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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1862-1868
TRANSPLANTATION
From the First Department of Pathology, and Department
of Orthopedic Surgery, Kansai Medical University, Moriguchi City,
Osaka, Japan.
A new bone marrow transplantation (BMT) method for treating severe
autoimmune diseases in chimeric resistant MRL/lpr mice is presented.
The method consists of fractionated irradiation (5.5 Gy × 2),
followed by portal venous (PV) injection of whole bone marrow cells
(BMCs) from allogeneic normal C57BL/6 (B6) mice and intravenous (IV)
injection of whole B6 BMCs 5 days after the PV injection (abbreviated
as 5.5 Gy × 2 + PV + IV). All recipients survived more than
1 year after this treatment (more than 64 weeks after birth). Abnormal
T cells
(Thy1.2+/B220+/CD3+/CD4
Various mouse strains that spontaneously develop
autoimmune diseases have contributed not only to a better understanding
of the fundamental nature of autoimmune diseases but also to the analysis of their etiopathogenesis.1 Using these mice, we
have previously found that allogeneic bone marrow transplantation (BMT) (not autologous BMT) can be used to treat autoimmune diseases such as
systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), immune
thrombocytic purpura (ITP), insulin-dependent diabetes mellitus (IDDM),
chronic glomerulonephritis, and a certain type of
non-insulin-dependent diabetes mellitus (NIDDM).2-10 In
contrast, we have found that the transplantation of T-cell-depleted
bone marrow cells (BMCs) or partially purified hematopoietic stem cells (HSCs) from autoimmune-prone mice to normal mice leads to the induction
of autoimmune diseases in the recipients.11,12 These findings have recently been confirmed even in humans; autoimmune diseases such as RA, SLE, multiple sclerosis (MS), and Crohn's disease
were resolved after allogeneic BMT.13-20 Conversely, the adoptive transfer of autoimmune diseases such as myasthenia gravis, IDDM, and Graves' disease by allogeneic BMT from donors to recipients has been reported.21-29 On the basis of these findings, we
have proposed that autoimmune disease is "a stem cell
disorder."9-11 However, in humans, autologous BMT or
peripheral blood stem cell transplantation (PBSCT) is now carried out
for the treatment of autoimmune diseases,30-32 because the
success rate of BMT across major histocompatibility (MHC) barriers is
not high as a result of (1) graft-versus-host reaction (GvHR), (2)
graft rejection, and (3) incomplete T-cell recovery. There have,
however, been reports on the rapid recurrence or persistence of
autoimmune diseases after autologous BMT.33
In mice, we have previously shown that allogeneic BMT can be used to
prevent and treat autoimmune diseases in B/WF1, BXSB, W/BF1, and NOD
mice.2-4,8 In MRL/lpr mice that are radiosensitive (<8.5
Gy), we have found that conventional BMT (8.5 Gy irradiation plus
allogeneic BMT) has a transient effect on autoimmune
diseases,2 whereas the autoimmune diseases recur 3 months
after BMT.8 However, we have found that BMT plus bone
grafts (to recruit donor stromal cells) completely prevents the
recurrence of autoimmune diseases in MRL/lpr mice.34
Donor-derived stromal cells play a crucial role in successful
allogeneic BMT,34,35 because MHC restriction exists between
HSCs and stromal cells.36 However, we have found that the
combination of BMT plus bone grafts has no effect on the treatment of
autoimmune diseases in MRL/lpr mice37; MRL/lpr mice become
more radiosensitive after the onset of lupus nephritis, due to uremic
enterocolitis. To determine the optimal radiation dose to treat
autoimmune diseases in MRL/lpr mice, we have irradiated MRL/lpr mice
with 6 to 9.5 Gy in combination with BMT plus bone grafts. Almost all
MRL/lpr mice (after the onset) died because of infection from the
intestine if the doses were more than 8.5 Gy. Because irradiation doses
less than 8.5 Gy do not kill abnormal HSCs in MRL/lpr mice (as we
previously described8), we carried out fractionated
irradiation and devised a new strategy. The strategy includes the
injection of cyclophosphamide (CY), fractionated irradiation (5 Gy × 2), bone grafts (to recruit stromal cells), and 2 transplantations of whole BMCs from B6 mice.37 However,
this strategy is not applicable to humans, because we have to carry out
bone grafts to recruit donor stromal cells.
Recently, we have found that most donor HSCs are trapped and retained
in the liver when they are injected either portal venously (PV) or even
intravenously (IV),38 and that the HSCs induce anergy in
host CD8+ T cells.39 In addition, we have found
that a strategy (PV [on day 0] plus IV [on day 5] injections of
donor whole BMCs) can induce persistent tolerance in the skin allograft
system.40 On the basis of these findings, we attempted to
establish a new strategy for allogeneic BMT applicable to humans:
fractionated irradiation 5.5 Gy × 2 and the PV administration
of 3 × 107 whole B6 BMCs, followed 5 days later by
the IV administration of 3 × 107 whole B6 BMCs.
Using this method, we show that severe autoimmune diseases in chimeric
resistant MRL/lpr mice are completely resolved without recourse to any immunosuppressants.
Mice
Preparation of allogeneic blood marrow cells and injection of
blood marrow cells via portal vein
Experimental protocols The onset of autoimmune diseases in MRL/lpr mice was monitored by proteinuria (more than 2.5+) and lymphadenopathy. The mice (4 to 5 months of age) with autoimmune diseases were irradiated in fractionated irradiations (5.5 Gy × 2 = 11 Gy; 4-hour interval). One day after the irradiation, the mice were transplanted with 3 × 107 whole BMCs via the portal vein (5.5 Gy × 2 + PV). MRL/lpr mice that had been irradiated 5.5 Gy × 2 and transplanted with 3 × 107 whole BMCs via the portal vein were further transplanted with whole BMCs intravenously 5 days after the PV administration (5.5 Gy × 2 + PV + IV). In addition, the following groups were prepared: (1) (5.5 Gy × 2 + IV), (2) (5.5 Gy × 2 + IV + IV), (3) (5 Gy × 2 + PV), (4) (5 Gy × 2 + PV + IV), (5) (6 Gy × 2 + PV), (6) (5.5 Gy × 2 + PV [ T] + IV [T]): fractionated irradiation, (5.5 Gy × 2) PV administration of T-cell-depleted BMCs
(3 × 107), and IV administration of
T-cell-depleted BMCs (3 × 107) 5 days after PV
administration; and (7) (8.5 Gy + IV): single dose irradiation (8.5 Gy), and IV administration of 3 × 107 whole BMCs.
Preparation of hepatic mononuclear cells (HMNCs) Mice were systematically perfused with 4 mL of heparinized (10 units/ mL) phosphate-buffered saline (PBS) (0.01 mol/L pH 7.2) to eliminate blood. The liver was further perfused with 5 mL of PBS containing collagenase (Type IV, 400 units/mL, Sigma Chemical Co, St Louis, MO) via the portal vein. After perfusion, the liver was suspended in 5 mL of the collagenase-PBS and incubated at 37°C for 40 minutes. A single cell-suspension was then obtained by simply cutting and flushing. After washing twice with PBS, the cells were suspended in 10 mL of PBS containing 1% FCS and placed on 10 mL of Lympholyte-Mammal density solution (1.0860 g/mL, Cedarlane Laboratories Ltd, Hornby, Ontario, Canada). After centrifugation for 30 minutes at 2500 rpm at room temperature, the mononuclear cells (MNCs) were collected from the defined layer at the interface.Immunological assays Recipient mice were killed, and their spleens were removed. The immunological functions of the mice were examined as follows: (1) antibody production against sheep red blood cells (SRBCs) and (2) mixed leukocyte reaction (MLR). In the anti-SRBC antibody response, 4 × 106 spleen cells were cultured with the same number of SRBCs in 24-well flat-bottom culture plates (INC Biomedicals Inc, Ohio) for 5 days, and anti-SRBC antibody production was measured by the modified Jerne's plaque-forming cell (PFC) assay, as previously described.8 MLR was performed as follows: Spleen cells were treated with the mixture of mAbs against B cells (B220, RA3-6B2), macrophages (Mac-1, M1/70), granulocytes (Gr-1, RB6), and erythroid-lineage cells (TER119) (PharMingen), in combination with magnetic beads conjugated with sheep antirat IgG Ab (Dynabeads M-450). The resultant T-cell-enriched cells were used as responders. Triplicate cultures were set up in 96-well flat-bottom microwell trays (Corning Inc, Corning, NY). Each well contained 2 × 105 responder T cells and 2 × 105 irradiated (12 Gy) stimulator spleen cells in a total of 0.2 mL of RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum, and 50 µmol/L 2-mercaptoethanol (2-ME: Wako, Osaka, Japan). The culture was incubated for 72 hours and pulsed with 0.5 µCi of 3H]-thymidine for the last 16 hours of the culturing period.Surface marker analyses FITC-coupled anti-H-2Db and PE-coupled anti-H-2Kk mAbs from PharMingen were used for H-2 typings. FITC- or PE-coupled mAbs against Thy 1.2, B220, CD4, and CD8 (PharMingen) were used to analyze the cell surface phenotypes. Lymph node and spleen cells were prepared from recipient mice, and the cells were stained with appropriate FITC- or PE-conjugated mAbs to detect abnormal T cells with the immunophenotypes of Thy1.2+/B220+/CD4 /CD8or
donor-derived cells. Cells were analyzed by a FACScan®.
Proteinuria Proteinuria was measured using testing papers (Albustix: Miles-Sankyo Ltd Co, Tokyo, Japan).Measurement of autoantibodies RF (IgG and IgM) and anti-ssDNA Abs (IgG and IgM) in the sera of the recipient mice were determined by a standard enzyme-linked immunosorbent assay (ELISA). Autoantibodies were measured by absorbance at OD405 nm, which is the maximum absorbance using the phosphatase substrate tablet (Sigma 104; SIGMAD).Pathologic findings The kidneys of the recipient mice were removed and fixed in 10% formalin, and the sections were stained with hematoxylin and eosin (H-E). For the immunofluorescence study, the specimens were frozen in dry ice/acetone, as previously described.7 Briefly, 3-µm sections were stained with FITC-conjugated rabbit antimouse IgG or FITC-conjugated antimouse C3 (Medical and Biological Laboratories, Nagoya, Japan).Statistical analyses Statistical analyses of the survival rate of recipient mice were performed using a log rank test.
Survival rates after various treatments MRL/lpr mice (4 to 5 months of age) that had developed the symptoms of autoimmune diseases such as massive lymphadenopathy and proteinuria (more than 2.5+) were first treated with (5.5 Gy × 2 + PV), as described in the "Methods." As shown in Figure 1, more than 70% of the mice thus treated survived more than 1 year, indicating that this treatment has some effect on the treatment of autoimmune diseases. We next treated autoimmune diseases in MRL/lpr mice with (5.5 Gy × 2 + PV + IV), as described in the "Methods." Thus treated MRL/lpr mice showed a 100% survival rate 1 year after the treatment, indicating that the supplemental IV injection is helpful for successful engraftment. In contrast, all the recipients treated with (8.5 Gy + IV) died within 4 weeks because of the side effects of radiation, as previously reported.37 The MRL/lpr mice treated with either (5.5 Gy × 2 + IV) or (5.5 Gy × 2 + IV + IV) showed survival rates of 33% and 40%, respectively, 21 weeks after the treatment. This appears to be due to graft rejection, because donor hematolymphoid cells cannot be detected in the recipients. These findings suggest that the PV injection of BMCs has much more effect on prolonging survival than the IV injection. To confirm that the PV injection is effective in successful engraftment of donor cells, the mice were transplanted with a small number (3 × 106) of whole BMCs via the portal vein. Sixty percent (6/10) of the recipients survived more than 32 weeks after the (5.5 Gy × 2 + PV [3 × 106]) treatment (data not shown), indicating an advantage to the PV administration of BMCs.
Chimerism in MRL/lpr mice treated with (5.5 Gy × 2 + PV) or (5.5 Gy × 2 + IV) We have recently found that most donor HSCs are trapped and retained in the liver after either PV or IV injection of HSCs, and that the percentage of allogeneic donor HSCs in the liver is significantly higher after the PV injection than the IV injection.38 Therefore, we next examined whether the donor cells were detected in the host hematolymphoid organs after the PV injection of BMCs. Hepatic mononuclear cells (HMNCs), spleen cells, and BMCs in the recipients were kinetically analyzed after the treatment with (5.5 Gy × 2 + PV) or (5.5 Gy × 2 + IV). When MRL/lpr mice were treated with (5.5 Gy × 2 + PV), percentages of donor-derived cells in HMNCs, spleen cells and BMCs gradually increased to almost 100% 14 days after the treatment (Figure 2A). The cells with mature lineage markers (B220+, CD4+, CD8+, Mac-1+, Gr-1+, or CD11c+) were contained in these donor-derived cells (data not shown). Therefore, hematolymphoid cells in the recipients were completely reconstituted with the cells of donor origin (6/6). In contrast, as shown in Figure 2B, donor cell-engraftment in the recipients treated with (5.5 Gy × 2 + IV) was transient in the spleen cells or HMNCs, although a high percentage of donor cells was found in the bone marrow (approximately 50% 14 days after treatment). These findings again indicate that the PV injection may facilitate the early engraftment of donor cells in the hematolymphoid organs.
Immunological findings in MRL/lpr mice treated with (5.5 Gy × 2 + PV + IV) Nontreated MRL/lpr mice at the age of 20 weeks showed increased anti-ssDNA Abs (IgG and IgM) and RFs (IgG and IgM), whereas MRL/lpr mice treated with (5.5 Gy × 2 + PV + IV) showed low autoantibody levels (almost to the normal level) 48 weeks after the treatment (Figure 3).
We have previously found that the IV injection of allogeneic BMCs
(T-cell-depleted) plus bone grafts after a single dose of irradiation
(8.5 Gy) has completely preventative effects on the autoimmune diseases
in MRL/lpr mice,34 and that 2 IV injections of allogeneic
whole BMCs plus bone grafts after the injection of CY and fractionated
irradiations (5 Gy × 2) can resolve autoimmune diseases.37 However, these strategies are not applicable to humans, because we have to carry out bone grafts to recruit donor stromal cells. Considering this problem, we have devised a new method
to treat severe autoimmune diseases in MRL/lpr mice. The method
includes the PV injection of whole B6 BMCs after fractionated irradiations (5.5 Gy × 2) without recourse to any
immunosuppressants or bone grafts.
We thank Ms Y. Tokuyama and Ms M. Shinkawa for their expert technical
assistance, and Mr Hilary Eastwick-Field and Ms K. Ando for their help
in the preparation of the manuscript.
Submitted August 19, 1999; accepted November 3, 1999.
This work was supported by a grant for Experimental Models for
Intractable Disease from the Ministry of Health and Welfare of Japan
and a grant from the Japanese Private School Foundation, a grant from
"Haiteku Research Center" of the Ministry of Education, grants-in-aid for scientific research (B) 11470062 and grant-in-aid for
scientific research on priority areas (A)10181225,11162221.
Reprints: Susumu Ikehara, MD, PhD, First Department of
Pathology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, Osaka 570-8506, Japan; e-mail: ikehara{at}takii.kmu.ac.jp.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
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Abstract
Introduction
