bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibodies to CD40 Promote Dendritic Cell Recovery and Anti-Tumor Effects after Syngeneic Bone Marrow Transplant (BMT).
Authors: Welniak Lisbeth A. , Berner Vanessa , Blazar Bruce R. , Wiltrout Robert H. , Murphy William J. 
Published: April 2020

Abstract
Disease relapse remains a principle cause of mortality following autologous hematopoietic transplant. Strategies to enhance immune function in the post-transplant setting are needed to eliminate residual disease. CD40 stimulation through the use of agonistic CD40 antibodies has been shown to promote anti-tumor activity both as a single agent and in combination with IL-2 administration with increases in dendritic cell numbers being observed. We hypothesized that CD40 stimulation in combination with myeloablative syngeneic hematopoietic cell transplantation can act together to promote anti-tumor responses. We developed a model in which anti-CD40 given with syngeneic BMT was assessed in advanced tumor-bearing mice. We have found that delaying administration of anti-CD40 for one week post-BMT could obviate the severe toxicity associated with immediate post-BMT administration. BALB/c were given a syngeneic renal cell carcinoma cell line (Renca) i.v. After 4 days, at which time lung metastases were established, the mice were treated with syngeneic BMT followed one week later with initiation of anti-CD40 treatment (100 μg/dose; daily, 4 days per week for 2 weeks). CD40 stimulation resulted in significant expansion of GR-1+/CD11b+ myeloid and CD11c+/I-A+ dendritic cells in the spleen, similar to the expansion of these populations observed in mice that received anti-CD40 and no BMT. However, while B220+ IgM+ B cells are significantly expanded following anti-CD40 administration in mice that do not receive a transplant, B cell recovery is reduced following transplant in mice that also received anti-CD40. T cell recovery post-transplant did not differ significantly in animals that received anti-CD40 or control antibody. Importantly, significant increases in survival of anti-CD40 treated, tumor-bearing recipients of syngeneic BMT were observed compared to either treatment alone (log-rank test p&lt; 0.001). This promotion of anti-tumor activity by CD40 stimulation was seen in mice that were profoundly T cell deficient due to the transplant. These data suggest that despite severe immune depletion that occurs after lethal TBI, immunomodulation by anti-CD40 can result in significant protection from the residual disease despite the severe lack of T cells at this time period.
CD4+CD25+ T Cells Can Inhibit CD8 T Cell Mediated GVHD: Requirement for In Vivo Recognition of Allogeneic Host MHC Class II Antigens.
Authors: Levy Robert B. , Jones Angela 
Published: April 2020

Abstract
CD4 regulatory T (Treg) cells have shown promise in the transplantation mileu including the ability to inhibit the development of graft vs host disease (GVHD) following allogeneic hematopoietic stem cell transplants (HCT). The antigen specificity of the Treg population(s) involved is not yet clear nor is the role of their activation following transplant. We are interested in determining the requirement for recognition of host MHC antigens following infusion of CD4+CD25+ T cells in an experimental model of GVHD. To clearly distinguish the requirements of regulatory vs GVH reactive cells, a model of CD8 T cell mediated GVHD was developed using highly purified BALB/c (H2d) donor CD8+ T cells (Miltenyi column, 95-98%). CD8 T cells were transplanted together with T cell depleted (TCD) BALB/c BMC into 12.0 GY (6.0 Gy split dose) TBI conditioned C57BL/6 (B6, H2b) recipients. To support development of GVHD by these cells, resistance was inhibited by treatment of recipients with anti-NK1.1mab (PK136) at Days -1, 0 and +7. BALB/c CD8+ T cells at doses of 5.0x106 but not 2.5x106 induced weight loss and some lethality in B6 recipients. 5x106 CD8+ T cells were then transplanted into B6-MHC class II−/ − recipients. GVHD symptoms including weight loss and lethality were readily apparent in these mice post-transplant. Interestingly, GVHD was consistently more severe with respect to the induction of weight loss and lethality in MHC Class II−/ − vs B6-wt recipients. Highly enriched BALB/c CD4+CD25+ T cells (&gt; 95%) were produced from spleen and lymph node cells following negative (B-cells, CD8 and NK) and positive (CD25) selection using Miltenyi magnetic bead columns. Co-transplant of 1x106 CD4+CD25+ T cells together with BALB/c CD8+ T cells into B6 recipients inhibited GVHD as assessed by the absence of weight loss and lethality compared to B6 recipients of CD8+ T cells alone. In contrast, BALB/c CD4+CD25+ T cells failed to protect B6-MHC class II−/ − recipients from severe CD8+ T cell mediated GVHD. These findings demonstrate that donor CD4+ T regulatory cells can suppress GVHD inducing CD8+ T cells after the former recognize host class II alloantigen following transplant. We hypothesize that activated CD4+CD25+ T regulatory cells inhibit GVH reactive T cells at the host APC interface. Future studies in this model can be designed to examine ex-vivo activated and expanded CD4+CD25+ T regulatory populations. Transplant of such cells will enable us to address questions regarding the importance of in vivo recognition of host class II in the regulation of GVHD by these cells.
Deficient Ribosomal Protein S19 in Diamond-Blackfan Anemia Causes a Reduction in bcl-2 and Bad and Leads to Apoptosis in Erythroid Progenitor Cells.
Authors: Miyake Koichi , Utsugisawa Taiju , Flygare Johan , Kiefer Thomas , Hamaguchi Isao , Richter Johan , Karlsson Stefan 
Published: April 2020

Abstract
Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein (RP) S19 gene. It is not known how the RPS19 deficiency impairs erythopoiesis and proliferation of hematopoietic progenitors. We have established an in vitro models for RPS19 deficient DBA using lentiviral vector mediated doxycycline (Dox) inducible small interfering RNA (siRNA) against RPS19 (Mol Ther.11:627–637. 2005). Suppression of cell growth and erythroid colony formation correlated with the suppression level of RPS 19, indicating that these cell lines are useful to determine the mechanisms of RPS19 deficient DBA. To elucidate molecular mechanisms in RPS19 deficient DBA, we analyzed cell cycle of Dox induced RPS19 deficient TF-1 cells. RPS19 deficient TF-1 cells showed G0/G1 arrest (82% vs 58%, p&lt;0.05) together with accumlation of p21 and p27, and apoptotic cells detected by Annexin-V analysis also increased compared to control Dox induced TF-1 cells (13% vs 3.1%, p&lt;0.05). Increase of apoptotic cells in RPS19 deficient cells was confirmed by TUNEL assay. Western blot analysis of apoptotic related protein showed that the level of bcl-2 and Bad was decreased in RPS19 deficient TF1 cells compared to control cells. This down-regulation of apoptotic related protein was improved by transduction with lentiviral vector expressing modified RPS19, which is not affected by siRNA but produce normal functional RPS19 protein and rescues the DBA phenotype. Moreover, primary CD34 positive cells from DBA patients detected by Annexin-V analysis also generate a high number of apoptotic cells compared to normal CD34 positive cells during in vitro culture (38% vs 8.9%, n=5, p&lt;0.001). These findings indicate that erythroid progenitor cells are more sensitive to apoptosis than other hematopoietic progenitors and that RPS19 deficiency causes apotosis and accelerated loss of erythroid progenitors in RPS19 deficient DBA.
Adoptive Infusion of Allogeneic KIR Ligand Mismatched NK Cells Reduce GVHD in an MHC Matched Allogeneic Stem Cell Transplantation Model.
Authors: Lundqvist Andreas , Samsel Leigh , Eckhaus Michael , Srinivasan Ramaprasad , Takahashi Yoshiyuki , Snoeijs Maarten , McCoy Philip J. , Berg Maria , Childs Richard 
Published: April 2020

Abstract
Retrospective data suggest NK cells play a role in protecting recipients from graft versus host disease (GVHD) in the setting of killer IgG-like receptor (KIR) ligand incompatibility. In humans, this protective effect is most evident with MHC mismatched transplantation, usually following in vivo or in vitro T-cell depletion. In MHC mismatched murine transplant models, lethal GVHD is reduced following the adoptive infusion of KIR ligand mismatched NK cells; it is unknown whether NK cells can mediate similar protective effects following MHC matched transplantation. Therefore, we investigated the impact of adoptively infusing KIR ligand mismatched NK cells on GVHD in an MHC matched T-cell replete murine model of allogeneic transplantation. Balb/C recipient mice underwent allogeneic bone marrow (8 x 106 cells) and splenocyte (15 x 106 cells) transplantation from B10.d2 donors following 950cGy of irradiation. Allogeneic B10.d2 donor NK cells were first isolated by negative depletion using magnetic beads selecting for CD4, CD5, CD8a, CD19, Gr-1 and Ter-119, and then expanded over 4-6 days in vitro in DMEM media containing 10% FCS and 500U/ml of IL-2. NK cell subsets (KIR ligand matched vs. KIR ligand mismatched) were then isolated by flow cytometry into Ly49I/C+ NK cells (KIR ligand mismatched in the GVHD direction for Balb/C recipients) and Ly49A/G+ NK cells (KIR ligand matched for Balb/C recipients). On day +4, recipient mice received a single tail vein injection with either KIR ligand matched, KIR ligand mismatched or unsorted “bulk” NK cells (0.5–1.0 x 106 NK cells). All (9/9) control transplant recipients (no adoptive NK cell infusion) as well as recipients of Ly49A/G (KIR ligand matched) NK cells (13/13) developed skin GVHD, in contrast to 4/7 (57%, p=0.03) recipients of bulk NK cells and only a minority (13% [1/8], p &lt; 0.01) of animals receiving KIR ligand mismatched NK cells. Using a cumulative clinical GVHD scoring system (total score = 9), overall GVHD was decreased in recipients of KIR ligand mismatched NK cells (median score = 0 at day +45) compared to mice that received KIR ligand matched NK cells (median score = 3; p = 0.15) or no NK cells (median score = 3; p= 0.12); no significant difference in survival was observed between cohorts. This murine model provides the first in vivo evidence that adoptively infused KIR ligand mismatched allogeneic NK cells reduce GVHD following T-cell replete MHC matched allogeneic transplantation. The impact of infusing multiple doses of KIR ligand mismatched NK cells on GVHD and their ability to induce a graft-vs-tumor effect in tumor bearing Balb/c mice is currently being evaluated.
Lymphopenia-Associated CD4+ T Cell-Mediated Colitis Correlates with Homeostatic but Not with Endogenous Proliferation.
Authors: Blank Christian , Schuster Kerstin , Andreesen Reinhard , Mackensen Andreas 
Published: April 2020

Abstract
Transfer of peripheral T cells into lymphopenic hosts results in a burst-like proliferation, called endogenous proliferation (EP) and an antigen-independent proliferation, called homeostatic proliferation (HP). Formerly both were named lymphopenic or homeostatic proliferation. T cells that undergo either endogenous or homeostatic proliferation acquire an activated phenotype, develop the ability to produce Interferon-gamma (IFN-g) and to lyse target cells specifically, but only homeostatic proliferating T cells acquire a CD44bright CD62Lbright phenotype.
We developed a murine model to distinguish effects of both types of lymphopenia-associated proliferation. In this model we were able to induce polyclonal populations of syngenic CD4+ or CD8+ peripheral T cells (derived from C57BL/6 mice) to proliferate homeostatically (after transfer into lymphopenic RAG−/− mice) whereas only EP occurred when transferring into mice that inherit only an additional single CD8+ T cell clone (transfer into the non-lymphopenic P14/RAG−/− mice).
CFSE dilution was observed from CD4+ or CD8+ T cells transferred into RAG−/− mice, whereas HP was inhibited when transferring the same cells into P14/RAG−/− mice, whereas EP occurred in both recipients. Independent of CFSE dilution T cells developed CD44bright phenotype after transfer into RAG−/− as well as in P14/RAG−/− mice as early as day 5, whereas the host P14tg CD8+ clone kept its naïve phenotype.
Applying our model on the CD4+ T-cell-induced colitis model, we found HP to play a pivotal role in induction of colitis. Despite the notion of EP being triggered by antigens from the bowel, colitis was only induced when HP occurred, independent of the occurrence of EP. In detail CD4+ T cells induced colitis 10 weeks after transfer into RAG−/− mice (EP and HP). However neither RAG−/− mice transplanted with CD8+ T cells nor P14/RAG−/− mice transplanted with CD4+ T cells (only EP) developed any signs of colitis. In addition the treatment with or without antibiotics during these 10 weeks did not influence on the induction of colitis.
We therefore conclude that the lymphopenia-mediated colitis after transfer of polyclonal CD4+ T cells correlates only with the occurrence of homeostatic proliferation. Furthermore the absence of regulatory CD4+CD25+ T cells within the suppressing P14 tg CD8+ clone indicates HP-induced colitis to be mediated by competition for cytokines or self-MHC stimulus. These findings might be of important relevance for research concerning chronic inflammatory bowel disease and donor lymphocyte induced colitis.
Graft-Versus-Tumor Activity Against Renal Cell Carcinoma in a Mouse Model of HSCT.
Authors: Ramirez-Montagut Teresa , Chow Andrew , Kochman Adam A. , Hubbard Vanessa M. , Suh David , Smith Odette M. , Sindhi Hamad , Terwey Theis H. , Kim Theo D. , Waldman Elisha , Alpdogan Onder , van den Brink Marcel R.M. 
Published: April 2020

Abstract
Patients undergoing hematopoietic stem cell transplantation (HSCT) have demonstrated responses against several solid tumors including renal cell cancer (RCC) (Childs et al. NEJM 2000). Currently, there is no murine model available to study the role of graft-versus-tumor (GVT) activity in RCC rejection. Here we demonstrate GVT activity against the renal cell carcinoma line RENCA in a MHC class I/II disparate model of C57BL/6 into BALB/c. This line has been transduced with the luciferase gene (RENCA-TGL) that allows for bioluminescence imaging (BLI) of tumor burden. Lethally irradiated recipients of T-cell depleted marrow (TCD) recipients challenged with RENCA succumb rapidly to tumor death while addition of 0.3x10^6 donor CD8+ T cells significantly prolongs survival (median survival of 34 vs 72 days, P &lt; 0.0001) and delays tumor progression (measured by BLI). Mortality in mice challenged with RENCA compared to RENCA-TGL is similar, demonstrating that rejection is not dependent on the immunogenicity of the transduced genes. Recipients of TCD-BM + CD8+ T cells without tumor cells survive and develop minimal graft-versus-host disease (GVHD), demonstrating that CD8+ T cells can mediate potent GVT activity without lethal GVHD activity. We used T cells from donor mice deficient in cytotoxic molecules including IFNγ, TNFα, perforin, and Fas ligand (FasL) to determine the mechanism of GVT activity and found that GVT activity against RENCA activity does not require TNFα or perforin but is dependent on IFNγ and FasL. We determined the clinical significance of our findings in a minimal residual disease model. Recipient mice were challenged with RENCA-TGL one week prior to HSCT to allow for seeding of lung micrometastases. Hosts receiving bone marrow and CD8+ T cells have significantly increased survival and delay in tumor progression compared to recipients of TCD-BM without T cells. These results demonstrate GVT activity in a model similar to the clinical presentation of patients diagnosed with RCC. In conclusion, CD8+ GVT activity against RCC is dependent on IFNγ and FasL and significantly increases host survival without lethal GVHD. Our results provide the first experimental mouse model to study strategies to enhance allogeneic HSCT in the treatment of RCC.
PedsQL™ and EuroQol Most Responsive Measures To Change in Health-Related Quality of Life in Children with Hodgkin’s Disease.
Authors: Klaassen Robert J. , Barrowman Nicholas J. , Barr Ronald D. , Krahn Murray , Hughes Joanna , Rogers Paul , Anderson Ronald , Grundy Paul , Ali S. Kaiser , Yanofsky Rochelle , Jardin Lawrence , Abla Oussama , Silva Mariana , Carret Anne-Sophie , Barnard Dorothy , Cappelli Mario 
Published: April 2020

Abstract
We evaluated four different health related quality of life measures to determine their ability to detect change over time. The four measures included the Health Utilities Index Mark 2 and 3 (HUI 2/3), the PedsQLTM 4.0 Generic Core and Cancer Module, the EuroQol and the Lansky Play - Performance Scale. Children with Hodgkin’s disease, their parents and the clinic nurse were all asked to complete the four measures at four time points: 2 weeks after the 1st course of chemotherapy, on the 3rd day of the 2nd course of chemotherapy, during the 3rd week of radiation and 1 year after diagnosis. At each follow up time point the respondents were asked to indicate whether the child’s HRQL had improved, stayed the same or became worse since the last measurement. 51 adolescents from 12 centres across Canada were enrolled in the study between May 1, 2002 and March 31, 2005. Two patients were excluded: one patient died shortly after the first time point, and the other patient failed to complete any of the questionnaires. The 49 patients included in the analysis had an average age of 14.7 years (8.9 - 17.9), with the two most common stages being IIA (39%) and IVA (18%). Complete data was available on 92% of patients at time 2, 89% at time 3 and 76% at time 4. Four of the 36 patients with complete follow up had relapsed (11%). The summary scores from the patients responses can be seen in the graph below.
Figure Figure
All measures showed a significant change between time 1 and time 4 (&lt;0.05). When the change in child scores was analysed between the time points using the child’s self-reported change in HRQL, the PedsQL and the EuroQol showed significant change at all time points.
Change in Measures According to Reported Global Rating of Change by Patient Time Period HUI2 HUI3 PedsQL PedsQL cancer EuroQol Lansky Improved 1 to 2, n = 7 0.022 0.011 0.015 0.046 0.001 NS 2 to 3, n = 15 NS NS 0.028 0.039 0.017 NS 3 to 4, n = 20 NS NS 0.011 NS &lt;0.001 &lt;0.001 Same 1 to 2, n = 16 NS NS 0.033 NS NS NS 2 to 3, n = 9 NS NS 0.039 0.006 NS 0.028 3 to 4, n = 1 NS NS NS NS NS NS Worse 1 to 2, n = 6 NS NS NS NS 0.033 NS 2 to 3, n = 0 NS NS NS NS NS NS 3 to 4, n = 1 NS NS NS NS NS NS
All of the measures were able to detect change in a diverse group of children with Hodgkin’s Disease. The PedsQL and the EuroQol appeared to be the most sensitive to change.
Quality of Life (QOL) in Sickle Cell Disease (SCD).
Authors: Pakbaz Zahra , Richards Leah , Treadwell Marsha , Hackney-Stephens Ekua , Quirolo Keith , Vichinsky Elliott 
Published: April 2020

Abstract
Introduction Assessment of QOL is important for clinicians, as it will allow them to provide the patients with better care. The objective of this study is to assess the QOL in SCD patients. Methods A convenience sample of 34 patients with SCD (50% female) with a mean age of 21 years (SD= 9.4 y), completed a Dartmouth Care Cooperative Chart System (COOP) questionnaire (Table 1) during a comprehensive clinic visit at Children’s Hospital & Research Center in Oakland. High scores (patient ratings of 4 or 5) represent unfavorable levels of health or major limitations. A score of 3 represents moderate impairment while scores of 1 or 2 indicate no impairment. A brief chart review was completed to obtain medical history. Results 60% of the transfused patients (Tx) had severe impairment in at least one domain and this was the case in 71% of non-transfused patients (Non-Tx). As shown in table 2, the most affected domains were different between the two groups of Tx and non-Tx. In non-Tx patients the most affected domains were those of pain, overall health, and social support. In Tx patients, the most affected domains were pain, daily activities, and change in health. Although both groups had a similar amount of pain (non-Tx=42% and Tx=50%), Tx patients reported a better overall QOL (question 9). The most common complications that non-Tx patients suffered from were AVN (71%), vaso-occlusive episodes (46%), acute chest syndrome (46%), pneumonia (17%), reactive airways disease (17%), chest pain (13%), headaches (13%), and sepsis episodes (13%). Data showed that 30% of the Tx patients suffered from strokes previous to start of transfusion. The most common complications found in these patients were acute chest syndrome (30%), reactive airways disease (50%), urinary tract infections (20%), and depression (20%). Conclusions Both transfused and non-transfused SCD patients suffer from serious impairments in QOL. We recommend all SCD patients undergo QOL assessments and intervention which focuses on affected domains. Studies are needed to determine the impact of complications on QOL.
Table 1. COOP Questionnaire Q1 Physical Fitness Q2 Feelings Q3 Daily Activities Q4 Social Activities Q5 Pain Q6 Change in Health Q7 Overall Health Q8 Social Support Q9 Quality of Life Table 2. Frequency of moderate to severe impairment of domains Non-Tx Tx Score 3 (%) Score 4/5 (%) Score 3 (%) Score 4/5 (%) Q1 13 25 10 10 Q2 33 25 11 11 Q3 27 1 22 22 Q4 1 1 0 20 Q5 21 42 10 50 Q6 21 17 38 25 Q7 29 33 10 30 Q8 26 30 13 13 Q9 33 17 20 0
The Likelihood of Hematopoietic Stem Cell Transplantation (HCT) in the United States: Implications for Umbilical Cord Blood Storage.
Authors: Pasquini Marcelo C. , Logan Brent R. , Verter Frances , Horowitz Mary M. , Nietfeld J.J. 
Published: April 2020

Abstract
HCT effectively treats a variety of malignant diseases. Availability of suitable grafts limits application in some cases, prompting the establishment of banks to store umbilical cord blood for later personal or family use. The likelihood of utilizing stored cells depends, in part, on the likelihood of developing a condition for which HCT is indicated. This study estimates the latter likelihood based on data for current HCT use as reported to the CIBMTR from 2001 through 2003. First, age-related incidences of HCT were calculated; then, using the cumulative incidence function, we calculated the lifetime likelihood under two scenarios. In scenario 1, we calculated the likelihood of receiving an autologous HCT by age, in decades, from birth to 70 years. In scenario 2, we calculated the likelihood of being a candidate for either an autologous or an allogeneic HCT. This likelihood was derived from the number of HLA-identical sibling HCTs multiplied by three (to account for patients considered acceptable candidates but lacking an HLA-matched sibling donor) in addition to the number of autologous HCT. The number of HCT performed represented fewer than 20% of the malignant diagnoses most commonly treated with HCT, according to Surveillance, Epidemiology and End Results (SEER) data. After the second decade of life, the age-related incidences of HCT under both scenarios steadily increased with age. The cumulative incidences for scenario 1 ranged from 0.02% (at age 20) to 0.23% (at age 70); for scenario 2 they ranged from 0.06% (at age 20) to 0.46% (at age 70) (Figure). Given the current indications for HCT, the lifetime likelihood of undergoing an autologous HCT or being a candidate for HCT is about 1 in 400 and 1 in 200, respectively. How closely these estimates correspond to the likelihood that a stored cord blood unit is used depends upon several conditions including a) sufficient number of stem cells; b) satisfactory stem cell quality after the storage period; and, c) relative attractiveness, in particular clinical situations, of cord blood cells compared to other graft sources (e.g. peripheral blood or bone marrow).
Figure Figure