Original Article
Chimerism after Liver Transplantation for Type IV Glycogen Storage Disease and Type 1 Gaucher's Disease
N Engl J Med 1993; 328:745-749March 18, 1993
- Abstract
Background
Liver transplantation for type IV glycogen storage disease (branching-enzyme deficiency) results in the resorption of extrahepatic deposits of amylopectin, but the mechanism of resorption is not known.
Methods
We studied two patients with type IV glycogen storage disease 37 and 91 months after liver transplantation and a third patient with lysosomal glucocerebrosidase deficiency (type 1 Gaucher's disease), in whom tissue glucocerebroside deposition had decreased 26 months after liver replacement, to determine whether the migration of cells from the allograft (microchimerism) could explain the improved metabolism of enzyme-deficient tissues in the recipient. Samples of blood and biopsy specimens of the skin, lymph nodes, heart, bone marrow, or intestine were examined immunocytochemically with the use of donor-specific monoclonal anti-HLA antibodies and the polymerase chain reaction, with preliminary amplification specific to donor alleles of the gene for the beta chain of HLA-DR molecules, followed by hybridization with allele-specific oligonucleotide probes.
Results
Histopathological examination revealed that the cardiac deposits of amylopectin in the patients with glycogen storage disease and the lymph-node deposits of glucocerebroside in the patient with Gaucher's disease were dramatically reduced after transplantation. Immunocytochemical analysis showed cells containing the HLA phenotypes of the donor in the heart and skin of the patients with glycogen storage disease and in the lymph nodes, but not the skin, of the patient with Gaucher's disease. Polymerase-chain-reaction analysis demonstrated donor HLA-DR DNA in the heart of both patients with glycogen storage disease, in the skin of one of them, and in the skin, intestine, blood, and bone marrow of the patient with Gaucher's disease.
Conclusions
Systemic microchimerism occurs after liver allotransplantation and can ameliorate pancellular enzyme deficiencies.
Media in This Article
Figure 1
Endomyocardial Tissue from Patient 2, with Type IV Glycogen Storage Disease.Figure 2
Sections of Lymph Nodes from Patient 3, with Type 1 Gaucher's Disease.Article Activity
- Article
In patients with type IV glycogen storage disease, deficiency of the branching enzyme α-1,4-glucan:α-1,4-glucan 6-glucosyltransferase is responsible for the accumulation in the liver and elsewhere of an insoluble and irritating amylopectin-like polysaccharide1. We recently described the absorption of this amylopectin from the extrahepatic tissues after liver transplantation,2 leading Howell to predict that an explanation of the benefit would “clearly teach us a great deal about transplantation”3. That prediction has been shown to be accurate by our observation in this study that patients with type IV glycogen storage disease in whom liver transplantation was successful became chimeras: the cells of the host organs became mixed with cells of the donor genome that had migrated from the allograft into the tissues of the recipient and apparently served as enzyme carriers. We also found evidence of similar chimerism and consequent metabolic benefits after liver transplantation in a patient who had type 1 Gaucher's disease, a disorder caused by a deficiency of the lysosomal enzyme beta-glucocerebrosidase4.
Case Reports
Patients 1 and 2 (Type IV Glycogen Storage Disease)
In April 1992, biopsy specimens of liver, endomyocardium, and skin were obtained from Patients 1 and 2, two brothers with type IV glycogen storage disease who had undergone liver replacement for hepatic failure 91 and 37 months earlier2. The patients were 31 and 20 months old at the time of transplantation and were subsequently treated with cyclosporine and prednisone. Their physical and intellectual development has been steady since the operation.
Patient 3 (Type 1 Gaucher's Disease)
The diagnosis of type 1 Gaucher's disease in Patient 3 (who was 20 years old in 1992) was proved by biopsy of a lytic lesion on the femoral neck of his left leg at the age of 4 years, and was confirmed by study of his spleen, which was removed at the age of 6. From 1979 to 1982 he was treated every six to eight weeks with unmodified human placental glucocerebrosidase (8 units per kilogram of body weight intravenously) at the National Institutes of Health. From November 1989 to January 1990 he was treated every two weeks with macrophage-targeted human placental glucocerebrosidase (30 units per kilogram intravenously; Ceredase, Genzyme, Cambridge, Mass.). There was no evidence of benefit during either period of enzyme treatment.
Because of hepatic failure and recurrent bleeding from esophageal varices, the patient underwent orthotopic liver transplantation in April 1990. Thereafter, he was treated with FK 506 and prednisone. His liver function has been normal since then, and his severe preexisting muscle weakness has steadily improved. In July 1990, three months after liver transplantation, enzyme treatment was resumed. In June 1992, 26 months after liver replacement, biopsy specimens were obtained from the allograft, skin, lymph node, jejunum (by endoscopy), and iliac-crest bone marrow.
Methods
The transplantation and biopsy procedures were considered essential for optimal care of all three patients and were performed with their parents' consent. Tissues were fixed in 10 percent formalin for conventional staining and frozen in Optimum Cold Temperature medium (OCT, Tissue-Tek, Ames Division, Miles Laboratories, Elkhart, Ind.) for immunocytochemical evaluation or in liquid nitrogen for DNA typing. Gaucher's cells and amylopectin inclusions were examined by light microscopy after staining with periodic acid-Schiff stain (PAS) with and without diastase digestion (PAS-D).
Immunocytochemical Evaluation
The HLA types of the three donors were determined at the time of organ procurement (September 1984 in the donor for Patient 1, March 1989 in the donor for Patient 2, and April 1990 in the donor for Patient 3). The HLA types of the recipients were determined just before transplantation. After investigators established which class I and class II antigens were present in the donor but not in the recipient, monoclonal antibodies were chosen from a library (whose sources were American Tissue and Cell Culture, Genetic Synterus, Seattle, and One Lambda, Canoga Park, Calif.) and used for phenotyping of the biopsy specimens by indirect immunofluorescence and immunoperoxidase (avidin-biotin complex) methods. The liver removed at the time of transplantation was used as a negative control for donor-specific antibodies; as an additional negative-control measure, staining was carried out with irrelevant anti-HLA antibodies and omission of the primary antibody. Livers with known HLA phenotypes stained with matching anti-HLA monoclonal antibodies were used as positive controls.
Polymerase Chain Reaction
Molecular typing of the beta chain of HLA-DR molecules was performed with use of the polymerase chain reaction, according to the protocol of the 11th International Histocompatibility Workshop,5 in which preliminary amplification of the HLA-DR beta-chain gene is performed before allele-specific amplification.
Results
Histologic Studies
Patients with Glycogen Storage Disease
In the patients with glycogen storage disease neither of the liver allografts had evidence of rejection or amylopectin deposition. At the time of our previous report on these patients,2 the area of heart tissue replaced by amylopectin in the younger brother (Patient 2) had decreased from 13 to 6 percent 14 months after transplantation. A further reduction to less than 1 percent occurred during the ensuing 22 months (Figure 1Figure 1
Endomyocardial Tissue from Patient 2, with Type IV Glycogen Storage Disease.). The heart of the older brother (Patient 1) was almost free of amylopectin when the first biopsy was performed, more than 5 years after transplantation2; it appeared the same 91 months after transplantation.Patient with Gaucher's Disease
A hilar lymph node removed with the native liver from the patient with Gaucher's disease in April 1990 contained numerous glucocerebroside-filled cells that profoundly distorted the nodal architecture. An inguinal lymph node removed 26 months later contained only a few of these cells, located predominantly in the medullary sinuses (Figure 2Figure 2
Sections of Lymph Nodes from Patient 3, with Type 1 Gaucher's Disease.). A biopsy of the allograft performed 26 months after transplantation showed that the architecture of the graft was intact, with no evidence of rejection and only a few Gaucher's cells scattered in the sinusoids. Specimens of the skin and small intestine were normal, and the bone marrow contained only very few Gaucher's cells.Immunocytochemical Studies
The endothelium and bile ducts of all three patients retained the phenotypes of the donors, whereas most of the Kupffer cells of the liver were replaced by those of the recipient, as previously described6-8.
Cells of the donor phenotype were found in the hearts of both patients with glycogen storage disease (Table 1Table 1
Features of Chimerism Demonstrated by Immunocytochemical Evaluation in Recipients of Liver Grafts for Type IV Glycogen Storage Disease (Patients 1 and 2) and Type 1 Gaucher's Disease (Patient 3).). These cells constituted a minority of the interstitial cardiac cells and were seen at a density of 8 to 10 cells per square millimeter in ultrathin sections (2 micrometers) (Figure 3Figure 3
Immunocytochemical Analysis of Heart, Transplanted Liver, and Native Liver in Patient 1, with Type IV Glycogen Storage Disease.). The vascular endothelial cells of the heart were exclusively of the phenotype of the recipient. The skin of both patients contained donor cells interspersed among the cells of the basal layer of epidermis and in the periadventitial tissue of dermal blood vessels. All epidermal and vascular endothelial cells had the recipient's phenotype. Cells with the donor's phenotype could be found in the lymph nodes but not the skin of the patient with Gaucher's disease (Table 1).Polymerase Chain Reaction
Chimerism was observed in the hearts of both patients with glycogen storage disease and in the skin of one of them on polymerase-chain-reaction analysis (Table 2Table 2
Distribution of Donor HLA-DR Alleles in the Three Liver Recipients, According to Polymerase-Chain-Reaction Analysis.). The HLA type of the patient with Gaucher's disease was DR2,7, and that of the donor was DR1,11 (Table 1). When HLA-DR1-specific primers and probes were used (Figure 4Figure 4
Demonstration of Donor DNA after Transplantation in Patient 3, with Type 1 Gaucher's Disease.), the donor's DNA was found in the blood, bone marrow, skin, and small bowel of the recipient (Table 2).Discussion
The resorption of amylopectin from the heart previously reported after liver transplantation in patients with glycogen storage disease2 was confirmed by endomyocardial biopsies after additional months of follow-up. Donor cells could be detected in the biopsy specimens and other tissues of the recipients by immunocytochemical and molecular techniques 91 and 37 months, respectively, after liver replacement. Similar donor cells were also found in the skin, lymph nodes, small bowel, bone marrow, and blood of a patient with Gaucher's disease.
We have proposed elsewhere6,9,10 that the successful engraftment of all whole-organ transplants connotes (and requires) an exchange between the organ and the recipient of cells of lymphocyte-macrophage lineage. Although the same process occurs with all organs, the high density and quality of the migratory cells leaving the liver or coming to it from the recipient are thought to be the basis for the “immunologic privilege” of a hepatic graft,6,9,10 including its so-called tolerogenicity in other organs from the same donor11.
The bone marrow-derived dendritic (antigen presenting) cells delineated by Steinman and Cohn12 that are normally associated with the induction of T-cell immunity rather than the induction of tolerance13,14 are thought to be the most prominent of the migratory cells moving from the liver to distant host tissues, with replacement by similar cells of the recipient that home to the graft. The distribution of the donor cells is similar to their distribution after bone marrow transplantation6,15,16. The consequent chimerism explains why the liver allograft can cause graft-versus-host disease17-20.
The occurrence of cell migration after liver transplantation explains why patients with lysosomal storage disorders -- Wolman's disease,21 Niemann-Pick disease,22 Gaucher's disease,23 and the sea-blue histiocyte syndrome (unpublished data) -- receive more benefit from liver replacement than simply improved hepatic function24. We had assumed that the lysosomal storage disorder of our patient with Gaucher's disease would progress after transplantation, prompting us to resume enzyme therapy; we now suspect that such treatment was unnecessary. For the absorption of the intracellular and extracellular amylopectin deposits of type IV glycogen storage disease, as well as the intracellular glucocerebroside deposits of Gaucher's disease, it is necessary for the enzyme produced by the donor cells to gain access to the substrate. Evidence from in vitro coculture experiments suggests that once the donor cells have moved to the appropriate location, an enzyme can be transported from normal to abnormal cells25. The number of allogeneic cells required to produce a metabolic effect appears from our results to be surprisingly low. The presumed transmission of enzymes from a small to a larger cell population raises intriguing questions about the potential cell-to-cell transfer of other molecules, including those involved in immunologic processes.
With the fuller understanding of what is actually accomplished by liver transplantation, past conclusions about the mechanisms of inborn errors of metabolism that were deduced from studies of liver-transplant recipients will require reexamination. For example, the decline in serum cholesterol concentrations after liver transplantation in patients with familial hypercholesterolemia26 that was ascribed to the low-density lipoprotein receptors of the allograft hepatocytes27 may reflect in part the presence of these receptors on widely disseminated donor cells that are not hepatocytes. Migratory Kupffer cells alone account for 10 to 15 percent of all cells in the liver and one fifth of the total hepatic lysosomal volume28.
If, as we have proposed,6,9,10 microchimerism differing only in degree is an integral feature of the successful engraftment of any organ, all such transplantation procedures could result in a gain in metabolic function. This could explain the report by Desnick et al.29 that native kidneys that had failed as a result of the accumulation of glycosphingolipid in a patient with Fabry's disease recovered their function after successful renal transplantation.
Supported in part by a grant (DK-29961) from the National Institutes of Health.
Source Information
From the Pittsburgh Transplant Institute and the Departments of Surgery (T.E.S., C.R., S.I., N.M., A.Z., D.V.T.), Pathology (A.J.D., M.T., A.Z.), Pediatrics (M.T., M.K., W.A.R.), and Medicine (D.V.T.), University of Pittsburgh Health Science Center, Pittsburgh; UCLA Tissue Typing Laboratory, Los Angeles (P.I.T.); and the Mary Bridge Children's Hospital, Tacoma, Wash. (R.S.K.).
Address reprint requests to Dr. Starzl at the Department of Surgery, 3601 Fifth Ave., 5C Falk Clinic, University of Pittsburgh, Pittsburgh, PA 15213.
- References
References
1
Brown BI ,Brown DH . Lack of an α-1,4-glucan:α-1,4-glucan 6-glycosyl transferase in a case of Type IV glycogenosis. Proc Natl Acad Sci U S A 1966;56:725-729
CrossRef | Web of Science | Medline2
Selby R ,Starzl TE ,Yunis E ,Brown BI ,Kendall RS ,Tzakis A . Liver transplantation for Type IV glycogen storage disease. N Engl J Med 1991;324:39-42
Full Text | Web of Science | Medline3
Howell RR . Continuing lessons from glycogen storage diseases. N Engl J Med 1991;324:55-56
Full Text | Web of Science | Medline4
Brady RO ,Kanfer JN ,Bradley RM ,Shapiro D . Demonstration of a deficiency of glucocerebroside-cleaving enzyme in Gaucher's disease. J Clin Invest 1966;45:1112-1115
CrossRef | Web of Science | Medline5
Hsia S, Tong JY, Parris GL, et al. 1992 Molecular compatibility and renal graft survival: the HLA DRB1 genotyping. Transplantation (in press).
6
Starzl TE ,Demetris AJ ,Murase N ,Ildstad S ,Ricordi C ,Trucco M . Cell migration, chimerism, and graft acceptance. Lancet 1992;339:1579-1582
CrossRef | Web of Science | Medline7
Porter KA. Pathology of the orthotopic homograft and heterograft. In: Starzl TE, ed. Experience in hepatic transplantation. Philadelphia: W.B. Saunders, 1969:464-5.
8
Gouw AS ,Houthoff HJ ,Huitema S ,Beelen JM ,Gips CH ,Poppema S . Expression of major histocompatibility complex antigens and replacement of donor cells by recipient ones in human liver grafts. Transplantation 1987;43:291-296
CrossRef | Web of Science | Medline9
Starzl TE. Cell migration and chimerism: a unifying concept in transplantation: with particular reference to HLA matching and tolerance induction. Transplant Proc (in press).
10
Starzl TE ,Demetris AJ ,Trucco M , et al. Systemic chimerism in human female recipients of male livers. Lancet 1992;340:876-877
CrossRef | Web of Science | Medline11
Calne RY ,Sells RA ,Pena JR , et al. Induction of immunological tolerance by porcine liver allografts. Nature 1969;223:472-476
CrossRef | Web of Science | Medline12
Steinman RM ,Cohn ZA . Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med 1973;137:1142-1162
CrossRef | Web of Science | Medline13
Steinman RM . The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991;9:271-296
CrossRef | Web of Science | Medline14
Lechler RI ,Batchelor JR . Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells. J Exp Med 1982;155:31-41
CrossRef | Web of Science | Medline15
Demetris AJ ,Murase N ,Starzl TE . Donor dendritic cells after liver and heart allotransplantation under short-term immunosuppression. Lancet 1992;339:1610-1610
CrossRef | Web of Science | Medline16
Ricordi C ,Ildstad ST ,Demetris AJ ,Abou El-Ezz AY ,Murase N ,Starzl TE . Donor dendritic cells repopulation in recipients after rat-to-mouse bone-marrow transplantation. Lancet 1992;339:1610-1611
CrossRef | Web of Science | Medline17
Ramsey G ,Nusbacher J ,Starzl TE ,Lindsay GD . Isohemagglutinins of graft origin after ABO-unmatched liver transplantation. N Engl J Med 1984;311:1167-1170
Full Text | Web of Science | Medline18
Burdick JF ,Vogelsang GB ,Smith WJ , et al. Severe graft-versus-host disease in a liver-transplant recipient. N Engl J Med 1988;318:689-691
Full Text | Web of Science | Medline19
Comenzo RL ,Malachowski ME ,Rohrer RJ ,Freeman RB ,Rabson A ,Berkman EM . Anomalous ABO phenotype in a child after an ABO-incompatible liver transplantation. N Engl J Med 1992;326:867-870
Full Text | Web of Science | Medline20
Roberts JP ,Ascher NL ,Lake J , et al. Graft vs. host disease after liver transplantation in humans: a report of four cases. Hepatology 1991;14:274-281
CrossRef | Web of Science | Medline21
Ferry GD ,Whisennand HH ,Finegold MJ ,Alpert E ,Glombicki A . Liver transplantation for cholesteryl ester storage disease. J Pediatr Gastroenterol Nutr 1991;12:376-378
CrossRef | Web of Science | Medline22
Daloze P ,Delvin EE ,Glorieux FH ,Corman JL ,Bettez P ,Toussi T . Replacement therapy for inherited enzyme deficiency: liver orthotopic transplantation in Niemann-Pick disease type A. Am J Med Genet 1977;1:229-239
CrossRef | Web of Science | Medline23
DuCerf C ,Bancel B ,Caillon P , et al. Orthotopic liver transplantation for type 1 Gaucher's disease. Transplantation 1992;53:1141-1143
CrossRef | Web of Science | Medline24
Parkman R . The application of bone marrow transplantation to the treatment of genetic diseases. Science 1986;232:1373-1378
CrossRef | Web of Science | Medline25
Neufeld EF . Lessons from genetic disorders of lysosomes. Harvey Lect 1981;75:41-60
Web of Science26
Starzl TE ,Bilheimer DW ,Bahnson HT , et al. Heart-liver transplantation in a patient with familial hypercholesterolaemia. Lancet 1984;1:1382-1383
CrossRef | Web of Science | Medline27
Bilheimer DW ,Goldstein JL ,Grundy SM ,Starzl TE ,Brown MS . Liver transplantation provides low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia. N Engl J Med 1984;311:1658-1664
Full Text | Web of Science | Medline28
Jones EA, Summerfield SA. Kupffer cells. In: Arias IM, Popper H, Schachter D, Shafritz DA, eds. The liver: biology and pathobiology. New York: Raven Press, 1982:507-23.
29
Desnick RJ ,Simmons RL ,Allen KY , et al. Correction of enzymatic deficiencies by renal transplantation: Fabry's disease. Surgery 1972;72:203-211
Web of Science | Medline
- Citing Articles (80)
Citing Articles
1
Richard J. Thompson, Bernard C. Portmann, Eve A. Roberts. 2012. Genetic and metabolic liver disease. , 157-259.
CrossRef2
Fayez K. Ghishan. 2012. Inborn Errors of Metabolism that Lead to Permanent Liver Injury. , 1155-1201.
CrossRef3
T. Okabayashi, A. M. Cameron, M. Hisada, R. A. Montgomery, G. M. Williams, Z. Sun. (2011) Mobilization of Host Stem Cells Enables Long-Term Liver Transplant Acceptance in a Strongly Rejecting Rat Strain Combination. American Journal of Transplantation 11:10, 2046-2056
CrossRef4
Josh Levitsky. (2011) Operational tolerance: Past lessons and future prospects. Liver Transplantation 17:3, 222-232
CrossRef5
Tatsuki Mizuochi, Akihiko Kimura, Hiroshi Nishiura, Yukihiro Inomata, Hideaki Okajima, Hideo Sugie, Hiroshi Mitsubuchi, Minoru Yagi, Masayoshi Kage. (2011) Liver biopsy is an important procedure in the diagnosis of glycogen storage disease type IV. Pediatrics International 53:1, 129-130
CrossRef6
Outi E Päiväniemi, Petra Musilova, Peter M Raivio, Paula K Maasilta, Hanni S Alho, Jiri Rubes, Kristiina Aittomäki, Ulla-Stina Salminen. (2011) Ingraft chimerism in lung transplantation - a study in a porcine model of obliterative bronchiolitis. Respiratory Research 12:1, 56
CrossRef7
Shikha S. Sundaram, Estella M. Alonso. 2011. Abnormalities of Carbohydrate Metabolism and the Liver. , 795-803.
CrossRef8
Norbert Gleicher. (2010) Does the Immune System Induce Labor? Lessons from Preterm Deliveries in Women with Autoimmune Diseases. Clinical Reviews in Allergy & Immunology 39:3, 194-206
CrossRef9
Stephanie Willot, Valerie Marchand, Andree Rasquin, Fernando Alvarez, Steven R Martin. (2010) Systemic Progression of Type IV Glycogen Storage Disease After Liver Transplantation. Journal of Pediatric Gastroenterology and Nutrition 51:5, 661-664
CrossRef10
R. M. Ayto, D. A. Hughes, P. Jeevaratnam, K. Rolles, A. K. Burroughs, P. K. Mistry, A. B. Mehta, G. M. Pastores. (2010) Long-Term Outcomes of Liver Transplantation in Type 1 Gaucher Disease. American Journal of Transplantation 10:8, 1934-1939
CrossRef11
Gregory M. Pastores. (2010) Recombinant Glucocerebrosidase (Imiglucerase) as a Therapy for Gaucher Disease. BioDrugs 24:1, 41-47
CrossRef12
Partha Dutta, William J Burlingham. (2009) Tolerance to noninherited maternal antigens in mice and humans. Current Opinion in Organ Transplantation 14:4, 439-447
CrossRef13
Hye Ryun Ban, Kyung Mo Kim, Joo Young Jang, Gu-Hwan Kim, Han-Wook You, Kyungeun Kim, Eunsil Yu, Dae Yeon Kim, Ki Hun Kim, Young Joo Lee, Sung Gyu Lee, Young Nyun Park, Hong Koh, Ki Sup Chung. (2009) Living Donor Liver Transplantation in a Korean Child with Glycogen Storage Disease Type IV and a GBE1 Mutation. Gut and Liver 3:1, 60
CrossRef14
Asif N. Butt, R. Swaminathan. (2008) Overview of Circulating Nucleic Acids in Plasma/Serum. Annals of the New York Academy of Sciences 1137:1, 236-242
CrossRef15
Michael K. Davis, David A. Weinstein. (2008) Liver transplantation in children with glycogen storage disease: Controversies and evaluation of the risk/benefit of this procedure. Pediatric Transplantation 12:2, 137-145
CrossRef16
Norbert Gleicher. (2008) Missed immunological opportunities in pregnancy. Expert Review of Clinical Immunology 4:1, 1-3
CrossRef17
Thomas E. Starzl. (2007) Acquired immunologic tolerance: with particular reference to transplantation. Immunologic Research 38:1-3, 6-41
CrossRef18
Norbert Gleicher. (2007) Pregnancy-related cell traffic, microchimerism and autoimmunity: the possibility of reducing autoimmune disease prevalence. Expert Review of Obstetrics & Gynecology 2:3, 341-345
CrossRef19
Ian N. Crispe, Matthew Giannandrea, Ingo Klein, Beena John, Bradford Sampson, Sherry Wuensch. (2006) Cellular and molecular mechanisms of liver tolerance. Immunological Reviews 213:1, 101-118
CrossRef20
Yao-Wen Fu, Wei-Gang Wang, Hong-Lan Zhou, Lu Cai. (2006) Presence of donor-and-recipient-derived DNA microchimerism in the cell-free blood samples of renal transplantation recipients associates with the acceptance of transplanted kidneys. Asian Journal of Andrology 8:4, 477-482
CrossRef21
Thomas E. Starzl, Fadi G. Lakkis. (2006) The unfinished legacy of liver transplantation: Emphasis on immunology. Hepatology 43:S1, S151-S163
CrossRef22
L. Almenar Bonet, E. Zorio Grima. (2005) Miocardiopatías restrictivas. Medicine - Programa de Formación Médica Continuada Acreditado 9:42, 2775-2789
CrossRef23
Thomas E. Starzl, Noriko Murase, Anthony J. Demetris, Massimo Trucco, Bijan Eghtesad, Paulo Fontes, Kareem Abu-Elmagd, Amadeo Marcos, John J. Fung. 2005. Cell Migration, Chimerism, and Graft Acceptance, with Particular Reference to the Liver. , 1183-1198.
CrossRef24
Suzanne V. Mcdiarmid. 2005. Liver Transplantation for Metabolic Disease. , 337-366.
CrossRef25
A.J. Demetris, Mike Nalesnik, Parmjeet Randhawa, Tong Wu, Marida Minervini, Chi Lai, Zhengbin Lu. 2005. Histological Patterns of Rejection and Other Causes of Liver Dysfunction. , 1057-1128.
CrossRef26
Jean-Bernard Otte. (2004) Paediatric liver transplantation-a review based on 20 years of personal experience. Transplant International 17:10, 562-573
CrossRef27
Jean-Bernard Otte. (2004) Paediatric liver transplantation?a review based on 20 years of personal experience. Transplant International 17:10, 562-573
CrossRef28
James Robert Wendt, Tom Ulich, P. Nagesh Rao. (2004) Long-Term Survival of Human Skin Allografts in Patients with Immunosuppression. Plastic and Reconstructive Surgery 113:5, 1347-1354
CrossRef29
Tong Wu, Kathleen Cieply, Michael A. Nalesnik, Parmjeet S. Randhawa, Aurelio Sonzogni, C. Bellamy, Kareem Abu-Elmagd, George K. Michalopolous, Ronald Jaffe, Robert L. Kormos, Bruno Gridelli, John J. Fung, Anthony J. Demetris. (2003) Minimal Evidence of Transdifferentiation from Recipient Bone Marrow to Parenchymal Cells in Regenerating and Long-Surviving Human Allografts. American Journal of Transplantation 3:9, 1173-1181
CrossRef30
Gaetano Ciancio, George W. Burke, Rolando Garcia-Morales, Kiliana Suzart, Anne Rosen, Camillo Ricordi, Norma S. Kenyon, James M. Mathew, Andreas G. Tzakis, Violet Esquenazi, Joshua Miller. (2002) Effect of living-related donor bone marrow infusion on chimerism and in vitro immunoregulatory activity in kidney transplant recipients1. Transplantation 74:4, 488-496
CrossRef31
Robert J. Wendt. (2002) DETERMINATION OF SURVIVAL OF HUMAN SKIN ALLOGRAFTS. Plastic and Reconstructive Surgery 109:6, 2168
CrossRef32
Takashi Nagahama, Kikuya Sugiura, Shinryu Lee, Haruo Morita, Yasushi Adachi, A-Hon Kwon, Yasuo Kamiyama, Susumu Ikehara. (2001) A New Method for Tolerance Induction: Busulfan Administration Followed by Intravenous Injection of Neuraminidase-Treated Donor Bone Marrow. Stem Cells 19:5, 425-435
CrossRef33
Shinryu Lee, Kikuya Sugiura, Takashi Nagahama, Hiroshi Iwai, Ryoji Yasumizu, Toshio Yamashita, Susumu Ikehara. (2001) NEW METHOD FOR THYROID TRANSPLANTATION ACROSS MAJOR HISTOCOMPATIBILITY COMPLEX BARRIERS USING ALLOGENEIC BONE MARROW TRANSPLANTATION1. Transplantation 72:6, 1144-1149
CrossRef34
Elizabeth Kang, Neelam Giri, Tong Wu, Stephanie Sellers, Martha Kirby, Yutaka Hanazono, John Tisdale, Cynthia E. Dunbar. (2001) In Vivo Persistence of Retrovirally Transduced Murine Long-Term Repopulating Cells Is Not Limited by Expression of Foreign Gene Products in the Fully or Minimally Myeloablated Setting. Human Gene Therapy 12:13, 1663-1672
CrossRef35
Thomas E Starzl. (2001) The birth of clinical organ transplantation11No competing interests declared.. Journal of the American College of Surgeons 192:4, 431-446
CrossRef36
Amrik Sahota, Sujuan Gao, John Hayes, Rahul M Jindal. (2000) Microchimerism and rejection: a meta-analysis. Clinical Transplantation 14:4, 345-350
CrossRef37
Peter E. M. Butler. (2000) Neonatal Induction of Tolerance to Skeletal Tissue Allografts without Immunosuppression. Plastic & Reconstructive Surgery 105:7, 2424-2430
CrossRef38
Raymond Pollak, Jacqueline M. Blanchard. (2000) ORGAN DONOR OR GRAFT PRETREATMENT TO PROLONG ALLOGRAFT SURVIVAL: LESSONS LEARNED IN THE MURINE MODEL1. Transplantation 69:11, 2432-2439
CrossRef39
Nadia Guerra, Philippe Goettelfinger, Florence Lecerf, Sonia Berrih-Aknin, Michèle German-Fattal. (2000) Kinetic analysis of microchimerism induced by intrathymic injection of allogeneic splenocytes in mice. Transplant Immunology 8:1, 31-37
CrossRef40
Anthony A. Amato. (2000) ACID MALTASE DEFICIENCY AND RELATED MYOPATHIES. Neurologic Clinics 18:1, 151-165
CrossRef41
Katsuhiro Narumoto, Toshiji Saibara, Takashi Maeda, Saburo Onishi, Yoshihiro Hayashi, Eriko Miyazaki, Makoto Hiroi, Hideaki Enzan, Nobuaki Kobayashi. (2000) Transforming growth factor-β1 derived from biliary epithelial cells may attenuate alloantigen-specific immune responses. Transplant International 13:1, 21-27
CrossRef42
Pierre Cochat. (1999) Primary hyperoxaluria type 1. Kidney International 55:6, 2533-2547
CrossRef43
Tienan Jin, Kikuya Sugiura, Junji Ishikawa, Shinryu Lee, Haruo Morita, Takashi Nagahama, Susumu Ikehara. (1999) Persistent Tolerance Induced after Portal Venous Injection of Allogeneic Cells Plus Cyclophosphamide Treatment. Immunobiology 200:2, 215-226
CrossRef44
Jorge Reyes, George V. Mazariegos. (1999) PEDIATRIC TRANSPLANTATION. Surgical Clinics of North America 79:1, 163-189
CrossRef45
Ronald J. Sokol, William R. Treem. (1999) Mitochondria and Childhood Liver Diseases. Journal of Pediatric Gastroenterology & Nutrition 28:1, 4-16
CrossRef46
Epstein, Franklin H., , Starzl, Thomas E., Zinkernagel, Rolf M., . (1998) Antigen Localization and Migration in Immunity and Tolerance. New England Journal of Medicine 339:26, 1905-1913
Full Text47
Alessandro Aiuti, Carla Cicchini, Silvia Bernardini, Giorgio Fedele, Laura Amicone, Antonio Fantoni, Marco Tripodi. (1998) Hematopoietic support and cytokine expression of murine-stable hepatocyte cell lines (MMH). Hepatology 28:6, 1645-1654
CrossRef48
Ajai Khanna, Mary A Antonysamy, Vladimir M Subbotin, Raymond J Steptoe, Wei Li, William A Rudert, Angus W Thomson. (1998) Impact of Flt-3 ligand on donor-derived antigen presenting cells and alloimmune reactivity in heart graft recipients given adjuvant donor bone marrow. Transplant Immunology 6:4, 225-234
CrossRef49
Masanobu Terakura, Noriko Murase, Anthony J. Demetris, Qing Ye, Angus W. Thomson, Thomas E. Starzl. (1998) LYMPHOID/NONLYMPHOID COMPARTMENTALIZATION OF DONOR LEUKOCYTE CHIMERISM IN RAT RECIPIENTS OF HEART ALLOGRAFTS, WITH OR WITHOUT ADJUNCT BONE MARROW1. Transplantation 66:3, 350-357
CrossRef50
Bernd M. Spriewald, Ralf Wassmuth, Hans-Dieter Carl, Ferdinand K??ckerling, Sandra Reichstetter, Anja Kleeberger, Michael Klein, Max Werner Hohenberger, Joachim R. Kalden. (1998) MICROCHIMERISM AFTER LIVER TRANSPLANTATION. Transplantation 66:1, 77-83
CrossRef51
Eiji Kobayashi, Yoko Yoshida, Masumi Nozawa, Shuuji Hishikawa, Takeo Yamanaka, Michio Miyata, Akio Fujimura. (1998) Auxiliary heterotopic liver transplantation in the rat: A simplified model using cuff technique and application for congenitally hyperbilirubimemic Gunn rat. Microsurgery 18:2, 97-102
CrossRef52
H. Luedeck, R. Blasczyk. (1997) Fluorotyping of HLA-C: differential detection of amplicons by sequence-specific priming and fluorogenic probing. Tissue Antigens 50:6, 627-638
CrossRef53
Kikuya Sugiura, Kazunori Kato, Futoshi Hashimoto, Tienan Jin, Yasuo Amoh, Yoshihisa Yamamoto, Haruo Morita, Ko Okumura, Susumu Ikehara. (1997) Induction of donor-specific T cell anergy by portal venous injection of allogeneic cells. Immunobiology 197:5, 460-477
CrossRef54
Cynthia McSherry, Annette Jackson, Marshall I. Hertz, R. Morton Bolman, Kay Savik, Nancy L. Reinsmoen. (1996) SEQUENTIAL MEASUREMENT OF PERIPHERAL BLOOD ALLOGENEIC MICROCHIMERISM LEVELS AND ASSOCIATION WITH PULMONARY FUNCTION1. Transplantation 62:12, 1811-1818
CrossRef55
S. J. Faas, R. Menon, E. R. Braun, W. A. Rudert, M. Trucco. (1996) Sequence-specific priming and exonuclease-released fluorescence detection of HLA-DQB1 alleles. Tissue Antigens 48:2, 97-112
CrossRef56
Hisanori Mayumi, Masayoshi Umesue, Kikuo Nomoto. (1996) Cyclophosphamide-Induced Immunological Tolerance: an Overview. Immunobiology 195:2, 129-139
CrossRef57
H Jauregui. (1996) Use of mammalian liver cells for artificial liver support. Cell Transplantation 5:3, 353-367
CrossRef58
E. van Twuyver, J. de Hoop, R. J. M. ten Berge, J. M. Wilmink, S. P. M. Lems, A. P. van de Berg, M. J. H. Slooff, L. P. de Waal. (1996) COMPARISON OF T CELL RESPONSES IN PATIENTS WITH A LONG-TERM SURVIVING RENAL ALLOGRAFT VERSUS A LONG-TERM SURVIVING LIVER ALLOGRAFT. Transplantation 61:9, 1392-1397
CrossRef59
Hugo R. Rosen, Paul Martin, Gary J. Schiller, Mary Territo, David N. Lewin, Christopher R. Shackleton, Ronald W. Busuttil. (1996) Orthotopic liver transplantation for bone-marrow transplant-associated veno-occlusive disease and graft-versus-host disease of the liver. Liver Transplantation and Surgery 2:3, 225-232
CrossRef60
Thomas C. Pearson, Diane Z. Alexander, Rose Hendrix, Eric T. Elwood, Peter S. Linsley, Kevin J. Winn, Christian P. Larsen. (1996) CTLA4-Ig PLUS BONE MARROW INDUCES LONG-TERM ALLOGRAFT SURVIVAL AND DONOR-SPECIFIC UNRESPONSIVENESS IN THE MURINE MODEL. Transplantation 61:7, 997-1004
CrossRef61
Hideki Taniguchi, Tomoko Toyoshima, Katashi Fukao, Hiromitsu Nakauchi. (1996) Presence of hematopoietic stem cells in the adult liver. Nature Medicine 2:2, 198-203
CrossRef62
THOMAS E. STARZL, NORIKO MURASE, ANGUS THOMSON, ANTHONY J. DEMETRIS, SHIGUANG QIAN, ABDUL S. RAO, JOHN J. FUNG. (1995) The Bidirectional Paradigm of Transplant Immunology. Annals of the New York Academy of Sciences 770:1 Bone Marrow T, 165-176
CrossRef63
CAMILLO RICORDI, THEODORE KARATZAS, GENNARO SELVAGGI, JOSE NERY, MARC WEBB, HUGO FERNANDEZ, PHILLIP RUIZ, SHEN-SHEN KONG, VIOLET ESQUENAZI, JOSHUA MILLER, EUGENE SCHIFF, ANDREAS G. TZAKIS. (1995) Multiple Bone Marrow Infusions to Enhance Acceptance of Allografts from the Same Donor. Annals of the New York Academy of Sciences 770:1 Bone Marrow T, 345-350
CrossRef64
Daniel C. Brennan, Thalachallour Mohanakumar, M.Wayne Flye. (1995) Donor-specific transfusion and donor bone marrow infusion in renal transplantation tolerance: A review of efficacy and mechanisms. American Journal of Kidney Diseases 26:5, 701-715
CrossRef65
Philip Rosenthal, Luis Podesta, Robert Grier, Jonathan W. Said, Linda Sher, Jose Cocjin, Frederick Watanabe, Eric Vasiliauskas, Robert Van De Velde, Leonard Makowka. (1995) Failure of liver transplantation to diminish cardiac deposits of amylopectin and leukocyte inclusions in type iv glycogen storage disease. Liver Transplantation and Surgery 1:6, 373-376
CrossRef66
Gottfried O H Naumann. (1995) The Bowman Lecture. Eye 9:4, 395-421
CrossRef67
Ko Bando, Irvin L. Paradis, Shari Similo, Hiroaki Konishi, Kanshi Komatsu, Thomas G. Zullo, Samuel A. Yousem, John M. Close, Adriana Zeevi, Rene J. Duquesnoy, Jan Manzetti, Robert J. Keenan, John M. Armitage, Robert L. Hardesty, Bartley P. Griffith. (1995) Obliterative bronchiolitis after lung and heart-lung transplantation. The Journal of Thoracic and Cardiovascular Surgery 110:1, 4-14
CrossRef68
Nancy L. Ascher. (1995) Microchimerism in organ transplantation. Liver Transplantation and Surgery 1:1, 43-46
CrossRef69
Nancy L. Reinsmoen, Cynthia McSherry, Blanche Chavers, Marshall I. Hertz, Arthur J. Matas. (1995) Correlation of donor antigen-specific hyporeactivity with allogeneic microchimerism in kidney and lung recipients. Pediatric Nephrology 9:S1, S35-S39
CrossRef70
Angus W. Thomson, Lina Lu, Noriko Murase, Anthony J. Demetris, Abdul S. Rao, Thomas E. Starzl. (1995) Microchimerism, dendritic cell progenitors and transplantation tolerance. Stem Cells 13:6, 622-639
CrossRef71
IAN R. MACKAY. (1994) Hepatology in Australia. Journal of Gastroenterology and Hepatology 9:6, 638-642
CrossRef72
Thomas E. Starzl, Luis A. Valdivia, Noriko Murase, Anthony J. Demetrism, Paulo Fontes, Abdul S. Rao, Rafael Manez, Ignazio R. Marino, Satoru Todo, Angus W. Thomson, John J. Fung. (1994) The Biological Basis of and Strategies for Clinical Xenotransplantation. Immunological Reviews 141:1, 213-244
CrossRef73
Haval Shirwan, Leonard Makowka, Elizabeth P. Blankenhorn, Donald V. Cramer. (1994) Polymerase chain reaction detection of chimerism in rats based on an allelic polymorphism for T cell antigen receptor Cβ genes. Transplant Immunology 2:3, 253-256
CrossRef74
Sophie Caillat-Zucman, Christophe Legendre, Caroline Suberbielle, Christine Bodemer, Laure-Hélène Noël, Henri Kreis, Jean-François Bach. (1994) Microchimerism frequency two to thirty years after cadaveric kidney transplantation. Human Immunology 41:1, 91-95
CrossRef75
C. Suberbielle, S. Caillat-Zucman, J-F. Bach, C. Legendre, L-H. Noël, H. Kreis, C. Bodemer. (1994) Peripheral microchimerism in long-term cadaveric-kidney allograft recipients. The Lancet 343:8911, 1468-1469
CrossRef76
Afzal Nikaein, Twyala Poole, Randi Fishbeck, Guido Ordonez, Lori Dombrausky, Marvin J. Stone, Robert H. Collins, Joseph W. Fay. (1994) Characterization of skin-infiltrating cells during acute graft-versus-host disease following bone marrow transplantation using unrelated marrow donors. Human Immunology 40:1, 68-76
CrossRef77
Shigwang Qian, Anthony J. Demetris, Noriko Murase, Abdul S. Rao, John J. Fung, Thomas E. Starzl. (1994) Murine liver allograft transplantation: Tolerance and donor cell chimerism. Hepatology 19:4, 916-924
CrossRef78
Thomas E. Starzl, Anthony J. Demetris, Massimo Trucco, Noriko Murase, Camillo Ricordi, Suzanne Ildstad, Hector Ramos, Satoru Todo, Andreas Tzakis, John J. Fung, Michael Nalesnik, Adriana Zeevi, William A. Rudert, Mirjana Kocova. (1993) Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance. Hepatology 17:6, 1127-1152
CrossRef79
Thomas E. Starzl, Anthony J. Demetris, Noriko Murase, Angus W. Thomson, Massimo Trucco, Camillo Ricordi. (1993) Donor cell chimerism permitted by immunosuppressive drugs: a new view of organ transplantation. Trends in Pharmacological Sciences 14:5, 217-223
CrossRef80
Good, Robert A., . (1993) Mixed Chimerism and Immunologic Tolerance. New England Journal of Medicine 328:11, 801-802
Full Text
