further immunosuppress the recipient
because the experience with patient no. 26 and with patients
receiving T cell-depleted BMT for hematologic malignancy has
demonstrated that further immunosuppression is necessary to prevent
graft rejection by the host.9
Bone marrow harvest, T cell depletion, and transpiantalion.
Bone marrow was aspirated from posterior iliac crests,
depleted of T cells, and infused as described previously.4 Only one
cycle of antibody and complement were used for each marrow
treatment. E rosette-positive and TI 1-positive cells are completely
removed by this treatment (Tl I + cells were measured by flow
cytometry). Mixed leukocyte reactivity and cytotoxic T cell generation
against allogeneic targets was usually but not invariably
decreased. Patient nos. 28 to 1 15 also received a portion (5% to 30%)
of donor marrow cells directly into their marrow space. Four to IS
mL ofconcentrated marrow cells was injected into the posterior iliac
crest(s).”
Assessment of engraftment and G VHD. The latest assessment
ofT lymphocytes is shown in Table 3. Engraftment ofdonor marrow
was also documented by HLA phenotyping of peripheral blood
lymphocytes and where possible by karyotypic analysis of peripheral
blood lymphocytes and RBC phenotyping.
The severity of GVHD was defined by the Seattle criteria.”
Diarrhea fluid loss for staging of GVHD of the gastrointestinal tract
was adjusted according to patient surface area, assuming an average
adult value of 1 732
664 Blood, Vol 70, No 3 (September), 1987: pp 664-669

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T CELL DEPLETED BONE MARROW TRANSPLANT 665
Table I . Cli nical Data
State of BM GVHD# Months
uPN Disease Age Pre * Prey T4 Health) Dosell (S/L/G) F/U Outcomett
Alive
028 SCID 20 None CTF Good 1 1.3 2/1/0 39 Well
057 SCID 6 None None Fair 12.2 1/0/0 27 Well
080 SCID 55 ARA-6. C2, TBI CTF Good 4.7 1/0/0 19 Well
087 SCID 65 ARA-6, C2, TBI TP5 Good 4.6 1/0/0 1 6 Well
094 SCID 10 None None Good 1 9.4 3/0/0 1 5 Well
026 WAS 2 B4, C4 None Good 9.8 0/0/0 39 Well
lOOa ADA 83 None CiT Poor 4.8 0/0/0 2.5 Temporary engr
bOb 85 ARA-6, C2. TBI None Poor 3.7 1/2/0 10 Improved
105 ADA 4 ARA-6, c2, B4 None Fair 5.7 1/0/0 14 Well
Not alive
023a SCID 1 2 None None Good 8. 1 0/0/0 5 No engraftment
023b 1 7 B4, C4 See 23a Poor 8.4 NE - Died (4)
027 SCID 56 None CTF Poor 9.5 2/1/0 - Died (28)
034 SCID 52 B4.C4 None Good 5.0 NE - Died (0)
086a SCID 23 None None Fair 6.5 0/0/0 9 Temporary engr
086b 34 ARA-6,C2,T8I See86a Poor NE - Died(-2)
093 SCID 58 ARA-6,C2.TBI CTF Poor 6.6 NE - Died(14)
099a SCID 80 None CTF Good 9.6 0/0/0 5 No engraftment
099b 86 ARA-6, C2, TBI See 99a Good 8.0 2/1/0 - Died (22)
1 10 CHH 1 3 ARA-6, C2, B4 None Fair 6. 1 3/2/2 - Died (15)
1 1 5 ADA 27 ARA-6. C2. B4 None Good 1 2.8 1/0/0 - Died (9)
UPN, unique patient number. Patient nos. 23, 86, 99, and 100 received transplants on two occasions (a - 1st transplant; b 2nd transplant). Only
patient nos. 87 and 100 are female.
tA e at the time of transplant in months.
B4, busulfan, 4 mg/kg/d x 4; C4, Cytoxan, 50 mg/kg/d x 4; c2, Cytoxan, 50 mg/kg/d x 2 except for patient nos. 105. 1 10, and 1 1 5 (45
mg/kg/d x 2); ARA-6, ara C, 3 g/m2 every 12 hours x 6 except patient nos. 105, 1 10. and 1 15 where the dose was 2 g/m2; TBI, 1.320 rad in eight
divided dOSeS. Patient no. 7 had his eyes shielded. Patient nos. 87 and 100 had lungs and eyes shielded.
§Previous therapy: CiT. cultured thymus fragment; TP5, thymopoietin pentapeptide.
State of health at the time of transplant: good, essentially normal; fair, slightly undernourished, past history of serious infection; po , actively
infected, marked wasting, often chronic diarrhea.
#{182}Dose of nucleated cells x 108/kg body weight administered after T cell depletion.
#S/L/G indicates the degree of involvement of skin, liver, and gut, respectively. The number indicates the clinical stage of involvement using Seattle
criteria (see the text). NE, not evaluated.
#{149} C Months of follow-up since transplant.
ttSee the text for details of death. Immune status is shown in subsequent tables. Temporary engr. temporary engraftment. The numbers in
parentheses are the days of death relative to BMT.
Monoclonal antibody cell surface markers. Antibodies directed
against various mononuclear cell populations were used for flow
cytometric analysis. The antibodies used were OKT3, OKT4,
OKT6, OKT8, Leu 1 1, Leu 7, anti-HLA-DR, BI, and B4.
Tcellfunctions. Mononuclear cells obtained by Ficoll-Hypaque
separation were assessed for proliferative responses to mitogens,
antigens and alloantigens and cytotoxic responses to alloantigen
targets by the usual methods.’2
B cell function testing. Serum immunoglobulin levels were
determined by rate nephelometry using a Beckman ICS Analyzer II
(Beckman Instruments, Inc. Fullerton, CA). Specific antibody levels
of IgG, IgA, and 1gM to the antigens Escherichia coli, tetanus
toxoid, and diphtheria-tetanus toxoids were determined by an
enzyme-linked immunosorbent assay (ELISA).’3 IgE levels were
determined by using an ELISA assay (Epsilon IgE, Beckman
Instruments, Inc, Carlsbad, CA).
RESULTS
As shown in Table 1,1 6 patients overall received transplants.
Eight are alive and well; eight have died. The major
cause of death was infection. Of the 16 transplant recipients
there were 1 1 patients with ADA-positive SCID, three
patients with ADA deficiency, one with CHH, and one
patient with WAS. The age at the time of transplant varied
from 2 months to 72/,2 years. The father was the BMT donor
for all transplants except for patient 99 where the mother
served as the donor. All donors and recipients were haploidentical,
except as noted. Donor cells were reactive against
the host in mixed lymphocyte culture (MLC) except for
patient no. 26 who was MLC compatible, HLA-B, -C, and
-DR identical, but HLA-A disparate with his donor (Table
2). Cytoreduction or ablative pretreatment was used in I 2 of
the 20 transplants performed. At the time of transplant or
transplant conditioning, the recipient was in good health in
ten, fair health in four (transplant nos. 57, 86, 105, and 1 10),
and in poor health in six (transplant nos. 23, 27, 86, 93, and
100) instances.
The number of treated nucleated bone marrow cells
received varied from 3.7 x 108/kg to 19.4 x l08/kg. In those
patients receiving immunosuppressive treatment before
transplantation, engnaftment of WBC was present 12 to 20
days after transplantation. Patients nos. 23 and 99 did not
show engraftment and died during a second transplant

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666 MOEN ET AL
Tab Ic 2. Im munolog ic Cha racteristi cs at Ti me of Transplant
D yR
PN Lymphs Ti 1 T3 T4 T8 MLCt B 1 lgG gA 1gM HLA Dispar MLC
Alive
SCID
028 273 1 1 0 0 0 15 32411

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T CELL DEPLETED BONE MARROW TRANSPLANT 667
attempt. In transplant nos. 86 and 100 only transient
engraftment occurred; patient no. 86 died before a retransplant
could be performed, but patient no. 100 has subsequently
received a successful transplant. Thus, in toto, of the
16 patients, 8 are alive and well and show engraftment.
Patient no. 26 initially showed donor engraftment of all cell
lines. He has continued to demonstrate good donor T cell
engraftment, but his red cells, platelets, monocytes, and B
lymphocytes are now entirely of the host type. He is chimeric
for Tcells.
GVHD. Engraftment occurred without significant
GVHD (Table 1). Only one patient (no. 1 10) demonstrated
GVHD of greater than grade 2 severity. In patient no. 94
stage III skin GVHD was present without liver or gastrointestinal
involvement. This patient and patient no. 1 10 were
treated with high-dose steroid therapy to control the acute
GVHD.’4 Patient nos. 28, 57, 87, and 100 required low-dose
prednisone therapy ( 1 to 2 mg/kg) for brief periods of time
(1 to 3 weeks). Patient nos. 80 and 105 did not receive any
steroid therapy for transient acute GVHD of the skin with
minimal liver involvement. Only patient no. 1 10 had clinical
evidence ofgastrointestinal GVHD. Chronic GVHD has not
occurred.
T cell reconstitution. From 3 to 1 2 weeks were required
before greater than 100 cells/zL stained with each of the
monoclonal antibodies listed. At no time after transplantation
were cells staining with monoclonal antibody OKT6
(indicative of thymocytes) found in peripheral blood. In all
cases, the number of T8 + cells exceeded the number of T4 +
cells for many months after transplantation. Table 3 lists the
relative number of T cells seen at the time of the most recent
follow-up.
Six to I 8 weeks were required after transplantation before
significant proliferation was observed in response to the
mitogens phytohemagglutinin (PHA), concanavalin A (Con
A), and pokeweed mitogen (PWM) and 48 weeks for the
soluble antigen Candida. Significant proliferation was
defined as the attainment of a level of proliferation in excess
of 3 SD of the mean response observed before treatment in 34
newly diagnosed patients with severe combined immunodeficiency
syndrome (ADA + ). Allogeneic cell (MLC) reactivity
was found by the 12th week. In almost all cases (except
patient no. 100) the proliferative responses were preceded by
the acquisition of significant numbers of T cells as determined
by monoclonal markers.
B cell reconstitution. The acquisition of B cell function
revealed a novel pattern. Since all patients were receiving
intravenous gamma globulin preparations, we evaluated
endogenous B cell function by following the IgA and 1gM
responses. Most patients showed substantial elevations in
IgA and/or 1gM levels, which peaked about 2 months after
transplantation. The serum levels subsequently decreased
only to rise again many months later. These immunoglobulin
changes occurred in all patients, even those not requiring any
blood product support posttransplant. Table 4 provides a
summary of current immunoglobulin levels and functional
antibody analyses for all surviving patients.
The IgE level remained

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668 MOEN ET AL
Table 4. B Cell Assessment
Responses to Specific Antigens
E coli
Diphtheria
Tetanus
Total
Ig
UPN Ig Before
Nowt
Before
Now
Before
Now
Isotypes
IgE
028 IgG 0 150 0 120 0 42 622

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T CELL DEPLETED BONE MARROW TRANSPLANT 669
consistently observed in patients with primary immunodeficiency.
Cytoreduction or ablation is often necessary but
needs to be properly defined and the agents carefully chosen
so as not to significantly add to the morbidity of the
transplant
procedure.
NOTE ADDED IN PROOF
Patient no. 100 now has normal immunity. Patient no. 26 was
retransplanted without further immunosuppression or T cell depletion
of the marrow and has a normal platelet count.
ACKNOWLEDGMENT
Dedicated expert clinical care was provided by the house staff and
nursing service of the University of Wisconsin Clinical Science
Center. Coordination of complex interdisciplinary procedures was
efficiently accomplished by Bridget Flynn. The referral of patients
by Drs G. Brashear, i. Casper, R. Cole, L. Eggman, R. Friedman, P.
Krueger, K. Rich, T. Silberstein, i. Twiggs, R. Wappner, and i.
Winkelstein is gratefully acknowledged. CT-2 monoclonal antibody
was generously provided by the Conejo Valley Cancer Center,
Westlake Village, CA.
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