Home > Cancer and Treatments > BMT Overview
The mission of the University of Michigan BMT Program is to create the "State of the Art" in BMT.
This goal is fostered by active programs both in basic immunobiology of BMT and in clinical research.
A major emphasis of both
clinical and
basic research programs
is the use of
allogeneic BMT to cure hematologic malignancies (e.g. leukemias and lymphomas).
This research focus is stimulated by our active clinical allogeneic BMT program, which is one of the largest
in the country (almost 150 transplants from family members and unrelated volunteer donors per year).
see also on this page:
Basic BMT Research Program
Acute Pulmonary dysfunction
Acute Pulmonary dysfunction remains a frequent and severe complication of BMT and limits the broader application
of this form of therapy. Lung injury can occur early (within weeks) or months after BMT. In approximately 50% of
the cases, no infection is identified in the lungs of affected patients and these cases are called idiopathic
(cause unknown).
Perhaps the most striking feature of idiopathic pneumonia is it's overall impact on survival; 50% to 90% of
our patients who develop this complication die early after BMT. Data has identified two pathways of lung injury:
one involving inflammatory proteins called
cytokines (specifically a cytokine called TNF) and the other driven by effector cells
called lymphocytes.
Lymphocytes are present in the donor bone marrow and can recognize and destroy tissues in the recipient.
These findings support a shift in the way physicians think about non-infectious "idiopathic" pneumonia
after BMT and have lead to a significant change in our treatment strategy for this complication. In a series of
three pediatric patients, a Enbrel (Immunex Corp., Seattle, WA), an FDA approved TNFa neutralizing agent, was
admininstered to patients with idiopathic pneumonia. The administration of Enbrel, in combination with standard
immunosuppressive therapy, was well tolerated and associated with significant improvements in pulmonary dysfunction
within the first week of therapy.
These preliminary data suggest that Enbrel may represent a safe and novel therapeutic option for patients
with idiopathic pneumonia and have formed the basis for two ongoing clinical trials at the University of Michigan
using Enbrel for both acute and chronic lung injury after BMT. We hope that ongoing laboratory research will
continue to translate into novel and improved treatment or prevention strategies for our BMT patient with lung
dysfunction.
Yanik, G., Hellerstedt, B., Custer, J., Hutchinson, R., Ferrara, J.L.M., Kwon, D., Uberti, J., and Cooke, K.R.
Etanercept as a novel therapy for Idiopathic Pneumonia Syndrome after allogeneic bone marrow transplantation.
In Press, Biol Blood Marrow Transplant.
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Allogeneic and Autologous BMT as Treatments for Multiple Myeloma Patients
In a recent study we compared allogeneic and autologous BMT as treatments for multiple myeloma patients who received
identical conditioning regimens of total marrow irradiation, busulfan and cyclophosphamide. Patients in the
autologous group (n=35) received peripheral blood stem cells mobilized with cyclophosphamide 4 gm/m2.
Patients in the allogeneic groups (n=21) received bone marrow or peripheral blood stem cells from HLA matched
or one-antigen mismatched (n=1) siblings. At two years both overall survival (66% v. 42%, p=.039) and progression-
free survival (60% vs 30% p=0.19) favored the allogeneic group, but numbers were too small to reach statistical
significance. The probability of disease progression was significantly lower in the allogeneic group (11% v 64%,
p<0.001) and overall survival at three years was significantly improved in the allogeneic group for patients under
age 50 (79% v 29%, p =0.03).
Thus allogeneic BMT reduces disease progression and may prolong progression-free and overall survival compared to
autologous BMT for patients with multiple myeloma.
Reynolds C, Ratanatharathorn V, Adams P, Braun T, Silver S, Ayash L, Carson E, Eisbruch A, Dawson LA,
McDonagh K, Ferrara JLM, Uberti J. Allogeneic Stem Cell Transplantation Reduces Disease Progression Compared to
Autologous Transplantation in Patients with Multiple Myeloma. Bone Marrow Transplantation,
27:801-807, 2001.
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The Anti-CD20 Monoclonal Antibody (Rituximab
In another publication, our team reported the use of an anti-CD20 monoclonal antibody (Rituximab)
to treat refractory immune mediated thrombocytopenia in a patient with chronic GVHD. This patient experienced
chronic GVHD after an allogeneic peripheral blood stem cell transplant from a sibling and developed severe
thrombocytopenia with platelet counts of less than 5 x 109/L that eventually became refractory to all
therapy including steroids, mycophenolate, tacrolimus, splenectomy, vincristine, and cyclophosphamide.
Platelet associated antibodies were detected and because B cell dysregulation may underline the autoimmune
aspects of this disease, treatment with anti-CD20 chimeric monoclonal antibody (Rituximab) was initiated.
Four weekly doses of Rituximab resulted in prolonged depletion of B cells disappearance of the platelet-associated
antibody, and return of platelet count to greater than 400 x 109/L. All immunosuppressive medication was eventually
tapered without a drop in platelet counts or flare of GVHD, and B cell numbers returned to normal.
This result suggests a potential use for Rituximab in certain cases of chronic GHVD.
Ratanatharathorn V, Carson E, Reynolds C, Ayash LJ, Levine J, Yanik G, Silver S, Ferrara JLM,
Uberti J. Anti-CD20 Chimeric Monoclonal Antibody Treatment of Refractory Immune-Mediated Thrombocytopenia in a
Patient with Chronic Graft-versus-Host Disease. Annals of Internal Medicine, 133:275-279, 2000.
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Back row, from left: Krystyna Olkiewicz, Tamatsu Ichiba, Rainer Ordemann, Amy Tesolin,
Ken Cooke, Ulrich Duffner, Debbie Williams
Front row, from left: Shawn Clouthier, Jamie Ferrara, Takanori Teshima
Acute graft versus host disease
Dr. Ferrara's laboratory investigates the immunobiology of bone marrow
transplantation. A major therapeutic benefit of allogeneic BMT resides in the graft versus leukemia (GVL)
effect which is mediated by cytotoxic pathways of cytolytic T cells and natural killer cells. The GVL effect
is tightly linked to graft versus host disease (GVHD), a major toxicity of BMT. Using well defined mouse models,
our research has shown that cascades of inflammatory cytokines amplify GVHD and that blockade of cascade checkpoints
can prevent GVHD. Furthermore, many of these anti-inflammatory strategies preserves cytolytic T lymphocyte function,
permitting a separation of GVL and GVHD in well defined animal models.
Alloantigen Expression on Host Antigen-presenting Cells
Alloantigen expression on host antigen-presenting cells (APCs) is essential to initiate acute graft-versus-host
disease (GVHD), and alloantigen expression on host target epithelium is therefore also thought to be essential for
tissue damage. We tested this assumption in mouse models of GVHD using bone marrow chimeras in which either MHC II
or MHC I alloantigen was expressed only on APCs. We found that both clinical and pathologic acute GVHD does not
require alloantigen expression on host target epithelium and that neutralization of tumor necrosis factor-?
and interleukin-1 prevents acute GVHD. These results pertain particularly to CD4-mediated GVHD but also apply,
at least in part, to CD8-mediated GVHD. These results challenge current paradigms about the antigen specificity of
GVHD effector mechanisms and confirm the central roles of both host APCs and inflammatory cytokines in acute GVHD,
suggesting new strategies to prevent this serious complication of allogeneic BMT.
Teshima T, Rainer O, Reddy P, Svetlana G, Liu C, Cooke KR, Ferrara JLM.
Acute graft-versus-host disease does not require alloantigen expression on host epithelium.
Nature Medicine (this link will open in a second browser window), in press.
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Explorations in the Mechanisms of GVHD on older BMT Recipients
Older BMT recipients are at greater risk for acute graft-versus-host-disease (GVHD) after allogeneic bone marrow transplantation (BMT), but the causes of this association are poorly understood. Using well-characterized murine BMT models we have explored the mechanisms of increased GVHD in older mice. GVHD mortality and morbidity, and pathologic and biochemical indices were all worse in old recipients. Donor T cell responses were significantly increased in old recipients both in vivo and in vitro when stimulated by antigen-presenting cells (APCs) from old mice, which also secreted more TNF-a and IL-12 after LPS stimulation. In an experimental model of GVHD to both major and minor histocompatibility antigens, CD4+ donor T cells, but not CD8+ T cells, mediated more severe GVHD in old mice. We confirmed the role of aged APCs in GVHD using BM chimeras created with either old or young BM as recipients. Four months after chimera creation allogeneic BMT caused significantly worse GVHD in old BM-chimeras. APCs from these mice also stimulated greater responses from allogeneic cells in vitro. These data demonstrate a hitherto unsuspected mechanism of amplified donor T cell responses by aged allogeneic host APCs that increases acute GVHD in aged recipients in this BMT model and suggest a new approach to reduce this morbidity of BMT.
Ordemann R, Hutchinson R, Friedman J, Burakoff SJ, Reddy P, Duffner U, Braun TM, Liu C, Teshima T, Ferrara JLM. Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease. Journal of Clinical Investigation (this link will open in a second browser window), 109:1249-1256, 2002.
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Interleukin (IL)-18
Interleukin (IL)-18 is a recently discovered cytokine that modulates
both T helper type 1 (Th1) and Th2 responses. IL-18 is elevated during GVHD. We investigated the role of IL-18 in
this disorder using a well-characterized murine BMT model of GVHD to both major and minor histocompatibility antigens.
Surprisingly, blockade of IL-18 accelerated acute GVHD-related mortality. In contrast, administration of IL-18 reduced
serum tumor necrosis factor (TNF)- a and lipopolysaccharide (LPS) levels, decreased intestinal histopathology, and resulted in significantly improved survival (75 vs. 15%, P < 0.001). Administration of IL-18 attenuated early donor T cell expansion and was associated with increased Fas (CD95) expression and greater apoptosis of donor T cells. The administration of IL-18 no longer protected BMT recipients from GVHD when Fas deficient (lpr) mice were used as donors. IL-18 also lost its ability to protect against acute GVHD when interferon (IFN)-? knockout mice were used as donors. Together, these results demonstrate that IL-18 regulates acute GVHD by inducing enhanced Fas-mediated apoptosis of donor T cells early after BMT, and donor IFN-? is critical for this protective effect. These findings suggest new strategies for preventing acute GVHD after allegeneic BMT.
Reddy P, Teshima T, Kukuruga M, Ordeman R, Liu C, Lowler K, Ferrara JLM. Interleukin-18 Regulates Acute Graft-Versus-Host Disease by enhancing Fas-mediated Donor T Cell Apoptosis, Journal of Experimental Medicine (this link will open in a second browser window), 194: 1433-1440, 2001
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-updated 5/02
