Original Article
Brief Report
Donor-Derived Long-Term Multilineage Hematopoiesis in a Liver-Transplant Recipient
N Engl J Med 1993; 328:762-765March 18, 1993
- Article
Graft-versus-host disease (GVHD) has been well documented in several recipients of liver transplants1-8. In this syndrome alloreactive cells from the donor attack the recipient's skin, gastrointestinal tissue, and hematopoietic tissue. Severe myelosuppression commonly results, but there has been a degree of recovery of hematopoiesis in some patients after immunosuppressive therapy. The recovery of hematopoiesis resulted from the recovery of the recipient's bone marrow in some cases,1,3 but it also could be due to the proliferation of hematopoietic precursor cells in the donor's liver, since the liver is a site of hematopoiesis in fetuses and, under certain circumstances, in adults. We investigated this possibility in a liver-transplant recipient in whom hematopoiesis recovered after treatment of GVHD. We found that the hematopoiesis in our patient derived from stem cells present in the donor's liver.
Case Report
A 65-year-old woman with cryptogenic cirrhosis received an orthotopic liver transplant from a 17-year-old boy. The recipient had no history, physical findings, or laboratory evidence suggestive of immunodeficiency. Immunosuppression after transplantation consisted of cyclosporine, prednisolone, and azathioprine. All blood products for transfusions were irradiated (2500 cGy). Twelve days after transplantation, the white-cell count decreased to 3200 per cubic millimeter and continued to decline thereafter. By day 23 after transplantation, the white-cell count was 1000 per cubic millimeter, and treatment with granulocyte colony-stimulating factor was begun. By day 32, however, the white-cell count had decreased to 300 per cubic millimeter, and the patient had become dependent on platelet and red-cell transfusions. The cellularity of the bone marrow was 5 percent. HLA typing of peripheral-blood mononuclear cells demonstrated only the phenotype of the donor. A presumptive diagnosis of GVHD was made, although the only other manifestation of GVHD was a faint macular rash over the upper part of the trunk. Treatment of GVHD was begun on day 32 and consisted of methylprednisolone (at an initial dose of 5 mg per kilogram of body weight per day, with a rapid tapering of the dose to 1 mg per kilogram per day) and Minnesota antilymphocyte globulin (10 mg per kilogram per day). The patient responded rapidly to treatment. On day 43 the white-cell count was 9100 per cubic millimeter, with 89 percent neutrophils; treatment with antilymphocyte globulin and granulocyte colony-stimulating factor was discontinued. For four weeks the patient did not need platelet transfusions. The white-cell count ranged from 2000 to 10,000 per cubic millimeter for the remainder of the patient's course. About 90 days after the transplantation, her clinical status began to decline. By day 128 bloody diarrhea and a faint macular rash over the upper part of the trunk had developed, suggesting a flare of GVHD. The dose of methylprednisolone was increased to 3 mg per kilogram per day. Although the diarrhea and rash improved, the patient's overall clinical status continued to deteriorate, and she died on day 135.
Postmortem examination showed pulmonary infection with cytomegalovirus, enterovirus, Torulopsis glabrata, and Enterobacter cloacae. Histologic examination of the small and large bowels suggested GVHD, with loss of the normal villous architecture and infiltration of the lamina propria by reactive lymphocytes and plasma cells. There was no histologic evidence of liver rejection. The cellularity of the bone marrow was 50 percent, with trilineage maturation. There was no evidence of extramedullary hematopoiesis.
Methods
HLA Typing and Analysis of Restriction-Fragment-Length Polymorphisms
Mononuclear cells were obtained from the donor's lymph nodes, the recipient's peripheral blood at various times, and the recipient's spleen, liver, and lymph nodes post mortem. Typing of HLA class I and II antigens was performed by a standard microcytotoxic assay with a two-color fluorescent technique. High-molecular-weight DNA was prepared from samples of peripheral blood and bone marrow. Analysis of restriction-fragment-length polymorphisms (RFLPs) was then carried out as previously described,9 with five highly polymorphic probes (Collaborative Diagnostics, Waltham, Mass.).
Analysis of Hematopoietic Progenitor Cells by Flow Cytometry and Cell Culture
Bone marrow cells were isolated and analyzed by flow cytometry as previously described10,11. Uncommitted stem cells and early committed progenitor cells were stained with anti-CD34 antibodies labeled with fluoroscein isothiocyanate, anti-CD38 antibodies labeled with phycoerythrin, and either anti-HLA-DR antibodies labeled with peridinin chlorophyll protein or anti-HLA-DR antibodies labeled with biotin followed by incubation with streptavidin allophycocyanin, before analysis and cell sorting (FACScan and FACStarPlus, Becton Dickinson Immunocytometry Systems, San Jose, Calif.). Myeloid, erythroid, and lymphoid progenitor cells were labeled with lineage-defining panels of immunofluorescent antibodies. The degree of forward and orthogonal light scattering and the presence of three fluorescence signals were determined for each cell. In addition, the cells were sorted directly onto a slide for sex-chromosome analysis or were sorted singly into 96-well flat-bottomed plates for culture to detect primitive hematopoietic blasts, as described previously11. Each well contained a mixture of alpha medium (Terry Fox Laboratory, Vancouver, B.C., Canada), β-fibroblast growth factor, insulin-like growth factor I, and several hematopoietic growth factors. The cultures were incubated in 5 percent carbon dioxide in air at 37 °C in a humidified incubator. The plates were examined on days 7 through 14 for the appearance of colonies.
Sex-Chromosome Analysis with Fluorescence in Situ Hybridization
Fluorescence in situ hybridization was performed as previously described12,13 on smears of bone marrow, directly sorted progenitor cells, and differentiated progeny derived from sorted single progenitor cells in the culture system described above. The bone marrow smears were stained with Wright's stain, and the cells were photographed; their location on the slides was noted with a graduated microscope stage. After the slides were denatured in formamide, probes for sex chromosomes were denatured separately, applied to the slides under coverslips, and allowed to anneal overnight. The probes used for hybridization included a probe labeled with Spectrum Orange dye that reacted with the centromere repeat sequences on the X chromosome (Imagenetics, Naperville, Ill.) and a biotinylated probe that detected the centromere of the Y chromosome (Oncor, Gaithersburg, Md.). The samples were washed, and fluorescein-labeled avidin (Vector, Burlingame, Calif.) was used to detect the biotinylated Y-chromosome probe. The previously photographed cells were relocated and were considered to be male if X and Y signals were identified and to be female if two X signals but no Y signal was seen. In addition to scoring photographed cells, we scored 200 to 400 other cells at random. Peripheral blood from normal women and men was used as a control. Additional hybridizations with the same probes were performed on frozen sections of spleen, lymph node, and lung obtained at autopsy and fixed with methanol-acetic acid.
Fluorescence in situ hybridization of sorted progenitor cells and cultured cells was carried out as described above, but different probes were used (provided by Kathy Yokobata, Becton Dickinson): a fluorescein isothiocyanate-labeled probe specific for the Y chromosome and a digoxigenin-labeled probe specific for the X chromosome. Anti-digoxigenin antibody conjugated to rhodamine was used to detect the X probe.
Results
HLA Typing and RFLP Analysis
The donor's HLA type was A2,24;B44,60;Bw4,w6;-Cw4,-;DR4,w8;DQw3,-;DRw52,53. The recipient's HLA type was A2,3;B7,44;Bw4,w6;DRw13,w14; DQw1,w6;DRw52 before transplantation. After transplantation, on days 32, 46, 53, 74, 81, 88, 95, 102, 109, and 129, HLA typing demonstrated only the donor's HLA type. Mononuclear cells obtained post mortem from abdominal and thoracic lymph nodes, liver, and spleen showed only the donor's HLA type.
On day 39, RFLP analysis of peripheral-blood cells showed that 90 to 95 percent of DNA was derived from the donor and only 5 to 10 percent was derived from the recipient. RFLP analysis of peripheral-blood cells and bone marrow cells on day 59 showed that approximately 75 percent of the DNA was derived from the donor, and 25 percent derived from the recipient. Subsequent RFLP analyses of peripheral-blood cells (on days 85 and 113) and bone marrow cells (on day 120) showed that at least 95 percent of the DNA was derived from the donor.
Sex-Chromosome Analysis of Differentiated Cells
Study of the control specimens indicated that fluorescence in situ hybridization could detect male and female cells with a high degree of accuracy; no signals for the Y chromosome were seen in any of the cells in the specimens from normal women, and both red and green signals, indicating an XY genotype, were seen in 96 percent of the cells from normal men. On the first analysis of the patient's bone marrow (results pooled from days 59 and 66), 74 percent of the cells were male (Figure 1Figure 1
Sex-Chromosome Analysis of Bone Marrow Cells from a Woman Who Received a Liver Transplant from a Teenage Boy.). The percentage of male cells differed among the various types of cells. Monocytes and macrophages, which were increased in number and present in small clusters, were over 90 percent male. Seventy-five percent of the lymphocytes and 66 percent of the granulocytes were male. Fifty-six percent of the nucleated red cells were male, and these types of cells were present in small groups of all-male or all-female cells. There were decreased numbers of megakaryocytes, but all 12 megakaryocytes studied were female. The second (day 101) and third (day 129) analyses showed that nearly all the bone marrow cells (>98 percent) were male (Figure 1). Megakaryocytes were rare in these specimens; however, the two studied were male.In frozen-tissue sections obtained post mortem and fixed with methanol-acetic acid, virtually all the cells in the sections of the spleen and lymph node were male. Sections from the lung contained both male and female cells, although it was not possible to correlate these results with histologic findings.
Analysis of Hematopoietic Progenitor Cells
Flow-cytometric analysis of bone marrow obtained on day 121 revealed only a few CD34+ progenitor cells (<1 percent). Among the CD34+ progenitor cells were uncommitted stem cells (CD34+, CD38-, HLA-DR-/+) and committed progenitor cells (CD34+, CD38+, HLA-DR+) (Figure 2AFigure 2
Flow-Cytometric Analysis of Stem Cells and Progenitor Cells in the Recipient's Bone Marrow Obtained on Day 121., 2B, and 2C). The maturation of neutrophils, monocytes, and erythrocytes, as assessed by flow cytometry, was normal. The frequency of B lymphocytes and B-cell progenitors was low. Sex-chromosome analysis (Figure 2D) of sorted bone marrow cells showed that among the uncommitted stem cells (CD34+, CD38-, HLA-DR-/+) there were XX as well as XY cells. Among the committed cells (CD34+, CD38+, HLA-DR+), early myeloid cells (CD33+, CD15±), late myeloid cells (CD33+, CD15+), erythroid cells (CD71+, CD45-), and T cells (CD3+, CD19-), the majority had X and Y chromosomes. In the culture assay, the clonal plating efficiency of single sorted cells was 88 percent among uncommitted stem cells (CD34+, CD38-, HLA-DR-/+) and 25 percent among committed progenitor cells (CD34+, CD38+, HLA-DR+). Colonies from the CD34+, CD38-, HLA-DR-/+ fraction were probed for the presence of cells containing XX or XY chromosomes. Fifty percent of the colonies were female, and 50 percent were male.Discussion
We found that stem cells with pluripotent function were present in the transplanted liver. These cells may have been normal residents of the liver, since hematopoiesis occurs in the fetal liver14 and in the adult liver under certain circumstances,15 and since hematopoietic stem cells have been detected in the liver of normal adult mice16. Since these cells circulate,17 however, they may have been derived from peripheral blood in the liver at the time of transplantation; although donor livers are extensively perfused before transplantation, small amounts of blood probably remain in the organ and associated lymphoid tissue.
Donor cells migrated to the bone marrow, spleen, lymph nodes, and lungs. Donor cells with the phenotype of hematopoietic stem cells (CD34+, CD38-, HLA-DR-/+)11 were identified in the bone marrow. These cells gave rise to mature donor cells of several hematopoietic lineages, and multilineage donor-derived hematopoiesis persisted for more than four months after transplantation. The donor uncommitted stem cells may have had lymphopoietic potential, since they had the phenotype of cells shown in other studies11 to have full lymphohematopoietic potential (CD34+, CD38-, HLA-DR-/+). It is possible, however, that the male lymphocytes detected in the recipient were long-lived mature cells that had migrated from the transplanted liver. Stem cells from the recipient also were detected. Although their contribution to hematopoiesis was substantial soon after recovery from GVHD, it was very limited later in the course. In summary, sufficient numbers of hematopoietic stem cells were present in the donor liver to give rise to long-term multilineage hematopoiesis in a patient whose lymphohematopoietic system had been severely suppressed by GVHD and immunosuppressive medications.
Supported in part by the Delta Delta Delta Cancer Research Fund and by a grant from the auxiliary board of the Cancer Research Center, University of Chicago. Dr. Anastasi is a special fellow of the Leukemia Society of America.
We are indebted to Dr. Michael Bennett for helpful discussions and to Ms. Ilona Lopez for assistance in the preparation of the manuscript.
Source Information
From Bone Marrow Transplantation Research (R.H.C., J.W.F.) and Immunology (A.N., M.J.S.), Charles A. Sammons Cancer Center, and Transplantation Services (G.K.), Baylor University Medical Center, Dallas; the Department of Hematopathology, University of Chicago, Chicago (J.A., J.F.); and Becton Dickinson Immunocytometry Systems, San Jose, Calif. (L.W.M.M.T.).
Address reprint requests to Dr. Collins at Bone Marrow Transplantation Research, Baylor University Medical Center, Sammons Tower, Suite 410, 3409 Worth St., Dallas, TX 75246.
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