Stem Cells 2005;23:365-370
www.StemCells.com
© 2005 AlphaMed Press
A New Strategy for Treatment of Malignant Tumor: Intra-Bone Marrow–Bone Marrow Transplantation Plus CD4– Donor Lymphocyte Infusion
Yasuhiro Suzukia,
Yasushi Adachia,b,c,
Keizo Minaminoa,
Yuming Zhanga,
Masayoshi Iwasakia,
Keiji Nakanoa,
Yasushi Koikea,
Susumu Ikeharaa,b,c
a First Department of Pathology,
b Regeneration Research Center for Intractable Diseases,
c Center for Cancer Therapy, Kansai Medical University, Osaka, Japan
Key Words. Donor lymphocyte infusion (DLI) • Malignant tumor • Graft-versus-host disease (GvHD) • Graft-versus-tumor (GvT) effect • Intra-bone marrow–bone marrow transplantation (IBM-BMT)
Correspondence: Susumu Ikehara, M.D., Ph.D., First Department of Pathology, Kansai Medical University, 10–15 Fumizonocho, Moriguchi City, Osaka, 570-8506, Japan. Telephone: 81-6-6993-9430; Fax: 81-6-6994-8283; e-mail: ikehara{at}takii.kmu.ac.jp
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ABSTRACT
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Donor lymphocyte infusion (DLI) is clinically used for the treatment of malignant tumors. We have found recently that intra-bone marrow–bone marrow transplantation (IBM-BMT) can be used to treat various autoimmune diseases, even when radiation doses are reduced. In addition, recently we have found that IBM-BMT can prevent not only graft failure but also graft-versus-host disease (GvHD). Based on these findings, we attempted to prevent and treat the progression of a tumor (Meth-A cell line: BALB/c-derived fibrosarcoma) by DLI plus IBM-BMT. When the tumors had grown to approximately 10 x 10 mm, the tumor-bearing BALB/c (H-2d) mice were irradiated with 5 Gy, and whole spleen cells from C57BL/6J (B6) (H-2b) mice (as DLI) were then intravenously injected into the BALB/c mice. Simultaneously, bone marrow cells (BMCs) from B6 mice were injected directly into the bone marrow cavity of the BALB/c mice (IBM-BMT). The tumors decreased in size, but the mice died of GvHD. However, when CD4+ T-cell–depleted spleen cells were used for DLI, the recipients showed only mild GvHD and survived longer, due to the slow growth of the tumor. In contrast, when CD8+ T-cell–depleted spleen cells were used for DLI, the recipients showed more severe GvHD than those injected with whole spleen cells. These results suggest that IBM-BMT plus DLI (the depletion or reduction of a certain cell population like CD4+ T cells) could be helpful to suppress both GvHD and tumor growth.
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INTRODUCTION
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It is well known that the graft-versus-leukemia reaction (GvLR) can cure patients with a variety of hematological malignancies [1, 2]. Recently, it has been reported that graft-versus-tumor (GvT) effects can induce partial (complete in some) remission of metastatic solid tumors, such as breast cancer [3–5] and renal cell carcinoma [6–11]. Based on these findings, donor lymphocyte infusion (DLI) has very recently been used for the treatment of malignant solid tumors even in humans. However, it is very difficult to completely eradicate the tumors, since extensive DLI induces graft-versus-host disease (GvHD). We have attempted to establish a new method for the treatment of malignant tumors. The method includes intra-bone marrow–bone marrow transplantation (IBM-BMT) plus DLI, since we have recently found that IBM-BMT can allow a reduction in radiation doses as a conditioning regimen and prevents GvHD in mice [12, 13]. Using the Meth-A cell line (BALB/c-derived fibrosarcoma), we here show that IBM-BMT plus injection of CD4+ T-cell–depleted (but not CD8+ T-cell–depleted) spleen cells (as DLI) can prevent GvHD but suppress the tumor growth. We also show that IBM-BMT plus extensive DLI (3 times every 2 weeks) leads to complete rejection of the tumor, although the success rate—3/50, so far—is not high.
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MATERIALS AND METHODS
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Animals
C57BL/6 (B6; H-2b) and BALB/c (H-2d) mice were purchased from Japan SLC, Inc. (Hamamatsu, Japan, http://133.1.15.131/SLC/file/TOP3.htm). B6 mice at the age of 8–12 weeks were used as donors, and BALB/c mice at the age of 8–12 weeks were used as recipients (in some experiments, as donors). All mice were housed in autoclaved -microisolator environments, and all manipulations were performed in a laminar flow hood.
Inoculation of Tumor Cells and Irradiation
BALB/c mice were exposed to a radiation dose (3 Gy at 1.0 Gy/min) from a 137Cs source (Gammacell 40 Exactor; MDS Nordion International Inc., Ottawa, Ontario, Canada, http://www.mds.nordion.com) 1 day before subcutaneous injection of the tumor cell line Meth-A (fibrosarcoma: H-2d) (2x106 cells/0.2ml). When the tumor size reached to approximately 10 x 10 mm, the BALB/c mice were exposed to a radiation dose (5 Gy at 1.0 Gy/min) from a 137Cs source. One day later, IBM-BMT plus DLI was carried out.
BMT and DLI
Bone marrow cells (BMCs) were harvested from the femoral, tibial, and humeral bones of B6 mice (BALB/c mice in some experiments as a control) and suspended in phosphate-buffered saline (PBS). The BMCs were then filtered through a 70-µm-nylon wool mesh (Becton, Dickinson Labware, Franklin Lakes, NJ, http://www.bd.com) and centrifuged at 1,500 rpm for 7 minutes at 4°C. After centrifugation, the BMCs were suspended and adjusted to 3.0 x 109 cells/ml in PBS containing 2% fetal calf serum (FCS). The thus-prepared BMCs were injected directly into the bone marrow cavity of the tibial bones (intra-bone marrow injection: IBM-injection), as previously described [12]. Briefly, the region from the inguen to the knee joint was shaved, and an approximately 5-mm incision was made on the thigh. The knee was flexed to 90 degrees, and the proximal side of the tibia was drawn to the anterior. A 26-gauge needle was inserted into the bone marrow cavity. Using a microsyringe (50 µl; Hamilton Company, Reno, NV, www.hamiltoncompany.com) containing the donor BMCs (3 x 107 cells/10 µl), the donor BMCs were injected from the said bone hole into the bone marrow cavity.
DLI was performed as follows: spleens were removed from donor B6 mice (from BALB/c mice in some experiments as a control) and then minced with scissors. Single cells were prepared by passing the minced spleen through stainless steel mesh in PBS containing 2% FCS. After centrifugation at 2,000 rpm for 10 minutes at 20° C, the pellets were suspended in PBS containing 2% FCS, then adjusted to 2.0 x 108 cells/0.2 ml (1.0 x 109cells/ml) in PBS containing 2% FCS. In some experiments, T-cell subsets were prepared using Dynabeads (Dynal A.S., Oslo, Norway, http://www.dynal.no) after the treatment of spleen cells with anti-CD4 or CD8 mAb (Pharmingen, San Diego, CA, www.bdbiosciences.com/pharmingen).
Measurement of Body Weight and Tumor Size
Body weight and tumor size were measured every day. In all experiments, the mice were weighed on a weighing machine, and the weight was expressed in grams. Tumor size was measured by vernier calipers and expressed as width (mm) x length (mm) x height (mm) = tumor size (mm3).
Statistical Analyses
Survival data were analyzed using the Kaplan-Meier Method in the Stat Mate software. Differences between groups were analyzed using the Log-Rank Test in the Stat Mate software p < .05 was considered to be significant.
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RESULTS
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In our preliminary experiments, we carried out conventional BMT (intravenous injection of BMCs: IV-BMT) as a control of IBM-BMT. However, the mice treated with IV-BMT plus DLI died of severe GvHD, as we previously reported [13]. Therefore, we used only IBM-BMT in the subsequent experiments.
Survival Rates in Tumor-Bearing Mice Treated with IBM-BMT Plus DLI
All the mice in the nontreated control group died of the tumor. The mean survival time was 40.8 days (range: 17–68 days, n = 20) after reaching a tumor size of 10 x 10 mm (Fig. 1A
). When BALB/c whole spleen cells were injected into tumor-bearing BALB/c mice via the tail vein, and when BALB/c bone marrow cells were injected directly into the bone marrow cavity of the tumor-bearing BALB/c mice as a control (BALB/c group), the mean survival time was 36.75 days (range: 31–45 days, n = 4). No significant difference was observed between the control group and the BALB/c group (Fig. 1A).
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Figure 1. Mean (A) survival time and (B) survival curve in each mouse group treated with IBM-BMT plus DLI. Mice in the nontreated control group died of the tumor: The mean survival time was 40.8 days after reaching a tumor size of 1 x 1 cm. The mean survival time in the BALB/c group (BALB/c mice treated with IBM-BMT [using BALB/c BMCs] + DLI [using BALB/c spleen cells]) was 36.7 days after reaching a tumor size of 1 x 1 cm and starting the treatment. The mean survival time in the whole group (BALB/c mice treated with IBM-BMT [B6 BMCs] + DLI [B6 whole spleen cells]) was 22 days. The mean survival time in the CD4– group (BALB/c mice treated with IBM-BMT [B6 BMCs] + DLI [B6 CD4+ T-cell–depleted spleen cells]) was 46.41 days (longest), whereas that in the CD8– group (BALB/c mice treated with IBM-BMT [B6 BMCs] + DLI [B6 CD8+ T-cell–depleted spleen cells]) was 17.6 days (shortest). *p < .05, **p < .01. Abbreviations: DLI, donor lymphocyte infusion; IBM-BMT, intra-bone marrow–bone marrow transplantation.
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In contrast, when B6 whole spleen cells were used as DLI in conjunction with IBM-BMT from B6 mice (whole group), the mean survival time was 22 days (range: 15–39 days, n = 11), which was significantly shorter than that of the control group or the BALB/c group (p < .001 and p < .05, respectively, Fig. 1A
). When CD4+ T-cell–depleted B6 spleen cells were injected into BALB/c mice in conjunction with IBM-BMT (CD4– group), the mean survival time was 46.41 days (range: 11–68 days, n = 22; Fig. 1A). When CD8+ T-cell–depleted B6 spleen cells were used for DLI (CD8– group), the mean survival time was 17.6 days (range: 8–46 days, n = 10; Fig. 1A), which was significantly shorter than that of the CD4– group. As shown in Fig. 1B, the group of mice treated with IBM-BMT plus CD4– DLI survived the longest in all the groups.
Changes in Body Weight of Tumor-Bearing Mice Treated with IBM-BMT plus DLI
We measured the body weight of mice treated with the various strategies almost every day, since it is well known that loss of body weight is the most reliable indicator of GvHD in mice. When mice were treated with various strategies, the mice in all the groups except for the control group lost weight until approximately 15 days (Fig. 2). It seems unlikely that this was due to GvHD, since the BALB/c group also lost weight. It is therefore conceivable that this was a side effect of radiation (5 Gy for IBM-BMT). Thereafter, the mice in the whole group and the CD8– group continued to lose weight gradually: the ranges were 2–12 g and 3–10 g, respectively. In contrast, the mice in the CD4– group and the BALB/ c group gained weight: the ranges were 2–10 g and 2–8 g, respectively. At the end point, the control group showed a sudden loss in weight due to tumor necrosis, followed by death. These results indicate that the BALB/c mice injected with CD4+ T-cell–depleted B6 spleen cells did not lose as much body weight as did those injected with B6 whole spleen cells or CD8+ T-cell–depleted B6 spleen cells.
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Figure 2. Changes in body weight of each mouse group treated with IBM-BMT plus DLI. As loss of body weight is the most reliable indicator of GvHD in mice, we measured the body weight of mice treated with IBM-BMT plus DLI. Mice in all groups except for the control group (nontreated group) lost weight until approximately 15 days, due to the side effect of irradiation. Thereafter, the whole group and the CD8– group both showed a continuous loss in weight. In contrast, mice in the CD4– group and the BALB/c group gained weight. Mice in the control group showed a sudden loss in weight due to tumor necrosis, followed by death. The BALB/c mice injected with CD4+ T-cell–depleted B6spleencellslostmuchlessbodyweightthandidthoseinjected with CD8+ T-cell–depleted B6 spleen cells. Abbreviations: DLI, donor lymphocyte infusion; GvHD, graft-versus-host disease; IBM-BMT, intra-bone marrow–bone marrow transplantation.
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It can be concluded that CD4+ (but not CD8+) T-cell–depleted spleen cells should be used as DLI to prevent GvHD.
Effects of IBM-BMT Plus DLI on Tumor Growth
We next analyzed the effects of IBM-BMT plus DLI on the suppression of tumor growth. Some mice in the CD4– group survived longer than did those in the control group and the BALB/c group. Until 20 days after IBM-BMT plus DLI, tumor growth was suppressed in the whole group, the CD4– group, and the CD8– group, in contrast to the control group and the BALB/c group (Fig. 3). However, thereafter, the mice in the CD4– group showed much less suppression of tumor growth than those in the whole group or the CD8–group. Although the mice in the whole group and those in the CD8– group showed continuously suppressed tumor growth, the mice in these groups died earlier than those in the CD4– group (p < .001 and .001, respectively).
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Figure 3. Changes in mean tumor size of recipient BALB/c mice after IBM-BMT plus DLI. Tumor size was measured almost every day, and tumor size is represented every 5 days in this figure. Until 20 days after IBM-BMT plus DLI, the tumor growth was suppressed in the whole group, the CD4– group, and the CD8– group, in contrast to the control group and the BALB/c group. However, thereafter, the mice in the CD4– group showed much less suppression of tumor growth than those in the whole group or the CD8– group. Although the mice in the whole group and the mice in the CD8–group showed continuously suppressed tumor growth, the mice in these groups died earlier than those in the CD4–group (p < .001 and .001, respectively). Abbreviations: DLI, donor lymphocyte infusion; IBM-BMT, intra-bone marrow–bone marrow transplantation.
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These results suggest that the best GvT effect (without undesirable side effects such as GvHD) results from injecting CD4+ T-cell–depleted spleen cells as DLI.
Complete Rejection of Tumor by IBM-BMT Plus Repeated DLI
Based on the above findings, we attempted to completely reject the tumor by repeated DLI plus IBM-BMT. We injected B6 whole spleen cells into the recipient BALB/c mice three times every 2 weeks. The body weight in both mice (no. 1 and no. 2 in Fig. 4A) remained almost unchanged. The tumor size increased gradually at the beginning, but thereafter decreased slowly but steadily (Fig. 4B); 45 days after the first DLI plus IBM-BMT, the tumor had in some cases (3 out of 50) completely disappeared (Fig. 4C). We confirmed that this was due to rejection based on immunological reaction, since we could not transplant Meth-A again, even when high doses (> 2 x 108) of Meth-A cells were injected into the mice that had previously rejected Meth-A.
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Figure 4. Changes in (A) body weight and (B) tumor size of the tumor-eradicated BALB/c mice. Repeated donor lymphocyte infusion (DLI) plus intra-bone marrow–bone marrow transplantation (IBM-BMT) were carried out: B6 whole spleen cells wereinjectedintotherecipientBALB/cmicethreetimesevery2 weeks. The body weight in both mice (no. 1 and no. 2) remained almost unchanged (A). The tumor size increased gradually at the beginning, but thereafter decreased slowly but steadily (B); 45 days after the first DLI plus IBM-BMT, the tumor had completely disappeared. (C): The left pictures are no. 1 mouse in (A) and (B), and the right pictures are no. 2 mouse in (A) and (B).
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DISCUSSION
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In the study reported here, we demonstrated that IBM-BMT in conjunction with DLI suppresses the growth of Meth-A cells (BALB/c-derived fibrosarcoma). When whole spleen cells were used for DLI, the survival time decreased due to the severe GvHD, in spite of the significant suppression of tumor growth (Figs. 2 and 3). When CD4+ T-cell–depleted spleen cells were used for DLI, GvHD was suppressed. However, the tumor growth was not as efficiently suppressed as seen in the case of whole spleen cells. In contrast, when CD8+ T-cell–depleted spleen cells were used for DLI, the result was similar to that of whole spleen cells: the survival time decreased due to the severe GvHD in spite of the significant suppression of tumor growth. These findings suggest the importance of CD4+ T cells in the induction of both GvHD and GvT effects. In addition, survival time seems to be determined by the balance of severity of GvHD and efficacy of GvT effects, as shown in Figure 1.
It has been reported that some murine splenic dendritic cells (DCs) express CD4 or CD8
[14, 15]. Therefore, when we depleted CD4+ or CD8+ cells using anti-CD4 or anti-CD8 Ab, not only CD4+ or CD8+ T cells but also CD4+ or CD8+ DCs could be depleted. However, using the peripheral blood cells (PBCs), which contain a very small number of DCs, we previously demonstrated that IBM-BMT in conjunction with CD4+ cell-depleted DLI has more suppressive effects on GvHD than does CD8+ cell-depleted DLI [13]. Therefore, it seems unlikely that the depletion of CD4+ DCs plays a crucial part in the prevention of GvHD in our system.
We previously found that IBM-BMT can be used to treat autoimmune diseases in radiosensitive and chimerism-resistant MRL/lpr mice, even when the radiation dose is reduced to 5 Gy x 2 [12]. This was found to be due to the reconstruction of hemopoietic cells (including pluripotent-hemopoietic stem cells: P-HSCs), as well as stromal cells (including mesenchymal stem cells: MSCs) by donor-derived cells [16], since we previously found that there is a major histocompatibility complex (MHC) restriction between P-HSCs and stromal cells [17, 18] and that the help of MHC-compatible donor stromal cells is essential for the proliferation of donor P-HSCs. In addition, we recently found that IBM-BMT in conjunction with DLI can prevent GvHD and HvG reaction (graft rejection), even when the radiation dose is reduced to 6 Gy [13]. This was found to be due to immunosuppressive cytokines (HGF [19], TGF-ß [20], etc.) produced by donor-derived stromal cells (including MSCs), resulting from the recruitment of donor-derived stromal cells by IBM-BMT. We reported that, in mice, GvHD is induced by donor T cells but can be suppressed by the depletion of CD4+ T cells [21]. In addition, several groups previously demonstrated that donor CD8+ T cells can help to promote marrow engraftment in mice [22] and humans [23]. We also found that CD4+ T cells have a crucial role in the induction of GvHD and that the depletion of CD4+ T cells from the BMCs or spleen cells of donors can prevent GvHD in mice [12, 13], although it has been reported that the depletion of CD8+ T cells from the BMCs can prevent GvHD in humans [24, 25].
These findings strongly suggest that GvHD can be prevented by removing a certain T-cell subset from the donor cells (whether they are T-cell–contaminated BMCs, PBSCs, cord blood, or DLI).
DLI is clinically used for the treatment of malignant tumors, but it is very difficult to completely eradicate the tumors, since extensive DLI induces GvHD. However, as shown in Figure 4, we succeeded in completely rejecting Meth-A by IBM-BMT plus repeated DLI, although the success rate (3/50) is so far not high.
These findings have encouraged us to establish more efficient strategies to eradicate the tumor. In addition, we are examining whether this strategy (IBM-BMT plus DLI) is applicable to other tumors in other animals. Indeed, we have obtained similar results in another system (colon cancer: ACL-15 in rats) (Y. Koike et al., manuscript in preparation) to those in the present study (Meth-A in BALB/c mice).
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ACKNOWLEDGMENTS
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We thank Mrs. M. Shinkawa, Ms. S. Miura, and Ms. Y. Tokuyama for their expert technical assistance, and Mr. Hilary Eastwick-Field and Ms. K. Ando for their help in the preparation of the manuscript. This work was supported by grants from Gakunai Zyosei in Kansai Medical University; a grant from the Haiteku Research Center of the Ministry of Education; a grant from Millennium of the Ministry of Education, Culture, Sports, Science and Technology; grants-in-aid for scientific research (B) 11470062 and (Hoga) 16659107; grants-in-aid for scientific research on priority areas (A) 10181225 and (A) 1162221 and Health and Labor Science research grants (Research on Human Genome, Tissue Engineering Food Biotechnology); a grant from the Science Frontier program of the Ministry of Education, Culture, Sports, Science and Technology; a grant from the the 21st Century COE Program of the Ministry of Education, Culture, Sports, Science and Technology; a grant from the Department of Transplantation for Regeneration Therapy (sponsored by Otsuka Pharmaceutical Company, Ltd.); a grant from Molecular Medical Science Institute, Otsuka Pharmaceutical Co., Ltd.; and a grant from Japan Immunoresearch Laboratories Co., Ltd. (JIMRO).
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REFERENCES
|
|---|
- Thomas ED, Blume KG. Historical markers in the development of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 1999;5:341–346.[CrossRef][Medline]
- Weiden PL, Flournoy N, Thomas ED et al. Antileukemic effect of graft-versus-host diseases in human recipients of allogeneic-marrow grafts. N Engl J Med 1979;300:1068–1073.[Abstract]
- Ben-Yosef R, Or R, Nagler A et al. Graft-versus-tumor and graft-versus-leukaemia effect in patient with concurrent breast cancer and acute myelocytic leukaemia. Lancet 1996;348:1242–1243.[Medline]
- Eibl B, Schwaigofer H, Nachbaur D et al. Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. Blood 1996;88:1501–1508.[Abstract/Free Full Text]
- Ueno NT, Rondon G, Mirza NQ et al. Allogeneic peripheral-blood progenitor-cell transplantation for poor-risk patients with metastatic breast cancer. J Clin Oncol 1998;16:986–993.[Abstract]
- Childs RW, Clave E, Tisdale J et al. Successful treatment of metastatic renal cell carcinoma with a nonmyeloablative allogeneic peripheral-blood progenitor-cell transplant: evidence for a graft-versus-tumor effect. J Clin Oncol 1999;17:2044–2049.[Abstract/Free Full Text]
- Childs R, Chernoff A, Contentin N et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000;343:750–758.[Abstract/Free Full Text]
- Appelbaum FR, Sandmaier B. Sensitivity of renal cell cancer to nonmyeloablative allogeneic hematopoietic cell transplantation: unusual or unusually important? J Clin Oncol 2002;20:1965–1967.[Free Full Text]
- Bregni M, Dodero A, Peccatori J et al. Nonmyeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with meta-static renal and breast cancer. Blood 2002;99:4234–4236.[Abstract/Free Full Text]
- Hentschke P, Barkholt L, Uzunel M et al. Low-intensity conditioning and hematopoietic stem cell transplantation in patients with renal and colon carcinoma. Bone Marrow Transplant 2003;31:253–261.[CrossRef][Medline]
- Rini BI, Zimmerman T, Stadler WM et al. Allogeneic stem-cell transplantation of renal cell cancer after nonmyeloablative chemotherapy: feasibility, engraftment, and clinical results. J Clin Oncol 2002;20:2017–2024.[Abstract/Free Full Text]
- Kushida T, Inaba M, Hisha H et al. Intra-bone marrow injection of allogeneic bone marrow cells: a powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice. Blood 2001;97:3292–3299.[Abstract/Free Full Text]
- Nakamura K, Inaba M, Sugiura K et al. Enhancement of allogeneic hematopoietic stem cell engraftment and prevention of GvHD by intra-bone marrow-bone marrow transplantation plus donor lymphocyte infusion. STEM CELLS 2004;22:125–134.[Abstract/Free Full Text]
- Vremec D, Pooley J, Hochrein H et al. CD4 and CD8 expression by dendritic cell subtype in mouse thymus and spleen. J Immunol 2000;164:2978–2986.[Abstract/Free Full Text]
- McLella AD, Kampgen E. Functions of myeloid and dendritic cells. Immunol Lett 2000;72:101–105.[CrossRef][Medline]
- Kushida T, Inaba M, Hisha H et al. Crucial role of donor-derived stromal cells in successful treatment for intractable autoimmune diseases in MRL/lpr mice by BMT via portal vein. STEM CELLS 2001;19:226–235.[Abstract/Free Full Text]
- Hashimoto F, Sugiura K, Inoue K et al. Major histocompatibility complex restriction between hematopoietic stem cells and stromal cells in vivo. Blood 1997;89:49–54.[Abstract/Free Full Text]
- Sugiura K, Hisha H, Ishikawa J et al. Major histocompatibility complex restriction between hematopoietic stem cells and stromal cells in vitro. STEM CELLS 2001;19:46–58.[Abstract/Free Full Text]
- Kuroiwa T, Kakishita E, Hamano T et al. Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function. J Clin Invest 2001;107:1365–1373.[Medline]
- Nicola MD, Carlo-Stella C, Magni M et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002;99:3838–3843.[Abstract/Free Full Text]
- Takeuchi K, Inaba M, Miyashima S et al. A new strategy for treatment of autoimmune diseases in chimeric resistant MRL/lpr mice. Blood 1998;91:4616–4623.[Abstract/Free Full Text]
- Kim YM, Mapara MY, Down JD et al. Graft-versus-host-reactive donor CD4 cells can induce T cell-mediated rejection of the donor marrow in mixed allogeneic chimeras prepared with nonmyeloablative conditioning. Blood 2004;103:732–739.[Abstract/Free Full Text]
- Champlin R, Ho W, Gajewski J et al. Selective depletion of CD8+ T lymphocytes for prevention of graft-versus-host disease after allogeneic bone marrow transplantation. Blood 1990;76:418–423.[Abstract/Free Full Text]
- Giralt S, Hester J, Huh Y et al. CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood 1995;86:4337–4343.[Abstract/Free Full Text]
- Alyea EP, Soiffer RJ, Canning C et al. Toxicity and efficacy of defined doses of CD4+ donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood 1998;91:3671–3680.[Abstract/Free Full Text]
Received September 30, 2004;
accepted for publication November 29, 2004.
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Abstract
Introduction
