Original Article
Brief Report
Chimerism and Tolerance in a Recipient of a Deceased-Donor Liver Transplant
N Engl J Med 2008; 358:369-374January 24, 2008
- Abstract
Complete hematopoietic chimerism and tolerance of a liver allograft from a deceased male donor developed in a 9-year-old girl, with no evidence of graft-versus-host disease 17 months after transplantation. The tolerance was preceded by a period of severe hemolysis, reflecting partial chimerism that was refractory to standard therapies. The hemolysis resolved after the gradual withdrawal of all immunosuppressive therapy.
Media in This Article
Figure 1
Fluorescence In Situ Hybridization for the X and Y Chromosomes on a Bone Marrow Aspirate Obtained from the Patient 12 Months after Transplantation.Figure 2
Flow-Cytometric Analysis of the Patient's Peripheral Blood.Article Activity
- Article
Case Report
Acute fulminant hepatitis after a nonspecific viral illness developed in a previously well 9-year-old girl. Her blood group was O, RhD-negative. She was referred to our institution, and at the time of admission she had markedly elevated aminotransferase levels and evidence of marked synthetic dysfunction (Table 1Table 1
Results of Laboratory Tests before and after Liver Transplantation and after Discontinuation of Immunosuppressive Therapy.). Extensive testing ruled out known viral, metabolic, drug-related, and autoimmune causes, and a diagnosis of “non–A-to-G viral hepatitis” was made. A liver biopsy was not performed because of severe underlying coagulopathy.Given the patient's fulminant hepatic failure (Table 1) requiring mechanical ventilation, urgent liver transplantation was performed with the use of a whole-organ transplant from an O, RhD-positive 12-year-old male donor who was positive for cytomegalovirus (CMV) (the recipient was also CMV-positive) and who died of hypoxic brain injury. The whole liver was transplanted (cold ischemic time, 9 hours 46 minutes), and the biliary anastomosis was a choledochocholedochostomy. The HLA status of the donor was A34,68;B50,76;DR4,13, and the recipient's HLA status was A2,24;B37,62;DR7,9.
Initial standard immunosuppressive therapy after liver transplantation consisted of tacrolimus (trough level, 12 to 15 μg per liter), intravenous methylprednisolone (2 mg per kilogram of body weight on days 0 through 2, 1.5 mg per kilogram on days 3 through 5, and then 1 mg per kilogram per day), and intravenous azathioprine (1.5 mg per kilogram per day). Other medications included intravenous ganciclovir for CMV prophylaxis (5 mg per kilogram per day) and antibiotic therapy. Antifungal prophylaxis was not administered.
On day 13 after transplantation, acute biliary obstruction developed, requiring operative choledochoduodenostomy and division of adhesions. Profound lymphopenia (lymphocyte count, 0.5×109 per liter), which had been noted at presentation, persisted for 25 weeks after transplantation; it was considered to be due to the precipitating viral agent and the immunosuppressive therapy. The patient was discharged 33 days after transplantation while receiving tacrolimus (trough level, 10 to 12 μg per liter) and prednisone (0.5 mg per kilogram per day). Azathioprine was discontinued 2 days after transplantation because of lymphopenia, and pneumocystis prophylaxis with cotrimoxazole was initiated.
Readmission was required 2 weeks after discharge, when a maculopapular exanthem, fever, and chest pain developed in the patient. Upper endoscopic examination and a biopsy specimen showed CMV esophagitis. The biopsy specimen showed viral inclusions and positive staining for CMV, and testing for CMV antigenemia was positive. The CMV esophagitis was successfully treated with a 2-week course of intravenous ganciclovir, which was then switched to oral valacyclovir because of lymphopenia (lymphocyte count 0.1×109 per liter), with a total white-cell count of 2.1×109 per liter. Three months after transplantation, immunosuppressive therapy consisted of tacrolimus (trough level, 8 to 10 μg per liter) and prednisone at a dose of 2.5 mg daily, and treatment of CMV was continued with valacyclovir. The lymphocyte count had improved (0.7×109 per liter).
Nine months after transplantation, a small-bowel obstruction developed, requiring surgical division of adhesions and resection of an ileal band. Routine preoperative blood grouping revealed that the patient's blood group had changed from O, RhD-negative, to O, RhD-positive (the donor's blood group), and a weakly positive direct antiglobulin test indicated coating of red blood cells with IgG antibodies. At that time, there was no evidence of spherocytosis on the blood film to suggest hemolysis; the hemoglobin level was 95 g per liter. This finding was confirmed by the Australian Red Cross Blood Service. Both parents had group O, RhD-negative blood with the phenotype ccdee, whereas their daughter's phenotype was now cDEe. However, serum samples showed mixed-field reactions with anti-D and anti-E typing.
Ten months after transplantation, after a mild upper respiratory tract infection, anemia (hemoglobin level, 64 g per liter) developed in the patient. Laboratory tests at that time showed active hemolysis, a strongly positive direct antiglobulin test result, and compensatory reticulocytosis (reticulocyte count, up to 29%). The indirect antiglobulin test and saline techniques showed high levels of active autoantibodies; the patient was treated with prednisone at doses of 5 mg per kilogram per day. Examination of a nasopharyngeal aspirate showed no respiratory viruses, and a serologic analysis to detect mycoplasma infection was negative. A transient improvement in the hemoglobin level was observed; however, as the prednisone was tapered, the anemia recurred. Severe intravascular hemolysis with hemoglobinuria and transient renal insufficiency developed. Multiple transfusions of group O, RhD-negative blood were required. The corticosteroid treatment resulted in severe cushingoid features; normal results of liver-function tests were maintained. Other therapies for treating the hemolysis included intravenous immune globulin and a switch from tacrolimus to cyclosporine.1
The change in this patient from group O, RhD-negative blood to group O, RhD-positive blood suggested the development of chimerism by engraftment of the recipient marrow from passenger hematopoietic stem cells within the transplanted liver. Fluorescence in situ hybridization studies for the X and Y chromosomes were performed on a bone marrow aspirate and peripheral-blood lymphocytes 3 months after the onset of hemolysis (post-transplantation day 395).2 Analysis of cells from the marrow, sorted by means of flow cytometry, showed that they were male (XY) in myeloid, erythroid, and CD19+ B cells. Analysis of peripheral-blood aliquots revealed a predominantly male (donor) population: of 50 T cells, 94% were male and 6% were female; of 50 B cells, 98% were male and 2% were female; of 50 granulocytes, 100% were male; and of 50 natural killer cells, 100% were male (Figure 1Figure 1
Fluorescence In Situ Hybridization for the X and Y Chromosomes on a Bone Marrow Aspirate Obtained from the Patient 12 Months after Transplantation.). A total of 190 sorted peripheral-blood cells were further assessed on post-transplantation day 417, and 250 cells were assessed on post-transplantation day 492 (2 months after immunosuppressive therapy had been discontinued); all of these cells were male.These results suggested that the hemolysis was due to the production of antibodies by residual B lymphocytes in the recipient against engrafted erythroid cells from the donor. A choice between two therapeutic options was then considered: the use of rituximab, an anti-CD20 monoclonal antibody, which would deplete all B cells (both host and donor cells), or withdrawal of all immunosuppressive therapy to allow full engraftment. The decision was made to withdraw the immunosuppressive therapy.
Fourteen months after transplantation (4 months after the onset of hemolytic anemia), cyclosporine was discontinued, and the prednisone dose was slowly tapered over a period of 3 months. The hemoglobin level remained stable without transfusions, and the reticulocyte count returned to normal, whereas the direct antiglobulin test remained weakly positive until 28 months later.
The patient remains well 5 years after transplantation. She has not received any immunosuppressive therapy for 4 years, and the results of her liver-function tests are normal. A repeat liver biopsy has not been performed because it has not been indicated clinically.
The patient has never had any dermatologic or gastrointestinal symptoms to suggest graft-versus-host disease. Repeat studies have shown conversion of her peripheral blood to the HLA of the donor: A34,68; B50,76; DR4,13. Furthermore, the loss of antibody responses to measles and mumps occurred after discontinuation of all immunosuppressive therapy despite normal antibody levels before transplantation, requiring immunization again with standard vaccines. Normal antibody responses to measles, mumps, and rubella were restored after revaccination.
The patient's lymphocyte T-cell subgroups CD4 and CD8, B cells, and natural killer cells are now normal. Analysis of her peripheral blood showed a predominantly naive, CD45RA-expressing CD4 population (Figures 2A and 2BFigure 2
Flow-Cytometric Analysis of the Patient's Peripheral Blood.).Assessment of the levels of T-cell–receptor excision circles, a marker of early T cells derived from the thymus, showed a high level in the recipient's peripheral blood, a finding suggestive of thymic engraftment rather than peripheral expansion of engrafting donor cells (Figure 3Figure 3
Analysis of T-Cell–Receptor Excision Circles.). Finally, assessment of antidonor responses in the patient by means of mixed-lymphocyte culture 3 years after transplantation showed donor-specific unresponsiveness with normal third-party responses (Figure 4Figure 4
Mixed-Lymphocyte Culture of Peripheral-Blood Mononuclear Cells.).3,4 Discussion
Complete hematopoietic chimerism classically occurs in bone marrow transplantation, during which all bone marrow–derived cells in the recipient are eliminated and replaced by donor cells.5 Partial or mixed chimerism in bone marrow transplantation occurs when milder forms of preconditioning are used, which initially do not completely ablate the host hematopoietic system.5 Microchimerism, or donor T-cell chimerism, is common after liver transplantation, but it usually disappears within the first 3 weeks.6 The effect of microchimerism in recipients of solid-organ transplants is uncertain, with reported findings ranging from correlation with graft acceptance and tolerance7 to no influence on either tolerance5,8 or the prevention of rejection.9,10
Severe hemolytic anemia 10 months after liver transplantation in this young girl was associated with mixed chimerism, and the initial studies showed the marrow and the majority of lymphocytes to be of donor origin. Since the patient had become RhD-positive, and high levels of hemolytic antibodies were detected, the likely source was her own B cells. The loss of antibodies to common vaccines in this patient provides further support for this theory, but their reappearance after revaccination suggests a donor-derived, naive B-cell compartment.
This patient resembles children with cancer and T-cell–deficient patients who have received bone marrow transplants after nonmyeloablative therapy and have evidence of thymic engraftment, with the appearance of naive CD4 T cells and high levels of T-cell–receptor excision circles.11,12 This patient's course is also consistent with animal models of mixed chimerism in which engrafting donor cells move through the thymus and host-reactive cells are deleted. This phenomenon is also found in mouse models in which viral superantigens in the thymus are expressed, leading to the deletion of cells expressing reactive T-cell receptor Vβs. Furthermore, central deletion of CD4 and CD8 alloreactive T-cell receptor transgenic T cells occurs within 4 weeks after mixed chimerism bone marrow transplantation, with no evidence of peripheral regulation.13-16
The achievement of central tolerance has been a major goal of transplantation research, but in clinical practice, it has been limited by the development of severe graft-versus-host disease and complications related to induction regimens. In a patient who had received an HLA-identical bone marrow transplant, subsequent successful liver transplantation from the same donor, with discontinuation of immunosuppressive therapy, was reported.17 The use of nonmyeloablative conditioning and stem-cell infusion, followed by receipt of a liver transplant from a living related donor, has also resulted in various levels of chimerism and tolerance after transplantation, although graft-versus-host disease usually precludes the withdrawal of immunosuppressive therapy.18 Graft-versus-host disease has also been reported to be a major complication of donor hematopoiesis occurring spontaneously after liver transplantation, resulting in either death of the patient18 or disease requiring ongoing immunosuppressive therapy.19-21 Furthermore, certain immune changes in peripheral blood may predispose liver-transplant recipients to “operational tolerance.”22
In this patient, the profound lymphopenia at presentation and in the subsequent months after transplantation, plus the immunosuppressive effects of drugs such as tacrolimus, azathioprine, and ganciclovir, may have contributed to the engraftment of donor hematopoietic stem cells. In addition, CMV infection, which resulted in clinically significant disease in the early period after transplantation, can have immune-modifying effects, which may have contributed to the eventual engraftment with donor cells.23,24 Finally, the numbers of stem cells from the liver may have been enhanced because of the relatively young age of the donor.
In summary, this patient required urgent liver transplantation for non–A-to-G hepatitis, and hemolytic anemia subsequently developed as a result of host-versus-graft disease, suggesting mixed hematopoietic chimerism. Withdrawal of immunosuppressive therapy resulted in resolution of the hemolytic anemia and the development of full hematologic chimerism. The complete absence of graft-versus-host disease and normal liver function in a fully HLA-mismatched, sex-mismatched liver allograft show that mixed chimerism with full tolerance can occur naturally under specific circumstances.
A Supplementary Appendix is available with the full text of this article at www.nejm.org.
Supported by a grant from the Juvenile Diabetes Research Foundation (4-2006-1025).
No potential conflict of interest relevant to this article was reported.
We thank Prof. Simon Robson for insightful suggestions and Dr. Geoff Zhang for his assistance.
Source Information
From the Centre for Kidney Research (S.I.A., M.H.); the Children's Hospital at Westmead and the Department of Paediatrics and Child Health, University of Sydney (S.I.A., N.S., A. Shun, S.D., A. Smith, B.W., P.J.S., A.L., M.O.S.); and the Australian National Liver Transplant Unit (D.V., A. Shun, S.D., M.O.S.) — all in Sydney.
Address reprint requests to Dr. Stormon at the Department of Gastroenterology, Children's Hospital at Westmead, Locked Bag 4001, 2145, Sydney, Australia, or at michaes6@chw.edu.au.
- References
References
1
Abu-Elmagd KM ,Bronsther O ,Kobayashi M , et al. Acute hemolytic anemia in liver and bone marrow transplant patients under FK 506 therapy. Transplant Proc 1991;23:3190-3192
Web of Science | Medline2
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 | Medline3
Kraus AB ,Shaffer J ,Toh HC , et al. Early host CD8 T-cell recovery and sensitized anti-donor interleukin-2-producing and cytolytic T-cell responses associated with marrow graft rejection follow-ing nonmyeloablative bone marrow transplantation. Exp Hematol 2003;31:609-621
CrossRef | Web of Science | Medline4
Ponchel F, Toomes C, Bransfield K, et al Real-time PCR based on SYBR-Green I fluorescence: an alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions. BMC Biotechnol 2003;3:18-18http://www.biomedcentral.com/1472-6750/3/18
CrossRef | Web of Science | Medline5
Wekerle T ,Sykes M . Mixed chimerism as an approach for the induction of transplantation tolerance. Transplantation 1999;68:459-467
CrossRef | Web of Science | Medline6
Domiati-Saad R ,Klintmalm GB ,Netto G ,Agura ED ,Chinnakotla S ,Smith DM . Acute graft versus host disease after liver transplantation: patterns of lymphocyte chimerism. Am J Transplant 2005;5:2968-2973
CrossRef | Web of Science | Medline7
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 | Medline8
Schlitt HJ . Is microchimerism needed for allograft tolerance? Transplant Proc 1997;29:82-84
CrossRef | Web of Science | Medline9
Sivasai KS ,Alevy YG ,Duffy BF , et al. Peripheral blood microchimerism in human liver and renal transplant recipients: rejection despite donor-specific chimerism. Transplantation 1997;64:427-432
CrossRef | Web of Science | Medline10
Schlitt HJ ,Hundrieser J ,Ringe B ,Pichlmayr R . Donor-type microchimerism associated with graft rejection eight years after liver transplantation. N Engl J Med 1994;330:646-647
Full Text | Web of Science | Medline11
Savage WJ ,Bleesing JJ ,Douek D , et al. Lymphocyte reconstitution following non-myeloablative hematopoietic stem cell transplantation follows two patterns depending on age and donor/recipient chimerism. Bone Marrow Transplant 2001;28:463-471
CrossRef | Web of Science | Medline12
Cavazzana-Calvo M ,Carlier F ,Le Deist F , et al. Long-term T-cell reconstitution after hematopoietic stem-cell transplantation in primary T-cell-immunodeficient patients is associated with myeloid chimerism and possibly the primary disease phenotype. Blood 2007;109:4575-4581
CrossRef | Web of Science | Medline13
Kurtz J ,Shaffer J ,Lie A ,Anosova N ,Benichou G ,Sykes M . Mechanisms of early peripheral CD4 T-cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: evidence for anergy and deletion but not regulatory cells. Blood 2004;103:4336-4343
CrossRef | Web of Science | Medline14
Wekerle T ,Kurtz J ,Ito H , et al. Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nat Med 2000;6:464-469
CrossRef | Web of Science | Medline15
Manilay JO ,Pearson DA ,Sergio JJ ,Swenson KG ,Sykes M . Intrathymic deletion of alloreactive T cells in mixed bone marrow chimeras prepared with a nonmyeloablative conditioning regimen. Transplantation 1998;66:96-102
CrossRef | Web of Science | Medline16
Nikolic B ,Sykes M . Bone marrow chimerism and transplantation tolerance. Curr Opin Immunol 1997;9:634-640
CrossRef | Web of Science | Medline17
Andreoni KA ,Lin JI ,Groben PA . Liver transplantation 27 years after bone marrow transplantation from the same living donor. N Engl J Med 2004;350:2624-2625
Full Text | Web of Science | Medline18
Donckier V ,Troisi R ,Toungouz M , et al. Donor stem cell infusion after non-myeloablative conditioning for tolerance induction to HLA mismatched adult living-donor liver graft. Transpl Immunol 2004;13:139-146
CrossRef | Web of Science | Medline19
Collins RH Jr ,Anastasi J ,Terstappen LW , et al. Donor-derived long-term multilineage hematopoiesis in a liver-transplant recipient. N Engl J Med 1993;328:762-765
Full Text | Web of Science | Medline20
Whitington PF ,Rubin CM ,Alonso EM , et al. Complete lymphoid chimerism and chronic graft-versus-host disease in an infant recipient of a hepatic allograft from an HLA-homozygous parental living donor. Transplantation 1996;62:1516-1519
CrossRef | Web of Science | Medline21
Gilroy RK ,Coccia PF ,Talmadge JE , et al. Donor immune reconstitution after liver-small bowel transplantation for multiple intestinal atresia with immunodeficiency. Blood 2004;103:1171-1174
CrossRef | Web of Science | Medline22
Li Y ,Koshiba T ,Yoshizawa A , et al. Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation. Am J Transplant 2004;4:2118-2125
CrossRef | Web of Science | Medline23
Mocarski ES Jr . Immune escape and exploitation strategies of cytomegaloviruses: impact on and imitation of the major histocompatibility system. Cell Microbiol 2004;6:707-717
CrossRef | Web of Science | Medline24
Wang EC ,McSharry B ,Retiere C , et al. UL40-mediated NK evasion during productive infection with human cytomegalovirus. Proc Natl Acad Sci U S A 2002;99:7570-7575
CrossRef | Web of Science | Medline
- Citing Articles (42)
Citing Articles
1
Jos Domen, Kimberly Gandy, Jignesh Dalal. (2012) Emerging uses for pediatric hematopoietic stem cells. Pediatric Research
CrossRef2
Manei Oku, Masayoshi Okumi, Akira Shimizu, Hisashi Sahara, Kentaro Setoyama, Hiroaki Nishimura, Masaharu Sada, Joseph Scalea, Akio Ido, David H. Sachs, Hirohito Tsubouchi, Kazuhiko Yamada. (2012) Hepatocyte Growth Factor Sustains T Regulatory Cells and Prolongs the Survival of Kidney Allografts in Major Histocompatibility Complex-Inbred CLAWN-Miniature Swine. Transplantation 93:2, 148-155
CrossRef3
Paul Szabolcs, William J. Burlingham, Angus W. Thomson. (2012) Tolerance after Solid Organ and Hematopoietic Cell Transplantation. Biology of Blood and Marrow Transplantation 18:1, S193-S200
CrossRef4
T. Hautz, G. Brandacher, T.O. Engelhardt, G. Pierer, W.P.A. Lee, J. Pratschke, S. Schneeberger. (2011) How Reconstructive Transplantation Is Different From Organ Transplantation—and How It Is Not. Transplantation Proceedings 43:9, 3504-3511
CrossRef5
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
CrossRef6
Patrizia Burra. (2011) The adolescent and liver transplantation. Journal of Hepatology
CrossRef7
G. Alex Bishop, Francesco L. Ierino, Alexandra F. Sharland, Bruce M. Hall, Stephen I. Alexander, Mauro S. Sandrin, P. Toby Coates, Geoffrey W. McCaughan. (2011) Approaching the Promise of Operational Tolerance in Clinical Transplantation. Transplantation 91:10, 1065-1074
CrossRef8
Mohamed Mabed. (2011) The Potential Utility of Bone Marrow or Umbilical Cord Blood Transplantation For the Treatment of Type I Diabetes Mellitus. Biology of Blood and Marrow Transplantation 17:4, 455-464
CrossRef9
Simon D. Tran, Robert S. Redman, A. John Barrett, Steven Z. Pavletic, Sharon Key, Younan Liu, Ashley Carpenter, Hieu M. Nguyen, Yoshinori Sumita, Bruce J. Baum, Stanley R. Pillemer, Eva Mezey. (2011) Microchimerism in Salivary Glands after Blood- and Marrow-Derived Stem Cell Transplantation. Biology of Blood and Marrow Transplantation 17:3, 429-433
CrossRef10
Agnieszka Czechowicz, Irving L. Weissman. (2011) Purified Hematopoietic Stem Cell Transplantation: The Next Generation of Blood and Immune Replacement. Hematology/Oncology Clinics of North America 25:1, 75-87
CrossRef11
M. Guo, K.-X. Hu, C.-L. Yu, Q.-Y. Sun, J.-H. Qiao, D.-H. Wang, G.-X. Liu, W.-J. Sun, L. Wei, X.-D. Sun, Y.-J. Huang, J.-X. Qiao, Z. Dong, H.-S. Ai. (2011) Infusion of HLA-mismatched peripheral blood stem cells improves the outcome of chemotherapy for acute myeloid leukemia in elderly patients. Blood 117:3, 936-941
CrossRef12
T. J. Grazia, R. J. Plenter, H. M. Lepper, F. Victorino, S. D. Miyamoto, J. T. Crossno Jr., B. A. Pietra, R. G. Gill, M. R. Zamora. (2011) Prolongation of Cardiac Allograft Survival by a Novel Population of Autologous CD117+ Bone Marrow-Derived Progenitor Cells. American Journal of Transplantation 11:1, 34-44
CrossRef13
Giuseppe Orlando. (2010) Finding the right time for weaning off immunosuppression in solid organ transplant recipients. Expert Review of Clinical Immunology 6:6, 879-892
CrossRef14
Maria Pleguezuelo, Giacomo Germani, Andrew K Burroughs. 2010. Liver Transplantation: Prevention and Treatment of Rejection. , 685-723.
CrossRef15
Manuela Battaglia. (2010) Potential T regulatory cell therapy in transplantation: how far have we come and how far can we go?. Transplant International 23:8, 761-770
CrossRef16
Samer A. Assaf, Linda M. Randolph, Kurt Benirschke, Samuel Wu, Ramin Samadi, Ramen H. Chmait. (2010) Discordant Blood Chimerism in Dizygotic Monochorionic Laser-Treated Twin–Twin Transfusion Syndrome. Obstetrics & Gynecology 116:Supplement, 483-485
CrossRef17
Peiguo Zheng, Yong Yang, Songgang Li, Jiyu Li, Wei Gong, Zhiwei Quan. (2010) A given number of effector T cells can only destroy a limited number of target cells in graft rejection. Transplant Immunology 23:3, 111-116
CrossRef18
Duncan D. Adams, John G. Knight, Alan Ebringer. (2010) Autoimmune diseases: Solution of the environmental, immunological and genetic components with principles for immunotherapy and transplantation. Autoimmunity Reviews 9:8, 525-530
CrossRef19
Agnieszka Czechowicz, Irving L. Weissman. (2010) Purified Hematopoietic Stem Cell Transplantation: The Next Generation of Blood and Immune Replacement. Immunology and Allergy Clinics of North America 30:2, 159-171
CrossRef20
J C Choy. (2010) Granzymes and perforin in solid organ transplant rejection. Cell Death and Differentiation 17:4, 567-576
CrossRef21
Yoshinori Ishikawa, Atsushi Hirakata, Adam D. Griesemer, Justin Etter, Shannon Moran, Joshua Weiner, Akira Shimizu, Kazuhiko Yamada. (2010) Tolerance and Long-Lasting Peripheral Chimerism After Allogeneic Intestinal Transplantation in MGH Miniature Swine. Transplantation 89:4, 417-426
CrossRef22
Dinh Quang Truong, Christophe Bourdeaux, Grégoire Wieërs, Pascale Saussoy, Dominique Latinne, Raymond Reding. (2009) The immunological monitoring of kidney and liver transplants in adult and pediatric recipients. Transplant Immunology 22:1-2, 18-27
CrossRef23
A. G. S. van Halteren, E. Jankowska-Gan, A. Joosten, E. Blokland, J. Pool, A. Brand, W. J. Burlingham, E. Goulmy. (2009) Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members. Blood 114:11, 2263-2272
CrossRef24
G. G. Borisenko. (2009) The prospect of pluripotent stem cell-based therapy. Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry 3:3, 248-258
CrossRef25
Mikaël Hivelin, Maria Siemionow, Philippe Grimbert, Laurent Lantieri. (2009) Extracorporeal photopheresis: From solid organs to face transplantation. Transplant Immunology 21:3, 117-128
CrossRef26
Kazunori Kanehira, Douglas L. Riegert-Johnson, Dong Chen, Lawrence E. Gibson, Stephen D. Grinnell, Gopalrao V. Velgaleti. (2009) FISH Diagnosis of Acute Graft-Versus-Host Disease Following Living-Related Liver Transplant. The Journal of Molecular Diagnostics 11:4, 355-358
CrossRef27
Rosa Ayala, Silvia Grande, Enriqueta Albizua, Almudena Crooke, Juan Carlos Meneu, Almudena Moreno, Baltasar Pérez, Florinda Gilsanz, Enrique Moreno, Joaquín Martínez-Lopez. (2009) Long-term follow-up of donor chimerism and tolerance after human liver transplantation. Liver Transplantation 15:6, 581-591
CrossRef28
S. Janes, P. Dhaliwal, K. Wood. (2009) Tolerance in renal transplantation: is mixed chimerism the missing link?. Nephrology Dialysis Transplantation 24:6, 1726-1729
CrossRef29
H. Haller, N. Richter, V. Bröcker, W. Gwinner, F. Gueler, A. Schwarz. (2009) Aktuelle Probleme der Nierentransplantation. Der Internist 50:5, 523-535
CrossRef30
Allan D. Kirk. (2009) Clinical Tolerance 2008. Transplantation 87:7, 953-955
CrossRef31
Kareem M. Abu-Elmagd, Guilherme Costa, Geoffrey J. Bond, Tong Wu, Noriko Murase, Adriana Zeevi, Richard Simmons, Kyle Soltys, Rakesh Sindhi, William Stein, Anthony Demetris, George Mazariegos. (2009) Evolution of the immunosuppressive strategies for the intestinal and multivisceral recipients with special reference to allograft immunity and achievement of partial tolerance. Transplant International 22:1, 96-109
CrossRef32
Manei Oku, Masayoshi Okumi, Hisashi Sahara, Atsushi Hirakata, Takashi Onoe, Adam D. Griesemer, Kazuhiko Yamada. (2008) Porcine CFSE mixed lymphocyte reaction and PKH-26 cell-mediated lympholysis assays. Transplant Immunology 20:1-2, 78-82
CrossRef33
Giuseppe Orlando, Tommaso Manzia, Leonardo Baiocchi, Alberto Sanchez-Fueyo, Mario Angelico, Giuseppe Tisone. (2008) The Tor Vergata weaning off immunosuppression protocol in stable HCV liver transplant patients: The updated follow up at 78 months. Transplant Immunology 20:1-2, 43-47
CrossRef34
Ann P. Chidgey, Richard L. Boyd. (2008) Immune Privilege for Stem Cells: Not as Simple as It Looked. Cell Stem Cell 3:4, 357-358
CrossRef35
Jerzy W Kupiec-Weglinski. (2008) Tolerance induction. Current Opinion in Organ Transplantation 13:4, 331-332
CrossRef36
Alexandru Schiopu, Kathryn J Wood. (2008) Regulatory T cells: hypes and limitations. Current Opinion in Organ Transplantation 13:4, 333-338
CrossRef37
P. F. Halloran, J. Bromberg, B. Kaplan, F. Vincenti. (2008) Tolerance Versus Immunosuppression: A Perspective. American Journal of Transplantation 8:7, 1365-1366
CrossRef38
Ann P. Chidgey, Daniel Layton, Alan Trounson, Richard L. Boyd. (2008) Tolerance strategies for stem-cell-based therapies. Nature 453:7193, 330-337
CrossRef39
(2008) Chimerism and Tolerance in a Recipient of a Deceased-Donor Liver Transplant. New England Journal of Medicine 358:19, 2075-2075
Full Text40
Starzl, Thomas E., . (2008) Immunosuppressive Therapy and Tolerance of Organ Allografts. New England Journal of Medicine 358:4, 407-411
Full Text41
Heidi Ledford. (2008) Organ transplants without rejection. Nature
CrossRef42
Dela Golshayan, Manuel Pascual. (2008) Tolerance-Inducing Immunosuppressive Strategies in Clinical Transplantation. Drugs 68:15, 2113-2130
CrossRef
- Letters
