bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD27/CD70 mediated negative regulation of inflammatory T cell response
Authors: ONeill Rachel , Leigh Nicholas , Du Wei , Kumar Sandeep , Chen Chuan , Qiu Jingxin , Chen George , Borst Jannie , Ashwell Jonathan D , McCarthy Philip , Cao Xuefang 
Published: January 2023

Abstract
Costimulatory pathways are involved in T cell activation and function. The costimulatory molecule CD27 is a TNF receptor family member expressed on T cells and its ligand, CD70, is known to be expressed on activated antigen-presenting cells, T-, B- and NK cells. The CD27/CD70 pathway has been shown to be critical for T cell activation, differentiation and survival. In this study we have used murine models to study the roles of CD27/CD70 in allogeneic graft-versus-host disease (GVHD) and syngeneic inflammatory bowel disease (IBD). Our results reveal a novel and negative regulatory role played by this pathway as specified in 3 aspects: 1) Allogeneic hematopoietic cell transplantation (allo-HCT) shows that both CD27−/− and CD70−/− donor T cells caused more severe GVHD than WT donor T cells, suggesting that CD27/CD70 signaling in donor T cells inhibits allogeneic T cell response. 2) When transplanted into syngeneic RAG1−/− hosts in an autoimmune IBD model, both CD27−/− and CD70−/− donor CD4+ CD25− T cells caused more severe IBD than WT T cells, suggesting that CD27/CD70 signaling in T cells inhibits autoimmune T cell response. 3) When used as hosts for allo-HCT, both CD27−/− and CD70−/− mice exhibited more severe GVHD compared to WT mice, suggesting that CD27/CD70 signaling in the host inhibits allogeneic T cell response. Mechanistic analyses reveal that this pathway executes immune suppression by limiting T cell expansion and effector function (e.g., TNFa and IFNg production) via a regulatory T cell-independent mechanism that at least partially involves activation-induced T cell death. Overall, our study demonstrates that CD27/CD70 signaling plays a novel role in suppressing allogeneic and autoimmune inflammatory T cell responses.
T-cell depleted haploidentical hematopoietic stem cell transplantation is the optimal graft source for patients with familial hemophagocytic lymphohistiocytosis who do not have matched family donors.
Authors: DENNISON Jayakumar David , Al Rawas Abdulhakeem , Al Ghaithi Hamed , Al Khabori Murtadha , Tauro Melanie , Al Mamari Sahimah , Al Zadjali Shoaib , Al Said Bushra , Nazir Hanan , Tony Surekha , Saad Ashraf , Al Abri Qamariah , Al Farsi Khalil , Al Tamemi Salem , Wali Yasser , Al Kindi Salam , El Shinawy Mohamed , Zachariah Mathew , Mathew Leni , Al Huneini Mohammed 
Published: January 2023

Abstract
Familial hemophagocytic lymphohistiocytosis (HLH) is a fatal disorder of immune regulation. When managed appropriately with systemic chemotherapy, cure can be achieved by subsequent allogeneic hematopoietic stem cell transplantation (HSCT). Although the best results are obtained with matched-family donors (MFD), alternative donor transplants may be necessary when such donors are not available. As there is urgency to proceed with curative therapy, T-cell depleted haploidentical HSCT could be a viable option as a parent or other haploidentical family member would be available instantly. Between August 2010 and September 2015 we performed haploidentical HSCT for six patients with HLH in this institution. These patients did not have MFDs, and in our center it was logistically easier to perform an haploidentical HSCT rather than to pursue with an unrelated donor or cord blood search from the international registries. The median age at transplant was 6 months (5–31 months) and all had perforin gene mutations. The first two patients had CD3/CD19 depleted procedures while the rest underwent TCR alpha/beta and CD19 depletion for faster immune reconstitution. All six patients engrafted following the transplant with minimal graft versus hot disease. Four patients are cured from the disease with a median follow-up of 3 years (7mths to 5 years). Two patients (siblings) who were transplanted in partial remission expired 2 months following transplant from multi-organ failure after successful engraftment. In the presence of an appropriate transplant laboratory facility, T-cell depleted haploidentical HSCT should be considered as the graft of choice for patients with HLH who do not have HLA-matched family donors.
A novel anti-CD40 antibody prevents activation of alloreactive T cells and prolongs skin allograft survival
Authors: Jangalwe Sonal N , Ralph Kerry , Ramanujam Meera , Greiner Dale L , Brehm Michael A 
Published: January 2023

Abstract
Targeting the CD40-CD154 pathway to induce transplantation tolerance has been of interest to transplantation immunologists for over two decades. The efficacy of anti-CD154 antibody (Ab) observed in murine and non-human primate models for preventing allograft rejection and suppressing autoimmunity, generated great interest in the development of this antibody for clinical use. However, clinical trials with anti-CD154 Ab resulted in thromboembolic complications in patients as a result of CD154 expression by human platelets and limited the clinical application. To develop an alternative approach to anti-CD154 Ab, recent efforts have focused on targeting its receptor, CD40. In this study we evaluated the effects of a novel murine antagonistic antibody to CD40 (BI CD40-1) on alloreactive immune responses. Costimulation blockade consisting of donor splenocytes (DST) and BI CD40-1 reduced activation of alloreactive CD8 T cells as shown by inhibition of expansion, decreased cytokine production and decreased killing of allogeneic targets using an in vivo cytotoxicity assay. Moreover DST/BI CD40-1 treatment significantly prolonged skin graft survival in a BALB/c to B6 MHC mismatch model. The efficacy of BI CD40-1 in preventing alloreactive T cell responses was similar to anti-CD154 Ab. These results indicate that anti-CD40 Ab is an attractive candidate for translation to clinical application.
The increase in thymopoiesis following T cell progenitor therapy is dependent upon the input population and continued interaction between developing T cells and the thymic microenvironment.
Authors: Smith Michelle J , Reichenbach Dawn K , Parker Sarah L. , Mohtashami Mahmood , Stefanski Heather E. , Hogquist Kristin Ann , Holländer Georg A. , Zúñiga-Pflücker Juan Carlos , Blazar Bruce R 
Published: January 2023

Abstract
The inclusion of in vitro derived T cell progenitor (proT) therapy with hematopoietic stem cell transplant (HSCT) aids in the recovery of the thymus damaged by total body irradiation and improves de novo thymopoiesis. To understand the interaction between proTs and the thymic microenvironment, wildtype (WT) mice were lethally irradiated and given T cell deficient donor (Rag1−/−) marrow along with in vitro generated proT from WT donors, limiting mature T cell development to infused proT. Donor proTs within the host thymus led to a significant increase in thymic epithelial cell (TEC) numbers by day 21 post-transplant, and increased actively cycling TECs as measured by Ki67 expression and BrdU uptake. However, that gain was temporary and lost by day 28, suggesting that continued signaling from proT cells is required to sustain TEC cycling and mass. We also find a significant improvement in total thymocyte number by day 21 followed by a significant increase in the total mature T cell number in the secondary lymphoid organs by day 28. This protective surge is also temporary, receding by day 60. In this time period, infused DN2 proTs selectively increased thymocyte number while DN3 proTs preferentially led to a greater TEC numbers. Interestingly, an exception in persistence occurs when DN3 proTs are used and the increase in mature T cells in the spleen persists at day 60. As a result of the lack of competition for thymic niches by cells from the Rag1−/− graft, a subpopulation of the infused proT persisted in the thymus in an immature state at day 60. These findings highlight the importance of the interaction between developing T cells and TECs in the proliferation and survival of these critical components of the thymic microenvironment.
Peripheral blood natural killer cell precursors arising in early post transplant period have a mixed myeloid and lymphoid phenotype
Authors: Schafer Jolie Rae , Ciurea Stefan , Lee Dean 
Published: January 2023

Abstract
Immune cell reconstitution after hematopoietic stem cell transplantation (HSCT) has a major impact on patient survival and cancer relapse. In studying immune reconstitution after haploidentical HSCT we observed that some patients had high NK-cell-like activity despite systemic immunosuppression and low numbers of mature CD3-CD16+CD56+ NK cells. Using high-parameter mass cytometry we identified a unique subset of immune cells with both myeloid and lymphoid phenotype and NK cell like function. These CD3-negative cells are the dominant cell type in the lymphocyte FSC/SSC region one month after haplo transplant. They are uniquely identified by the expression of CD4, CD14, and KIR2DL2/3, and also express CD16, HLA-DR, CD11a, CD80, CD86, and NKG2A. To determine their proliferative capacity, we purified myeloid-like NK-like cells by sorting CD3−/4+/14+/KIR2DL2+ cells from peripheral blood of patients and expanded these cells in the presence of the K562 clone9.mbIL21 feeder cells. The average expansion was 32 fold after 2 weeks. After expansion, the myeloid-like NK-like cells lost expression of CD4 and reduced expression of CD14 and KIR2DL2/3, but gained expression of CD56. Our data is consistent with recent reports suggesting that some NK cells may differentiate from myeloid progenitors. Additional phenotyping and functional analysis is being investigated, as is assessing their frequency in normal peripheral blood, cord blood, or after HSCT from other donor types.
NKT cells in the liver are important for periferal tolerance induction
Authors: peng wang zhan , hongyu liu , zhuonan li , Reyes Jorge D. , Perkins James D. , wei li 
Published: January 2023

Abstract
NKT cells are mainly located in the liver in mice. The role of liver inherent NKT cells are still unclear.

Method
In this study, we employed mouse orthotopic liver transplantation and heterotopic heart transplantation models to critical examine the role of liver NKT cells in liver and peripheral tolerance induction.

Results
NKT cells were increased in the tolerated liver grafts which expressed higher levels of CD95L and PD-L1, while the CD4+CD25+Foxp3+ regulatory T cells (Treg) were markedly increased in the both liver and spleen at day 7 post transplantation. The heart allograft survival were prolonged significantly in the recipient which accepted donor spleen cells by portal vein (p.v.) injection in contract to the recipient which received the donor spleen cells by tail vein (i.v.) injection. In vitro immunological assay revealed that the number of NKT cells in the liver was increased and Treg were increased in both liver and spleen from the p.v. treated mice significantly. The IL-2 expression was decreased, IL-4 and IL-10 were increased. Further, significantly increased IL-4, IL-10, and IFN-γ production was detected from liver NPCs under aGalCer stimulation.

Conclusion
NKT cells are important to liver transplant tolerance induction, appear to play a key role in down regulation of peripheral immune responses and facilitate CD4+CD25+Foxp3+ Treg induction.
Non-hepatic Islet transplantation: Local Delivery of Reagents to Aid in Islet Engraftment
Authors: Gebe John A , Gooden Michel D , Vernon Robert B 
Published: January 2023

Abstract
Islet transplantation offers a potential cell replacement treatment for type 1 diabetes, but faces a number of significant challenges, including: 1) poor short-term islet survival and 2) long term islet loss by alloimmunity and recurring autoimmunity.

Method
We have developed a Bioengineered Islet Implant (BII) device that incorporates local biological reagent delivery to promote islet immune tolerance and survival. The BII consists of two integrated components: a poly-vinyl-alcohol (PVA) scaffold to support islets within a collagen hydrogel, and a local drug delivery mechanism located within the implant device through incorporating drug-alginate delivery system.

Results
The implant device is capable of reversing STZ-induced diabetes when implanted in mesentery or subcutaneous sites. Short-term islet survival measured at 24 hours is enhanced in recipient transplants utilizing BII incorporating local delivery of VEGF. As proof-of-concept for delivery of local immunomodulators together with transplanted islets, we incorporated anti-CD3e MAb (2C11) or anti-CD95 MAb (Jo-2) within the BII, and respectively found dramatically reduced lymphocyte infiltration into islets and a delay in the onset of diabetes in the DO11/RIP-Ova murine model of T1D. In addition, local delivery within the BII of the extracellular component hyaluronic acid led to the generation of enhanced antigen-specific IL-10 responses.

Conclusion
These data demonstrate the potential for a novel strategy of islet cytoprotection during transplantation, providing a suitable matrix and local immunomodulation capable of supporting islet cell engraftment, survival, and function in non-hepatic sites without encapsulation.
Decreased frequency and impaired function of circulating Tregs from renal transplant patients under long-term Belatacept treatment
Authors: ALVAREZ EVELYN KATY , CORTÉS ARIMELEK , ALEMÁN GERMÁN , ALBERÚ JOSEFINA , GARCÍA EDUARDO , SOLDEVILA MARIA GLORIA 
Published: January 2023

Abstract
Regulatory T cells are cells with immunosuppressive capacity that are important in tolerance maintenance after organ transplantation. Belatacept, is an effective alternative to CNI that appears to preserve graft survival and function. However, the impact of this drug in the homeostasis of Tregs in transplanted patients remains controversial. Here, we report a detailed phenotypic and functional characterization of Tregs from kidney recipients undergoing 7 years of treatment with Belatacept or Cyclosporine A. We found a significant reduction in the proportion of CD4+ CD25hiCD127lo/−FOXP3+ T cells in all patients compared to controls. Interestingly, only Belatacept treated patients displayed an enrichment of the CD45RA+ “naïve” Tregs, while the percentage of Helios+ Tregs remained unaffected. Functional analysis demonstrated that Tregs from transplanted patients displayed a significant reduction in their suppressive capacity compared to Tregs from controls, which correlated with decreased levels of FOXP3 and CD25. Finally, methylation studies at the Treg-specific demethylation region (TSDR) of the FOXP3 gene showed that Belatacept treatment may result in methylation of CpG islands within the TSDR, which correlated with the impaired Treg suppression function. Our data indicate that Belatacept can have deleterious effect on the frequency and function of Tregs cells, suggesting that the beneficial effects reported by Belatacept cannot be explained by circulating Tregs.
CD62L+ NKT cells have superior in vivo persistence and anti-tumor activity
Authors: Tian Gengwen , Courtney Amy N , Jena Bipulendu , Heczey Andras , Liu Daofeng , Marinova Ekaterina , Guo Linjie , Xu Xin , Dotti Gianpietro , Cooper Laurence J , Metelitsa Leonid S 
Published: January 2023

Abstract
Va24-invariant Natural Killer T cells (NKTs) have potent antitumor properties and are being developed for cellular immunotherapy of cancer. Such therapy requires extensive ex vivo expansion of primary NKTs while preserving their longevity and function. However, the mechanism responsible for NKT-cell maintenance remains poorly understood. In this study we analyzed the proliferative potential of human NKT-cell subsets and found that antigen-induced in vitro expansion of primary NKTs is associated with the accumulation of a CD62L-positive subset. Following magnetic sorting, only CD62L-positive cells survived and proliferated in response to TCR-stimulation in vitro. After transfer to NSG mice, CD62L-positive NKTs persisted 5 times longer and had higher therapeutic efficacy in a lymphoma model compared with CD62L-negative NKTs. Proliferating CD62L-positive cells downregulated or maintained CD62L expression when they were activated via TCR alone or in combination with co-stimulatory receptors, respectively. After testing 161 clones of K562 cells, genetically modified to express CD1d and various combinations of co-stimulatory molecules, we selected the B-8-2 clone (HLAnullCD1dmedCD86high4-1BBmedOX40Lmed) which induced the highest rate of NKT-cell expansion with the preservation of CD62L-positive cells. Compared with NKTs expanded with autologous PBMC, those expanded with B-8-2 exhibited a prolonged in vivo persistence and superior antitumor activity. Thus, our results reveal a previously unanticipated functional hierarchy in human NKTs that can be exploited for cancer immunotherapy.
Crytotanshinone Induces the Maturation of Human Dendritic Cells through Activation of NF-kB, p38 and JNK MAPKs
Authors: Liu Shuo , Xin Haiyun , Nie Yingjie , Trivett Anna , Oppenheim Joost J. , Yang De 
Published: January 2023

Abstract
Danshen or Salvia miltiorrhiza Bunge is often used in Traditional Chinese Medicine (TCM) for the treatment of a variety of diseases including cancer. Cryptotanshinone and tanshinone II are two major tanshinones isolated from the roots of Danshen. In this study, we found that cryptotanshinone, but not tanshinone II, possesses the capacity to induce maturation of human dendritic cells (DCs). Treatment of human monocyte-derived DCs with cryptotanshinone upregulated DC surface expression of costimulatory molecules (CD80, CD86) and HLA-DR, as well as DC production of proinflammatory cytokines. In addition, DCs treated with cryptotanshinone acquired the capacity to migrate in response to CCL21/SLC, suggesting the upregulation of CCR7. Cryptotanshinone treatment reduced the level of I-kBa in DCs, indicative of NF-kB activation. Cryptotanshinone also increased the levels of phosphorylated p38 and JNK mitogen-activated protein kinases (MAPKs), but not phosphorylated Erks. Thus, cryptotanshinone can induce the maturation of human DCs through activation of NF-kB, p38 and JNK MAPKs, and may have the capacity to promote adaptive immune responses.
Reciprocal regulation of neutrophils and B cells elicits autoantibody-associated protumorigenic effects in human hepatocellular carcinoma
Authors: Liu Rui-Xian , Kuang Dong-Ming 
Published: January 2023

Abstract
Despite recent advances in identifying autoantibody-mediated carcinogenesis in animal models, direct evidence supporting the important role of autoantibodies in the immunopathogenesis of human cancers is still lacking. We recently found that neutrophils are accumulated in hepatocellular carcinoma (HCC), and their levels positively correlated with poor survival of patients. Here we detected high titers of proteinase 3 (PR3)-specific anti-neutrophil cytoplasmic autoantibodies (ANCA) in plasma from patients with advanced stage HCCs, and that increased titers of anti-PR3 autoantibodies also correlated with poor clinical outcome of patients. Neutrophils, B cells, plasma cells all predominantly accumulated in the peritumoral stroma of HCC tumors. The neutrophils isolated from HCC tumors, but not paired blood, significantly and effectively secreted PR3 proteins; accordingly, only B cells/plasma cells derived from HCC tumors markedly produced anti-PR3 autoantibodies. Further kinetic experiments revealed addition of conditioned medium from HCC tumor neutrophils to the ex vivo induction system of plasma cells led to sequential B cell activation, somatic hypermutation, and anti-PR3 autoantibody secretion. Reciprocally, we also demonstrated that, in the presence of anti-PR3 autoantibodies, the neutrophils are more potent to produce protumorigenic factors oncostatin M and matrix metalloproteinase-9. Thus, the secretion of PR3 by tumor neutrophils may represent a novel mechanism that links the autoimmunity to disease progression in the tumor milieu.
EGFR antibodies in immunotherapy: complement optimized antibody enhances polymorphonuclear cell mediated killing
Authors: Schwanbeck Ralf , Derer Stefanie , Roesner Thies , Kellner Christian , Beurskens Frank , Lohse Stefan , Peipp Matthias , Valerius Thomas 
Published: January 2023

Abstract
Antibodies against epidermal growth factor receptor (EGFR) are used in therapy for solid cancers such as head and neck cancer, colorectal and non-small lung carcinoma. Though complement-dependent cytotoxicity (CDC) is thought to be an important mechanism involved in immunotherapy, single unmodified EGFR IgG1 antibodies fail to trigger efficient CDC. Here, we generated a CDC-optimized variant of the EGFR antibody matuzumab (H425-wt) by introducing amino acid substitutions K326A/E333A (H425-mt). This antibody was used to investigate the impact of complement activation on the capacity of effector cells such as mononuclear cells (MNC) and polymorphonuclear cells (PMN) to exert antibody-dependent cell-mediated cytotoxicity (ADCC). H425-mt but not H425-wt significantly induced complement deposition, release of anaphylatoxins and CDC against distinct tumor cell lines, while no differences in ADCC by isolated MNC or PMN were detected. Notably, compared to H425-wt stronger cytotoxicity was induced by H425-mt in whole blood assays and in experiments using MNC or PMN combined with serum. While MNC-ADCC was not affected by C5 cleavage, PMN’s cytotoxic activity in the presence of serum strongly depended on C5 cleavage, suggesting a direct interaction between complement and PMN-ADCC. PMN, which strongly express C5a receptors, were stimulated with C5a resulting in an up-regulation of activated complement receptor 3 (CR3) and an enhanced CR3-dependent PMN-ADCC against tumor cells. In conclusion, complement-optimized EGFR antibodies may constitute a promising strategy to improve tumor cell killing by enhancing the interaction between humoral and cellular effector functions in antibody-based tumor therapy.
A high-throughput image cytometry-based screening method for the detection of IL2-induced peripheral blood mononuclear cell-mediated cytotoxicity
Authors: Chan Leo , McCulley Kelsey , Banerjee Pinaki 
Published: January 2023

Abstract
Cell-mediated cytotoxicity assays have been an important functional test for investigating the cytotoxic effect of immune effector on target cancer cells. Cytotoxicity assays have traditionally been performed using the 51Chromium (51Cr) release assay, which involves labeling the tumor cells (target) with radioisotopes. The 51Chromium release assay is highly hazardous, time-consuming, and can only acquire end point readout. Furthermore, it can generate inconsistent results due to batch variation, ability of the target cell for 51Cr uptake, and low sensitivity. In this work, we demonstrate a novel high-throughput cytotoxicity screening assay using the Celigo imaging-cytometry method. First the live K562 target cells were stained with Calcein AM, and were co-cultured with PBMCs from two healthy donors in a flat- bottom 96-well plate in the presence or absence of IL-2. Direct cell counting of Calcein positive cells was implied to calculate the changes in number of live target cells in the same well from T = 0 to T = 4 hours. Thus, accurate cell-mediated killing was determined using the “self-referencing” calculation, which could be a more direct method for assessing cytotoxicity than 51Cr release. The donor PBMCs were added to each well with different Calcein-stained target cells at Effector-to-Target (E:T) ratios. The 96-well microplate was scanned and analyzed using the Celigo image cytometer at different time points to measure the % lysis of target cell. The proposed image cytometry method can scan and analyze in 7 min, which can be utilized to perform high-throughput screening of potential antibody- or chemical-based cancer drug, which could be a more efficient method for academic, industry, and clinical research.