Strategy Optimization and Clinical Analyze of Multiple Nucleotide Polymorphism Analysis in the Chimerism Detection after Allogeneic Hematopoietic Stem Cell Transplantation / 中国实验血液学杂志

AbstractObjective: To investigate the sample selection, result correction and clinical application value of multi nucleotide polymorphism chimerism detection method based on Next-generation sequencing.@*METHODS@#The chimerism samples from November 2018 to June 2020 were collected, and Pearson correlation coefficient (r) was used to analyze the consistency of bone marrow and peripheral blood results detected by MNPseq; according to the different information integrity before transplantation, the calibration model was constructed to analyze the correction value of the micro chimerism results in each model; the clinical results were retrospectively analyzed to verify the reliability and practicability of chimerism results correction and the clinical value of MNPseq method.@*RESULTS@#The results of bone marrow and peripheral blood chimerism detected by MNPseq method were consistent with each other and showed significant correlation (r=0.985, P<0.01). The three groups of calibration models were constructed according to different pre-transplant information. For the no donor and pre-transplant patients information group, the correction value was 1%; while for the group with pre-transplant patients and without donor information, 0.61% of the chimerism rate and 13 heterotopic points were used as the correction value; 0.26% of the chimerism rate and 21.57% of the heterotopic points were used as the correction value for the group with pre-transplantation patients and donor information. After correction, the number of the patients with incomplete chimerism decreased from 276 (74.19%) to 141 (37.91%) (P<0.01). Among 18 (18/141, 12.77%) patients with incomplete chimerism, the results of MNPseq in the patients were 25-39 days earlier than those in STR and flow MRD, and the result showed statistical significance.@*CONCLUSION@#MNPseq method can be used to monitor chimerism with peripheral blood instead of bone marrow samples, and the results can be corrected to detect the changes of graft status in vivo in a more timely manner.

Establishment of A Mouse Model of Hematopoietic Stem Cell Transplantation Infected with Respiratory Syncytial Virus / 中国实验血液学杂志

OBJECTIVE@#To establish a mouse model of respiratory syncytial virus (RSV) infection after hematopoietic stem cell transplantation, so as to lay the foundation for future research on RSV infection and related complications after hematopoietic stem cell transplantation.@*METHODS@#Bone marrow cells and spleen cells were transplanted to C57BL/6 mice after myeloablative treatment to establish a mouse model of allogeneic hematopoietic stem cell transplantation. The chimerism rate was detected by flow cytometry 3 and 7 weeks after transplantation. The transplanted mice were infected with RSV by nasal drops. The lung tissues were collected 5 days after infection for identification of infection, and lung tissues were analyzed for pathology 2 weeks and 2 months after infection.@*RESULTS@#The chimerism rate was > 90% at 3 and 7 weeks after transplantation. Successful infection was detected 5 days after RSV infection, and there were severe and persistent pathological changes in the lung tissues of the mice 2 weeks and 2 months after infection.@*CONCLUSION@#RSV infection in stable chimeric mice after hematopoietic stem cell transplantation can cause significantly persistent lung disease, which lays foundation for the prevention and treatment of RSV infection and the mechanism of later bronchiolitis obliterans after hematopoietic stem cell transplantation.

Evaluación De Quimerismo En Pacientes Con Injerto De Células Progenitoras Hematopoyéticas En Panamá Del 2000­20 / Evaluation of Chimerism in Patients with Graft Hematopoietic Progenitor Cells in Panama from 2000­2018

Introducción: El Injerto de células progenitoras hematopoy éticas (ICPH) es actualmente un trata­miento para diferentes desórdenes hematológicos malignos y no malignos. El análisis del quimeris­mo post ICPH, y la cuantificación de cada población celular, deben ser monitoreados. El presente trabajo tiene como objetivo: el evaluar los res ultados de quimerismo completo y mixto en sangre periférica del receptor pos trasplante obtenidos por método cualitativo y cuantitativo del año 2000 al 2018. Material y método: El presente es un estudio descriptivo, observacional, transversal de dos mé­ todos de quimerismo efectuados a receptores y donantes de ICPH alogénico. Resultados: De los 79 pacientes estudiados por el método cualitativo: 65 (82.2%) resultaron con qui­ merismo completo y 14 (17.7%) con quimerismo mixto. No fue posible cuantificar por este método el % de células del donante y del receptor.Conclusión: El método cuantitativo es un método exacto, que determina el % de células del receptor y del donante presentes en la muestra. Con este método se evalúan un mayor número de marcadores genéticos que con el método cualitativo, y se obtienen un mayor número de loci informativos del quimerismo al compararlo con el método cualitativo.

Introduction: Hematopoietic progenitor cell grafting (ICPH) is currently a treatment for different ma­ lignant and non­malignant hematological disorders. The analy sis of post­ICPH chimerism, and the quantification of each cell population, should be monitored. The present work has as objective: to evaluate the results of complete and mixed chimerism in peripheral blood of the post­trans plant reci­pient obtained by qualitative and quantitative method from the year 2000 to 2018. Material and method: The present is a descriptive, observational, cross­sectional study of two met­ hods of chimerism performed on allogeneic ICPH recipients and donors . Results: Of the 79 patients studied by the qualitative method: 65 (82.2%) resulted with complete chi­ merism and 14 (17.7%) with mixed chimerism. It was not possible to quantify by this method the% of donor and recipient cells. Conclusion: The quantitative method is an exact method, which determi­nes the% of recipient and donor cells present in the sample. With this method, a greater number of genetic markers are evaluated than in the qualitative method, and a greater number of information loci of chimerism are obtained than with the qualitative method.

Impact of Day 14 Peripheral Blood Chimerism after Allogeneic Hematopoietic Stem Cell Bone Transplantation on the Treatment Outcome of Non-Malignant Disease

BACKGROUND: The impact of early peripheral blood chimerism on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear. We aimed to determine whether day 14 peripheral blood chimerism after allo-HSCT predicts outcomes in patients with non-malignant diseases. METHODS: Data from 56 patients who received allo-HSCT between April 2007 and March 2016 were retrospectively analyzed. Chimerism was evaluated using short-tandem repeat polymerase chain reaction, with mixed chimerism (MC) defined as greater than 1% recipient cells which was further categorized into low-level MC (> 1% and < 15% of recipient-derived cells) and high-level MC (≥ 15% of the recipient-derived cells). RESULTS: Thirty-six patients showed complete donor chimerism (CC), 14 low-level MC, and 6 high-level MC at day 14 post-transplant. The estimated 5-year event-free survival (EFS) was higher in the CC or low-level MC groups than in the high-level MC group (86.1% vs. 71.4% vs. 33.3%; P = 0.001). In BM or peripheral blood stem cell (BM/PBSC) transplants, the 5-year EFS was higher in the CC or low-level MC group than in the high-level MC group (93.1% vs. 66.7% vs. 0%; P < 0.001). However, in cord blood transplants, the 5-year OS and EFS according to the day 14 peripheral blood chimerism did not reach statistical significance. CONCLUSION: Although CC is not always necessary after allo-HSCT for non-malignant diseases, our data suggest that day 14 peripheral blood chimerism may predict outcomes in patients with non-malignant diseases who underwent BM/PBSC transplants.

The role of fetal-maternal microchimerism as a natural-born healer in integrity improvement of maternal damaged kidney

ABSTRACT Purpose: To identify the fetal stem cell (FSC) response to maternal renal injury with emphasis on renal integrity improvement and Y chromosome detection in damaged maternal kidney. Materials and Methods: Eight non-green fluorescent protein (GFP) transgenic Sprague-Dawley rats were mated with GFP-positive transgenic male rats. Renal damage was induced on the right kidney at gestational day 11. The same procedure was performed in eight non-pregnant rats as control group. Three months after delivery, right ne- phrectomy was performed in order to evaluate the injured kidney. The fresh perfused kidneys were stained with anti-GFP antibody. Polymerase chain reaction (PCR) assay was also performed for the Y chromosome detection. Cell culture was performed to detect the GFP-positive cells. Technetium-99m-DMSA renal scan and single-photon emission computed tomography (SPECT) were performed after renal damage induction and 3 months later to evaluate the improvement of renal integrity. Results: The presence of FSCs was confirmed by immune histochemical staining as well as immunofluorescent imaging of the damaged part. Gradient PCR of female rat purified DNA demonstrated the presence of Y-chromosome in the damaged maternal kidney. Moreover, the culture of kidney cells showed GPF- positive cells by immuno- fluorescence microscopy. The acute renal scar was repaired and the integrity of dam- aged kidney reached to near normal levels in experimental group as shown in DMSA scan. However, no significant improvement was observed in control group. Conclusion: FSC seems to be the main mechanism in repairing of the maternal renal injury during pregnancy as indicated by Y chromosome and GFP-positive cells in the sub-cultured medium.

Late chimerical status after bone marrow transplantation in severe aplastic anemia according to two different preparatory regimens

ABSTRACT Background: This study investigated the influence of two conditioning regimens on the chimerical status of 104 patients with acquired severe aplastic anemia. Methods: Patients were monitored for at least 18 months after related bone marrow transplantation and reaching partial or complete hematologic recovery. Group I patients (n = 55) received 200 mg/kg cyclophosphamide alone and Group II (n = 49) received 120 mg/kg cyclophosphamide associated with 12 mg/kg busulfan. Patients were classified in three chimerism levels according to the percentage of donor cells in the peripheral blood. Results: Chimerism ≤50% occurred in 36.4% of Group I and none of Group II; chimerism 51-90% was found in 20.0% of Group I and 10.2% of Group II; and chimerism >90% was found in 43.6% of Group I versus 89.8% of Group II. A significant association (p-value < 0.001) was found between conditioning type and chimerism levels. A higher number of infused cells was associated with higher levels of chimerism only in Group I (p-value = 0.013). Multivariate analysis showed that chimerism >90% is associated with the cyclophosphamide plus busulfan conditioning (p-value < 0.001) and higher number of infused cells (p-value = 0.009), suggesting that these factors are predictive of graft outcome. Regarding hematological recovery, higher chimerism levels were associated with higher neutrophil (p-value = 0.003) and platelet counts (p-value < 0.001) in Group I only. These results show that myeloablative conditioning favors full donor chimerism and non-myeloablative conditioning predisposes to mixed chimerism or autologous recovery of hematopoiesis. Conclusion: These data show that autologous recovery depends on the intensity of immunosuppression and that the immunosuppressive function of cyclophosphamide alone can induce this type of hematopoietic recovery.

Allogeneic hematopoietic stem cell transplantation in congenital hemoglobinopathies with myeloablative conditioning and rabbit anti-thymocyte globulin

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for β-thalassemia major (TM) and sickle cell disease (SCD) in children. Graft-versus-host disease (GVHD) and treatment-related mortality (TRM) remain significant challenges to improving survival after HSCT. Here, we analyzed the outcome of TM and SCD patients, who received allogeneic HSCT with myeloablative conditioning at our institution. METHODS: Twenty-two patients (15 TM, 7 SCD), with a median age of 9 years (range, 1.6–16.9), underwent allogeneic HSCT using busulfan, cyclophosphamide and rabbit anti-thymocyte globulin-based conditioning. Cells were derived from either the bone marrow (8 patients), or peripheral blood stem cells (14 patients). The majority of patients received HSCT from a matched sibling donor (N=18). GVHD prophylaxis included cyclosporine and short course methotrexate. RESULTS: All patients achieved donor engraftment. Two SCD patients died from TRM-related grade IV gut GVHD (N=1) or severe bronchiolitis obliterans (BO) (N=1). Cumulative incidence of acute and chronic GVHD was 36.4% and 32.7%, respectively. Veno-occlusive disease (VOD) occurred in 8 patients (36.4%), but resolved in all instances. Epstein-Barr virus (EBV)-related post-transplantation lymphoproliferative disease (PTLD) occurred in 1 patient. The overall survival (OS) was 90.9% (TM 100%, SCD 71.4%), with all patients achieving transfusion independence, while 8 achieved complete donor chimerism. CONCLUSION: Busulfan, cyclophosphamide, and ATG-based conditioning for HSCT of TM and SCD patients did not result in graft failure, although modifications may be required to reduce VOD incidence. Further changes to donor type and cell source prioritization are necessary to minimize TRM and morbidity caused by GVHD.

A Case of Erdheim-Chester Disease Developed during Treatment of Leukemia in a Child / 임상소아혈액종양

Erdheim-Chester disease (ECD) is a rare non-Langerhan's cell histiocytosis disorder characterized by replacement of normal tissue by lipid-laden histiocytes affecting various organs. A few pediatric cases have been reported worldwide. Here we present a child with leukemia who was diagnosed as ECD. A 2-year and 11-month old boy diagnosed with high risk acute lymphoblastic leukemia (ALL) at the age of 17 months, received allogeneic hematopoietic stem cell transplantation (HSCT) at the age of 2 years old. Six months after the transplantation, the patient was admitted to the hospital with palpable left calf nodules. Bone marrow study suggested ECD without leukemia with complete chimerism status. Excisional biopsy of the left calf nodule showed ‘aggregation of non-Langerhan's cell type epitheloid histiocytes’; clinically suggestive of ECD. The patient was started on vinblastine and corticosteroid treatment.

Establishment of Trace Amount Bone Marrow Hematopoietic Stem Cells of Adult Mouse Transplantation System / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To establish a transplantation system for a trace amount of adult mouse bone marrow hematopoietic stem cells (HSCs).</p><p><b>METHODS</b>The HSCs from bone marrow cells of GFP adult mouse were seperated by using marker combination ESLAM (CD45CD201CD150CD48) The goal cell population acquired by flow cytometry sorting were injected into lethally irradiated recipient mouse plus protective cells. And the peripheral blood cells from recipient mice tail veins at different time points were acquired to observe the reconstruction level and lineage differentiation. Then the receptor mouse was killed and the cells from thymus, spleen, marrow, and peripheral blood were acquired to measure tissue chimerism.</p><p><b>RESULTS</b>The results of peripheral blood of recipient mice after transplantation showed that the reconstructive efficiency was 100% after 4th week. The proportion of GFP cells at different time points in various lines (myeloid, erythroid, B, T and megakaryocytes) were different and the change tendency of reconstruction were different. From different tissues (peripheral blood, bone marrow, spleen, thymus) after 6 months, the intramedullary spleen and thymus chimerism can be seen and showed a high proportion of GFPcells in the peripheral blood erythroid and megakaryocytes and there were no GFPcells in the myeloid and lymphatic cells, but the myeloid cells in the bone marrow cells of the recipient mice contained a higher proportion of GFPcells. The B cells in the spleen had a higher proportion of GFP cells, and the T cells in the thymus contained a higher proportion of GFP cells.</p><p><b>CONCLUSION</b>The ESLAM combination can be highly efficient one for the enrichment of HSCs with long-term reconstructive ability, and the results of peripheral blood 6 months after the transplantation suggests that it may have the inclination to erythroid and megakaryocyte differentiation.</p>

Cytogenetics and Molecular Genetic Analysis of Chimerism in Marmosets (Callithrix: Primates)

ABSTRACT The birth of fraternal twins is a characteristic frequently observed in callitrichids. Cytogenetic studies have demonstrated hematopoietic chimerism in marmosets with the occurrence of two cell lines 2n=46,XX/46,XY in females and males co-twins, without phenotypic changes. Amplification by PCR have also been used to verify the presence of the SRY gene in female chimaeras. Our aim was to verify the occurrence of chimerism in Callithrix sp. individuals considered as hybrids according to their intermediate phenotypes between C. jacchus and C. penicillata. Blood samples from 37 Callithrix sp. individuals were collected. Hematopoietic chimerism 2n=46,XX/46,XY was detected by cytogenetic analysis in five individuals, three males and two females. A fragment of approximately 200bp of the SRY gene was amplified in seven females with normal external genitalia. The percentage of 32% of chimeric individuals detected in the present study is similar to that observed for pure specimens of Callithrix. These data suggests that hybridization probably does not interfere with the occurrence of twin gestation, nor of chimerism. Although cytogenetics is the main tool to identify the two cell lineages present in cases of chimerism, the amplification of the SRY gene by PCR has proved to be more efficient to identify the Y chromosome in cases of chimeric female marmoset.

Implicaciones médico legales del quimerismo / Medicolegal implications of chimerstry

Los recientes avances en tecnologías biomédicas proporcionan herramientas a la Medicina Legal para el esclarecimiento de casos complejos y ejercer justicia basada en evidencia científica. ¿Pero qué ocurre cuando se imponen obstáculos como el quimerismo que podrían llevar a decisiones equivocadas? A pesar de que este fenómeno se creía casi inexistente, se han reportado interesantes casos, que han puesto a prueba la utilidad de las pruebas de ADN. El quimerismo se define como la presencia de líneas celulares con distinto material genético proveniente de diferentes orígenes en un único cuerpo. Esto tiene grandes implicaciones medico legales, principalmente en la investigación criminal. Por ejemplo en una escena de crimen, se pueden encontrar muestras de tejidos de un mismo individuo pero estas podrían tener ADN distinto si se trata de un individuo quimérico llevando a una mala interpretación de la información. También cabe resaltar las implicaciones del quimerismo en las pruebas de paternidad, ya que este fenómeno puede ocasionar falsos negativos en estas pruebas y por lo tanto un diagnóstico incierto de paternidad. El objetivo de esta revisión es describir las diferentes implicaciones médico legales del quimerismo y proponer posibles soluciones a los conflictos que podrían presentarse ante tales casos.

Recent advances in biomedical technologies are able to clarify today’s complex cases that are faced by Legal Medicine; allowing this branch of medicine to exercise justice based in scientific evidence. But what happens when an obstacle such as chimerism is present and may lead to false decisions? Although this phenomenon was thought to be inexistent, interesting cases have been reported. Chimerism is defined as the presence of different cell linings in a unique organism. This phenomenon has important implication in Legal Medicine, especially in criminal investigation. For example, in a crime scene the samples gathered may present different DNA and lead to misinterpretation of the information. On the other hand, paternity tests are also implicated in the presence of a chimera since it may originate a false negative result. The purpose of this review is to describe different Legal Medicine’s implications linked to chimerism and propose possible solutions to the conflicts that may arouse from a case of a chimera.

A Case of Long-term Survival with Autologous Recovery after Double Cord Blood Transplantation for Juvenile Myelomonocytic Leukemia / 임상소아혈액종양

A 1.1 year old boy was admitted to the Seoul National University Children's Hospital because of incidental findings of hepatosplenomegaly, skin lesion and multiple intra- abdominal lymphadenopathies. Anemia and thrombocytopenia were found based on the initial complete blood count (CBC) measurements. Because of bicytopenia and hepatosplenomegaly, bone marrow examination was performed which revealed hypercellular marrow with increased monocytes and granulopoiesis. The hemoglobin F level was high for his age, and monocyte production was increased. The patient was diagnosed with juvenile myelomonocytic leukemia at the age of 1.2 years. Chemotherapy with cytarabine, etoposide, vincristine, and isotretinoin was initiated. After 6 cycles of chemotherapy, the CBC normalized. He underwent double cord blood transplantation (dCBT), but chimerism studies showed autologous recovery. However, he did not show relapse during the 5 years post-transplant during which he received isotretinoin. He is surviving disease-free 9 years after dCBT.

Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: recent advances and controversies

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory clinical syndrome of uncontrolled immune response which results in hypercytokinemia due to underlying primary or secondary immune defect. A number of genetic defects in transport, processing and function of cytotoxic granules which result in defective granule exocytosis and cytotoxicity of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells have been well identified at the cellular and molecular level. Important advances have been made during the last 20 years in the diagnosis and treatment of HLH. The Histiocyte Society has proposed diagnostic guideline using both clinical and laboratory findings in HLH-2004 protocol, and this has been modified partly in 2009. HLH used to be a fatal disease, but the survival of HLH patients has improved to more than 60% with the use of chemoimmunotherapy combined with hematopoietic cell transplantation (HCT) over the past 2 decades. However, HCT is still the only curative option of treatment for primary HLH and refractory/relapsed HLH after proper chemoimmunotherapy. The outcome of HCT for HLH patients was also improved steadily during last decades, but HCT for HLH still carries significant mortality and morbidity. Moreover, there remain ongoing controversies in various aspects of HCT including indication of HCT, donor selection, timing of HCT, conditioning regimen, and mixed chimerism after HCT. This review summarized the important practical issues which were proven by previous studies on HCT for HLH, and tried to delineate the controversies among them.

A Case of Long-term Survival with Autologous Recovery after Double Cord Blood Transplantation for Juvenile Myelomonocytic Leukemia / 임상소아혈액종양

A 1.1 year old boy was admitted to the Seoul National University Children's Hospital because of incidental findings of hepatosplenomegaly, skin lesion and multiple intra- abdominal lymphadenopathies. Anemia and thrombocytopenia were found based on the initial complete blood count (CBC) measurements. Because of bicytopenia and hepatosplenomegaly, bone marrow examination was performed which revealed hypercellular marrow with increased monocytes and granulopoiesis. The hemoglobin F level was high for his age, and monocyte production was increased. The patient was diagnosed with juvenile myelomonocytic leukemia at the age of 1.2 years. Chemotherapy with cytarabine, etoposide, vincristine, and isotretinoin was initiated. After 6 cycles of chemotherapy, the CBC normalized. He underwent double cord blood transplantation (dCBT), but chimerism studies showed autologous recovery. However, he did not show relapse during the 5 years post-transplant during which he received isotretinoin. He is surviving disease-free 9 years after dCBT.

Quantification of mixed chimerism allows early therapeutic interventions

Hematopoietic stem cell transplantation is the curative option for patients with myelodysplastic syndrome; however, it requires a long post-transplantation follow-up. A 53-year-old woman with a diagnosis of myelodysplastic syndrome underwent related donor allogeneic hematopoietic stem cell transplantation in July 2006. Three months after transplantation, a comparative short tandem repeat analysis between donor and recipient revealed full chimerism, indicating complete, healthy bone marrow reconstitution. Three years and ten months after hematopoietic stem cell transplantation, the patient developed leukopenia and thrombocytopenia. Another short tandem repeat analysis was carried out which showed mixed chimerism (52.62%), indicating relapsed disease. A donor lymphocyte infusion was administered. The purpose of donor lymphocyte infusion is to induce a graft-versus-leukemia effect; in fact, this donor's lymphocyte infusion induced full chimerism. Successive short tandem repeat analyses were performed as part of post-transplantation follow-up, and in July 2010, one such analysis again showed mixed chimerism (64.25%). Based on this finding, a second donor lymphocyte infusion was administered, but failed to eradicate the disease. In September 2011, the patient presented with relapsed disease, and a second related donor allogeneic hematopoietic stem cell transplantation was performed. Subsequent short tandem repeat analyses revealed full chimerism, indicating complete bone marrow reconstitution. We conclude that quantitative detection of mixed chimerism is an important diagnostic tool that can guide early therapeutic intervention...

Research advances on microchimerism / 中国实验血液学杂志

The microchimerism is a status of the microcell or DNA of an individual in another one with genetic differences. Taking an overall view about the discovery and research of the microchimerism, it was found that although the study of the microchimerism emphasizes the formation, origin, distribution, type, relationship to disease and several other aspects, the objects of the study are always the microchimerism that obtained naturally. As it is known to all, the microchimerism can also be produced in some clinical treatment, such as in the transplant and transfusion, but compared with the microchimerism gained naturally, obviously, the study for the iatrogenic microchimerism formed in the treatment is not elaborate enough. The curative effect of micro transplantation, a new technique for leukemia treatment, is obvious, but its mechanism is unclear, whether that is related to microchimerism still needs further research. This review summarizes the study history and perspective of the microchimerism so as to provide some ideas for studying the action mechanism of microchimerism in micro transplantation.

The First Known Case of Blood Group Chimerism in Monochorionic Dizygotic Twins in Korea

No abstract available.

Clinical Immune Tolerance in Liver Transplantation: Present and Future / 한양의대학술지

Liver transplantation is the most effective treatment for end-stage liver diseases (ESLD) with satisfactory clinical results and so is considered as the treatment of choice for ESLD and early hepatocellular carcinoma with cirrhotic liver. Unfortunately, adverse effects of life-long immunosuppression prevent the development of alternative strategies to achieve better long-term outcome. Achieving clinical operational tolerance is one of the ultimate goals in the clinical transplantation field. Around 15% of liver transplantation recipients develop spontaneous operational tolerance after immunosuppression withdrawal, and the percentage may be even higher in pediatric living donor liver transplantation recipients. One of the possible explainable mechanisms is a T cell fatigue from large amount of antigen loaded. Despite continuing progress, clinical operational tolerance is still rare in liver transplantation. Reprogramming the recipient immune system by creating chimerism and utilizing regulatory cell therapies are among the newer promising means to achieve clinical liver transplantation tolerance in the future. In animal studies, administration of donor specific regulatory T cells allows a prolonged survival without immunosuppressive agents. In this review, proposed mechanisms for clinical tolerance will be offered and current experimental trial will be introduced.

The potential use of mesenchymal stem cells in hematopoietic stem cell transplantation

In the last 10 years, mesenchymal stem cells (MSCs) have emerged as a therapeutic approach to regenerative medicine, cancer, autoimmune diseases, and many more due to their potential to differentiate into various tissues, to repair damaged tissues and organs, and also for their immunomodulatory properties. Findings in vitro and in vivo have demonstrated immune regulatory function of MSCs and have facilitated their application in clinical trials, such as those of autoimmune diseases and chronic inflammatory diseases. There has been an increasing interest in the role of MSCs in allogeneic hematopoietic stem cell transplantation (HSCT), including hematopoietic stem cell engraftment and the prevention and treatment of graft-versus-host disease (GVHD), and their therapeutic potential has been reported in numerous clinical trials. Although the safety of clinical application of MSCs is established, further modifications to improve their efficacy are required. In this review, we summarize advances in the potential use of MSCs in HSCT. In addition, we discuss their use in clinical trials of the treatment of GVHD following HSCT, the immunomodulatory capacity of MSCs, and their regenerative and therapeutic potential in the field of HSCT.