bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pure Hematopoietic Stem Cells Reconstitute Immunity in Allogeneic Hosts Superior to Bone Marrow: Immunosuppression by Subclinical Graft-Versus-Host Disease.
Authors: Tsao Gabriel J. , Allen Jessica A. , Logronio Kathryn , Lazzeroni Laura C. , Shizuru Judith A. 
Published: October 2019

Abstract
Antigen specific immune responses are known to be impaired following allogeneic hematopoietic cell transplantation (HCT). Some clinical studies suggest that graft T cell depletion for the prevention of graft-versus-host disease (GVHD) leads to poorer immune recovery, while other correlate GVHD with delayed immune reconstitution. Our studies sought to examine the degree to which the co-transplantation of GVHD-inducing mature cells mediated protective immunity post-HCT. We compared the transplant of FACS purified hematopoietic stem cells (HSC: cKit+Thy1.1loSca+Lin-) with bone marrow (BM) between congenic (BA to B6Ly5.2), minor-antigen mismatched (BA to BALB.B), haploidentical (BAxSWR F1 to BALB/cxSWR F1) and MHC-mismatched (BA to BALB/c) donor and host pairs. We show that grafts composed solely of purified HSC give uniformly superior lymphoid reconstitution across all mismatched pairs, both qualitatively and quantitatively. Although absolute blood lymphocytes counts were increased in recipients of BM compared to HSC, lymphoid reconstitution as measured by lymph node size, counts and architecture was significantly improved in the HSC groups regardless of minor or major mismatches between donor and host. Proliferative responses to the allele specific peptides of the antigen hen egg lysozyme were also significantly increased in the HSC as compared BM recipients (p=0.028), with fully MHC mismatched BM recipient cells showing almost no proliferative response. The use of MHC allele specific antigens also revealed that T cell responses post-HCT are dominated by donor-restricted elements. These data suggest that subclinical GVHD mediated by mature cells in the donor BM result in impaired immune reconstitution. While there may be an increase in absolute lymphocyte numbers, this increase does not correlate with an increase in immune cell function. These findings provide important insight into the benefits of purified HSC for preventing post-HCT infectious complication in addition to its known GVHD prophylaxis benefits. Our data highlights the benefit of transplanting a pure HSC population, as the relatively small number of T cells that are found in mouse bone marrow or that remain in the graft after T cell depletion in humans can still result in immune impairment due to subclinical GVHD.
IL-2- and IL-15-Activated Alloreactive NK Cells Infusion Reduces GVHD, Mediates Graft-Versus-Leukemia Effects and Prolongs Survival in Recipients of MHC-Mismatched Hematopoietic Cell Transplantation.
Authors: Chen Guanghua , Wu De Pei , Yang Mingzhen , Sun Ai-ning 
Published: October 2019

Abstract
Alloreactive NK cells with killer immunoglobulin-like receptor (KIR) ligand incompatibility have been implicated to reduce graft-vs-host disease (GVHD) and myeloid leukemia relapse in clinical hematopoietic cell transplantation (HCT). Murine NK cells express subgroups of H-2-specific receptors of the C-type lectin superfamily, termed Ly49, that regulate their function. IL-2 and IL-15 are two important NK cell growth cytokines. We investigated if IL-2- and IL-15-activated alloreactive NK cells would reduce GVHD and mediate graf-versus-leukemia effects in mice undergoing MHC-mismatched allogeneic HCT. 6–8-week-old female specific pathogen-free BALB/c mice were injected intravenously with 1×106 EL9611 erythroblastic leukemia via lateral tail vein. Eight days following leukemia inoculation, leumemia-bearing mice were irradiated (800cGy) with 6MV X—ray and transplanted with 5x106 bone-marrow cells and 10x106 splenocytes from MHC-mismatched C57BL/6 mice. One day following transplantation, recipient mice were given a single infusion of 1×107 IL-2- and IL-15-activated donor NK cells. Recipients of alloreactive NK cells had a significant reduced clinical GVHD scores(p<0.01), and prolonged survival (p<0.01) compared to HCT recipients not receiving alloreactive NK cells. These data provide an in vivo evidence that a single infusion of alloreactive NK cells can reduce GVHD and prolong leukemia-bearing mice survival via graft-versus-leukemia effects following MHC-mismatched allogeneic HCT.
Post Allogeneic Stem Cell Transplant Complications - Single Centre Experience from Pakistan.
Authors: Raza Shahid , Ullah Khalil , Ahmed Parvez , Satti Tariq , Khan Badshah 
Published: October 2019

Abstract
Over last five years 154 patients received HLA matched sibiling transplants at Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan. Indications for transplant included Aplastic anemia, B-Thalassaemia major, Chronic Myeloid leukemia, Acute leukemias, and miscellaneous disorders which included Myelodysplastic syndrome, Fanconi’s anemia, Non-Hodgkin lymphoma, and Gaucher’s disease. All patients received standard conditioning regimens and GvHD prophylaxis. Pre-transplant infection surveillance was carried out in all patients and strict prophylaxis against infection was observed as per our transplant policy. During post transplant follow up we encountered certain infective and non infective complications. These included: acute GvHD (grade II–IV) 28.5%, chronic GvHD 15.5%, haemorrhagic cystitis 9.7%, VOD liver 5.1%, acute renal failure 3.2%, bacterial infections 51.2%, fungal infections 15.0%, CMV infection 4%, herpes zoster 4%, tuberculosis 2.6%, pneumocytitis jiroveci infection 0.6%, malaria 0.6% patient, graft rejection 5.2% patients and relapse in 4%patients. We encountered certain rare unexpected post transplant complications which have been rarely reported in literature before. These included Hickman catheter embolization, Guillain Barre syndrome, co-infection with pneumocystis jirovicii and a rare fungus trichosporon beigilii, cyclosporine induced uncontrolled seizures, idiopathic polycythemia, haemorrhagic pericardial effusion with cardiac temponade, deep vein thrombosis, dengue fever and measles. These complications were effectively managed in our centre. There was only one death associated with these complications. Mortality was observed in 27.2% patients. Mortality related to non-infective complications was 14.2%. Major non-infective causes of mortality were GvHD, VOD, disease relapse, intracranial haemorrhage and acute renal failure. Mortality related to infections was 13%. Fatal infections included CMV disease, disseminated aspergillosis, pseudomonas septicaemia and tuberculosis.
Mesenchymal Stem Cells for Treatment of Refractory Chronic Graft-Versus-Host Disease.
Authors: Jianyu Weng , Du Xin , Peng Xiang , Xiumin Zhang , Wu Suijin , Lu Zesheng , Luo Chengwei , Guo Rong , Deng Chengxin , Ling Wei , Lin Wei , Huang Zilun 
Published: October 2019

Abstract
Refractory extensive chronic graft-versus-host disease (GVHD) after allogeneic stem-cell transplantation (SCT) is associated with high mortality [Margolis J., SeminOncol 2000].However, conventional therapies including steroids are often unsuccessful in those patients with multiorgan involvement and are associated with significant therapy-related complications and poorly life quality. Mesenchymal stem cells (MSCs) have immunomodulatory effects [Tse WT et al., Transplantation 2003; Spees JI et al.,Proc Natl Acad Sci USA 2003]. Recently MSCs have been given intravenously to treat seven steroid resistant acute GVHD patients and one patient with chronic GVHD. MSCs effects in chronic GVHD is rarely known, although this successfully experience suggests that MSCs have been well tolerated and had a powerful immunosuppressive effects on acute GVHD. [Katarina Le Blanc et al., Lancet 2004; Olle Ringden., Transplantation 2006 ]. Here, we present our experience of using MSCs for treatment of Thirteen patients with refractory chronic GVHD. Between May 2005 and March 2007, thirteen patients (8 male, 5female) with hematological malignancies with a median age of 26(range:15 to 40) years who had received peripheral stem cells from sibling donors. All patients developed steroid resistant or extensive chronic GVHD, with progressive involvement of the skin(13), liver(10), oral mucosa(12),ocular glands(12), and thrombocytopenia (1) when the immunosuppressive agents were taped after five to twenty-four months. The MSC dose was median 1.0 ×106 cells/kg body weight of the recipient. In all, thirteen patients had at least received one dose, seven patients received more than two doses. MSC donors were in seven cases HLA-identical siblings, six unrelated mismatched donors. No side-effects were seen after MSCs infusions. All patients have responded after follow-up of the median time 15 months. One patient with moderate cGVHD had a complete responses, and discontinued all of the immunosuppressive agents without relapse more than 18.4 months after MSC infusion. Three moderate and two patients with severe chronic GVHD improved to mild degree, and six severe turned to moderate degree. Complete resolution was seen in gut(2/3), liver(5/10), skin(5/13), oral(6/12) and eye(2/12). One patient responded in skin, liver, oral mucose and eye, but developed in lung (bronchiolitis obliterans, BO) score of 2 which are considered severe chronic GVHD. Mean follow-up periods was 27m (rang: 14 to48m), Leukemia free survival(LFS)rate were 85%(11/13), and the overall survival (OS)rate were 92.3%(12/13). Our experience suggests that MSC infusion is a safe and effective adjunct therapy for refractory extensive chronic GVHD with resistance to conventional therapy. But more prospective, controlled studies with MSCs for treatment of GVHD should be performanced to evaluate this new treatment exactly.
Treatment of Intractable Graft-Versus-Host Disease with Bone Marrow Derived Mesenchymal Stem Cells - A Pilot Clinical Trial.
Authors: Lee Je-Hwan , Choi Seong-Jun , Lee Jung-Hee , Seol Miee , Lee Young-Shin , Ryu Seong-Gil , Kang Young-Ah , Lee Kyoo-Hyung 
Published: October 2019

Abstract
Recent studies have shown that mesenchymal stem cells (MSCs) have profound immunomodulatory function, both in vitro and in vivo. There are several reports to treat effectively therapy-resistant graft-versus-host disease (GVHD) using ex vivo expanded MSCs. We performed a pilot clinical trial to treat intractable GVHD with bone marrow derived MSCs. All of 5 patients, 3 males and 2 females, with steroid-refractory GVHD were included in this study. Age range was 27 to 48 years old. Diagnosis of underlying disease was CML in 2, AML in 1, ALL in 1, and MDS in 1. Hematopoietic stem cell (HSC) donor was a sibling in 2 and an unrelated volunteer in 3. The donor of MSCs was a sibling in all patients: two donors were the same to HSC donors, but other three were not. About 20 mL of bone marrow was aspirated from donors and MSCs were cultured ex vivo. After about 3 weeks, MSCs were harvested for the first infusion, and 4 more weeks’ culture was done for the planned second infusion. The infused doses of MSCs were 5.3 to 6.9 x 106/kg for the first infusion and 1.8 to 7.0 x 106/kg for the second infusion. The onset of GVHD was post-transplant day 24 to 191 and the times from the onset of GVHD to the infusion of MSCs were 73 to 2469 days. There were no adverse events related to the infusion of MSCs. Three patients did not show any response to the treatment of MSCs for GVHD and two showed minimal response: transient improvement of jaundice and diarrhea without improvement of skin GVHD lesions in one patient, and improvement of performance status without significant increase of pulmonary function test parameters in another patient with lung involvement of GVHD. There were no significant changes in hemoglobin, and peripheral blood counts of platelets, leukocytes, lymphocytes, CD3+ cells, CD4+ cells, CD8+ cells, NK cells and B cells over 6 months’ period after the infusion of MSCs. Results of our pilot study suggest that the treatment effects of MSCs may be limited in patients with chronic established GVHD. Further studies on MSCs for GVHD should be focused on acute or exacerbated GVHD.
Adapting Cyclosporine to Calcineurin Activity Rather Than to Cyclosporine Blood Levels: Toward a Functional Management of Graft-Versus-Host Disease Prophylaxis.
Authors: Sanquer Sylvia , Maury Sebastien , Hicheri Yosr , Martin Elvira , Robin Marie , Pautas Cecile , Barouki Robert , Socie Gerard , Kuentz Mathieu , Cordonnier Catherine 
Published: October 2019

Abstract
We have previously shown [1] that a calcineurin activity (CA) < 28 pmol RII/mg proteins/min was significantly associated with the absence of acute GVHD after allogeneic stem cell transplant (SCT). The CA is poorly correlated with cyclosporine (CsA) trough level which is not a good marker of CsA efficacy. Therefore, the in vitro assessment of CA could help in adapting the cyclosporine doses for GVHD prophylaxis, better than blood CsA levels. Objective: The aim of this prospective study was to evaluate the feasibility of adapting the CsA doses to the values of in vitro CA either until GVHD occurs, or until day 100, whichever occurs first.
Methods: CA assessment methods in PBMC of transplant patients and monoclonal CsA level measurement methods were previously reported [1]. CA and CsA levels were measured once a week from d0–d15, twice a week from d16–d35, then once a week up to d100. The CsA doses were adapted in order to maintain a CA < 28 from transplant by 20% progressive changes of the CsA daily dose. Adaptation was stopped in case of clinical CsA blood levels ≥ 600 ng/ml, creatinine clearance < 40 ml/mn, serum bilirubin > 40 m/L, or severe clinical toxicity.
Patients: 39 adult patients with malignant hemotologic diseases (acute leukemia: 28; chronic leukemia: 4; others: 4) or aplastic anemia (3), and undergoing myeloablative SCT were included (HLA-id donor: 20; unrelated donor: 19). GVHD prophylaxis consisted in short course Methotrexate and CsA (initial dose: 3 mg/kg IV).
Results: Out of 39 patients, 2 were adapted until d100 and did not develop GVHD; 27 were adapted without CsA toxicity until they developed GVHD (grade I: n=2; grade II: n=18; grade III–IV: n=7). In 10 (26%) patients, adaptation was stopped before d100, due to neurologic (n=1), renal (n=2) or liver (n=2) toxicity, severe nausea (n=1), investigator decision (n=1) or protocol violation (no CsA increase despite high CA and no CsA toxicity: n=3).
Conclusion: Our study shows that CsA dose adaptation is feasible on the basis of CA regular assessment within the safety limits defined in our protocole. This adaptation is, however, limited by CsA toxicity, due to the need to significantly increase the CsA dose to get a CA < 28 pmol in 26% of the patients. A prospective controlled study is needed to compare the routine use of CA to the use of CsA blood levels for managing CsA doses in GVHD prophylaxis.
Efficacy and Safety of Early Administration of Mycophenolate Mofetil to Steroid-Resistant Acute Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation: A Single Institution Study.
Authors: Mori Masaki , Muroi Kazuo , Matsuyama Tomohiro , Oka Satoko , Yamamoto Chizuru , Ozawa Keiya 
Published: October 2019

Abstract
Introduction: Acute graft-versus-host disease (aGVHD) remains a major problem following allogeneic hematopoietic stem cell transplantation (HSCT), and is associated with significant morbidity and mortality. Mycophenolate mofetil (MMF) has been known as a key drug, with which aGVHD and chronic GVHD are treated in Western countries, but it remains unclear when and how MMF is administered to GVHD in Japan. We evaluated the efficacy of treatment with MMF to steroid-resistant aGVHD.
Patients and Methods: For eligibility, thirteen patients were ten men and three women after eighty-eight HSCT in our center from 2001 to 2007, retrospectively. Among them, 6 acute myelogenous leukemia, 2 acute lymphoblastic leukemia, 2 chronic myelogenous leukemia, 2 lymphoblastic lymphoma, and 1 adult T-cell leukemia were diagnosed. Four peripheral bloods, 8 bone marrows and 1 cord blood were transplanted from 2 mothers, 4 siblings and 7 unrelated donors with the conditioning treatments, including 9 total-body irradiation-based regimen, 2 busulfan plus cyclophosphamide and 2 reduced-intensity regimen. The numbers of HLA-mismatch locus were serologically one at 4/6, four at 5/6, and genetically one at 2/6, three at 4/6 and three at 5/6. GVHD prophylaxis included FK506 plus methotrexate (MTX) and/or antithymocyte globulin for 9 patients, and cyclosporine and MTX for 4 patients. Steroid at a dose of 1∼2 mg/kg per day firstly was administered for the treatment of aGVHD of grade II to IV. Then, all of refractory or steroid-tapering-failure cases were treated with the second-line MMF as the steroid-refractory aGVHD, including methylprednisolone pulse therapy in eight.
Results: Max doses of MMF at 1g of three patients, 2g of nine patients and 3g of one patient were required in our cases, but less than in Western countries as reported. Onsets of MMF starting day were from 27 days to 139 days after HSCT, and less than 53 days among them except for one. Target organs were skin (more than stage 3) in seven, skin+gastrointestinal tracts (GI) in four, and skin+GI+liver in two. Acute GVHD grades were II–IV in all and III–IV in six, even though 12 patients were improved and successfully tapered the amounts of steroid. The adverse events were diagnosed as cytopenia in 2 patients (15%) and infectious events in 7 patients (54%) including CMV antigenemia in 5 patients, though were tolerable to all patients except for one, which discontinued MMF due to grade 3 neutropenia. GI tract disorder was not complicated in all patients. As a consequence, relapse mortality was 31% (4/13), but non-relapse mortality was zero percent.
Conclusion: We consider that MMF is more beneficial and well tolerated for the treatment of steroid-refractory aGVHD, and the early administration of MMF as a second-line therapy is more important.
Chronic Graft Versus Host Disease and Pretransplant Disease Status Predict Outcomes in Patients with Hematologic Malignancies Undergoing Reduced Intensity Allogeneic Stem Cell Transplantation.
Authors: Shah Megha A. , Agha Mounzer , Mapara Markus , Lenhart Kate , Raptis Anastasios 
Published: October 2019

Abstract
Reduced intensity stem cell transplantation (SCT) is an effective treatment modality for patients with hematologic malignancies who are not candidates for conventional myeloablative SCT. We conducted a retrospective review of all patients with hematologic malignancies receiving a reduced intensity allogeneic SCT from July 2002 to July 2007. Data pertaining to patient demographics, engraftment, disease status pre and post transplant, graft versus host disease (GVHD), and HLA matching was analyzed to identify factors significantly affecting the clinical outcome. Seventy three patients, with a median age of 55 (range of 19–70) and with the diagnoses of ALL (n=8), AML (n=30), CLL (n=3), CML (n=1), Hodgkin’s (n=7), non-Hodgkin’s (n=7), MDS (n=11), and MM (n=6) underwent a reduced intensity SCT using a fludarabine based conditioning regimen. Thirty nine (53%) received unrelated donor grafts and 34 (47%) received sibling donor grafts. Fifty six patients (77%) received fully matched grafts whereas 17 patients (23%) had an antigen or allele mismatch. Acute GVHD grade II-IV was observed in 27 of the 73 patients and chronic GVHD was seen in 18 of the 48 patients who could be evaluated. Seventeen patients developed transplant related fatal complications and 30 patients died from disease progression or relapse. Median time to neutrophil recovery was 15 days (range of 9–41 days) and median time to platelet recovery was 18 days (range of 9–42 days). Graft failure was observed in 6 of the 73 patients. Median overall survival and disease free survival for all patients was 7.7 and 6.6 months respectively. Median overall survival for patients with persistent disease or in remission at the time of the SCT was 5.6 and 21.8 months (p= 0.01) while that for disease free survival was 5.7 and 8.4 months (p=0.06). Median overall survival with and without chronic GVHD was 25.6 and 9.4 months (p <0.0001) while median disease free survival was 18.2 and 6.0 months (p< 0.0001). Patients with limited chronic GVHD have not yet reached median overall survival while the median disease free survival was 18.4 months. Those with no or extensive chronic GVHD had medians of 9.4 and 9.2 months for overall survival and 6.0 and 9.2 months for disease free survival (p= 0.004 and p=0.02). The source of the stem cells as well as the administration of allele or single antigen mismatch grafts did not affect the outcome. Reduced intensity SCT is an effective treatment modality in patients with hematologic malignancies, though it is most effective in patients who are in remission at the time of transplant and should be offered in this setting. Patients with limited chronic GVHD had a better outcome suggesting the presence of potent anti-tumor activity of the donor immune competent cells without the detrimental effects in clinical outcome caused by extensive chronic GVHD.