Pancreatic islets engineered with a FasL protein induce systemic tolerance at the induction phase that evolves into long-term graft-localized immune privilege.

We have previously shown that pancreatic islets engineered to transiently display a modified form of FasL protein (SA-FasL) on their surface survive indefinitely in allogeneic recipients without a need for chronic immunosuppression. Mechanisms that confer long-term protection to allograft are yet to be elucidated. We herein demonstrated that immune protection evolves in two distinct phases; induction and maintenance.

Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE).

Chimeric antigen receptor (CAR) T cells are a novel class of anti-cancer therapy in which autologous or allogeneic T cells are engineered to express a CAR targeting a membrane antigen. In Europe, tisagenlecleucel (Kymriah™) is approved for the treatment of refractory/relapsed acute lymphoblastic leukemia in children and young adults as well as relapsed/refractory diffuse large B-cell lymphoma, while axicabtagene ciloleucel (Yescarta™) is approved for the treatment of relapsed/refractory high-grade B-cell lymphoma and primary mediastinal B-cell lymphoma. Both agents are genetically engineered autologous T cells targeting CD19.

Transfer of Hexon- and Penton-selected adenovirus-specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation.

Adenovirus (HAdV) infections confer a high risk of morbidity and mortality for immunocompromised patients after stem cell transplantation (SCT). Treatment with standard antiviral drugs is of limited efficacy and associated with a high rate of adverse effects. HAdV-specific T cells are crucial for sustained viral elimination and the efficacy of adoptive T-cell therapy with donor-derived HAdV-specific T cells has been reported by several investigators.

Human neutrophils depend on extrinsic factors produced by monocytes for their survival response to TLR4 stimulation.

LPS delays neutrophil apoptosis by a process generally assumed to involve cell-intrinsic TLR4 signaling. However, neutrophil survival responses to LPS have been reported to be monocyte-dependent, which would indicate more complexity than is currently appreciated. We compared the survival responses of conventionally purified highly purified neutrophils to confirm or refute the need for secondary cell-types and to identify the cellular or molecular mechanisms involved.

Rapid On-Demand Extracellular Vesicle Augmentation with Versatile Oligonucleotide Tethers.

Exosomes show potential as ideal vehicles for drug delivery because of their natural role in transferring biological cargo between cells. However, current methods to engineer exosomes without negatively impacting their function remain challenging. Manipulating exosome-secreting cells is complex and time-consuming, while direct functionalization of exosome surface proteins suffers from low specificity and low efficiency.

Robust Th1 cellular and humoral responses generated by the Yersinia pestis rF1-V subunit vaccine formulated to contain an agonist of the CD137 pathway do not translate into increased protection against pneumonic plague.

Yersinia pestis is the causative agent of plague and is a re-emerging pathogen that also has the potential as a biological weapon, necessitating the development of a preventive vaccine. Despite intense efforts for the last several decades, there is currently not a vaccine approved by the FDA. The rF1-V vaccine adjuvanted with Alhydrogel is a lead candidate subunit vaccine for plague and generates a strong Th2-mediate humoral response with a modest Th1 cellular response.

CAR-Expressing Natural Killer Cells for Cancer Retargeting.

Since the approval in 2017 and the outstanding success of Kymriah® and Yescarta®, the number of clinical trials investigating the safety and efficacy of chimeric antigen receptor-modified autologous T cells has been constantly rising. Currently, more than 200 clinical trials are listed on clinicaltrial.gov.

Development of Automated Separation, Expansion, and Quality Control Protocols for Clinical-Scale Manufacturing of Primary Human NK Cells and Alpharetroviral Chimeric Antigen Receptor Engineering.

In cellular immunotherapies, natural killer (NK) cells often demonstrate potent antitumor effects in high-risk cancer patients. But Good Manufacturing Practice (GMP)-compliant manufacturing of clinical-grade NK cells in high numbers for patient treatment is still a challenge. Therefore, new protocols for isolation and expansion of NK cells are required.

A Novel Form of 4-1BBL Prevents Cancer Development via Nonspecific Activation of CD4 T and Natural Killer Cells.

Costimulation through 4-1BB (CD137) receptor generates robust CD8 T-effector and memory responses. The only known ligand, 4-1BBL, is a trimeric transmembrane protein that has no costimulatory activity as a soluble molecule. Thus, agonistic antibodies to the receptor have been used for cancer immunotherapy in preclinical models and are currently being evaluated in the clinic.

FL/GCSF/AMD3100-mobilized Hematopoietic Stem Cells Induce Mixed Chimerism With Nonmyeloablative Conditioning and Transplantation Tolerance.

Background: Mobilization of hematopoietic stem cells (HSCs) has become the preferred approach for HSC transplantation. AMD3100, a competitive inhibitor of C-X-C motif chemokine receptor-4, has been found to be a rapid mobilizing agent. The present study evaluated approaches to optimize the product collected.

A Method for Islet Transplantation to the Omentum in Mouse.

Islet transplantation has been proposed to be a potential treatment for type 1 diabetes. Recent compelling evidence indicates that intravascular islet infusion is far from ideal and therefore, the omentum is re-emerging as a potentially valuable site for islet transplantation. This experiment requires the isolation of high quality islets and the implantation of the islets to the diabetic recipients.

Synthetic poly(ethylene glycol)-based microfluidic islet encapsulation reduces graft volume for delivery to highly vascularized and retrievable transplant site.

Transplant of hydrogel-encapsulated allogeneic islets has been explored to reduce or eliminate the need for chronic systemic immunosuppression by creating a physical barrier that prevents direct antigen presentation. Although successful in rodents, translation of alginate microencapsulation to large animals and humans has been hindered by large capsule sizes (≥500 μm diameter) that result in suboptimal nutrient diffusion in the intraperitoneal space. We developed a microfluidic encapsulation system that generates synthetic poly(ethylene glycol)-based microgels with smaller diameters (310 ± 14 μm) that improve encapsulated islet insulin responsiveness over alginate capsules and allow transplant within vascularized tissue spaces, thereby reducing islet mass requirements and graft volumes.

Corrigendum: Triplebody Mediates Increased Anti-Leukemic Reactivity of IL-2 Activated Donor Natural Killer (NK) Cells and Impairs Viability of Their CD33-Expressing NK Subset.

[This corrects the article DOI: 10.3389/fimmu.2017.

Facilitating cells: role in inducing transplantation tolerance.

Purpose Of Review: This review discusses the role and mechanisms by which facilitating cells promote stem cell engraftment and induce tolerance in HLA-disparate kidney transplant recipients.

Recent Finding: Facilitating cells in both mice and human are heterogeneous, consisting of several subpopulations. They have been shown to enhance stem cell engraftment in allogeneic recipients.

Fms-Like Tyrosine Kinase 3-Ligand Contributes to the Development and Function of the Subpopulation of CD8α Plasmacytoid Precursor Dendritic Cells in CD8 /TCR Facilitating Cells.

Facilitating cells (FC) are a CD8 TCR bone marrow subpopulation that enhance engraftment of purified hematopoietic stem cells (HSC) and induce antigen-specific CD4 CD25 FoxP3 regulatory T cell (Treg) in vivo. The major subpopulation in FC resembles plasmacytoid precursor dendritic cells (p-preDC) both phenotypically and functionally. Here, we report that the number of FC was significantly reduced in Fms-like tyrosine kinase 3-ligand-knockout (Flt3-L-KO) mice.

Local immunomodulation Fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance.

Islet transplantation is a promising therapy for type 1 diabetes. However, chronic immunosuppression to control rejection of allogeneic islets induces morbidities and impairs islet function. T effector cells are responsible for islet allograft rejection and express Fas death receptors following activation, becoming sensitive to Fas-mediated apoptosis.

Tolerance induction in HLA disparate living donor kidney transplantation by facilitating cell-enriched donor stem cell Infusion: The importance of durable chimerism.

Successful solid organ transplantation currently requires the life-long use of medications to suppress the immune system in order to prevent transplant rejection. Drug-based immunosuppression significantly increases the risk of infection and cancer, as well as being very costly. Development of new therapies to minimize or eliminate entirely the need for anti-rejection drugs is of great interest to the transplant community.

Adenovirus Lacking E1b Efficiently Induces Cytopathic Effect in HPV-16-Positive Murine Cancer Cells via Virus Replication and Apoptosis.

Conditionally replicative adenoviruses (CRAds) replicate poorly in murine cancer cells; however, E1b-deleted CRAds may replicate effectively in HPV16-E6/E7-positive murine cancer cells (TC-1). The HPV16 E7 open reading frame encodes functions analogous to these deleted adenovirus E1 proteins. In this study, an E1b-deleted CRAd (Adhz60) was evaluated for its ability to replicate and induce oncolysis in TC-1 cells.

Mast Cell-Dependent CD8 T-cell Recruitment Mediates Immune Surveillance of Intestinal Tumors in Apc Mice.

The presence of mast cells in some human colorectal cancers is a positive prognostic factor, but the basis for this association is incompletely understood. Here, we found that mice with a heterozygous mutation in the displayed reduced intestinal tumor burdens and increased survival in a chemokine decoy receptor, ACKR2-null background, which led to discovery of a critical role for mast cells in tumor defense. ACKR2Apc tumors showed increased infiltration of mast cells, their survival advantage was lost in mast cell-deficient ACKR2SAApc mice as the tumors grew rapidly, and adoptive transfer of mast cells restored control of tumor growth.

Current challenges for cancer vaccine adjuvant development.

Introduction: Although much progress has been made in the last decade(s) toward development of effective cancer vaccines, there are still important obstacles to therapeutic successes. New generations of cancer vaccines will benefit from a combination adjuvant approach that targets multiple branches of the immune response.

Areas Covered: Herein we describe how combinatorial adjuvant strategies can help overcome important obstacles to cancer vaccine development, including antigen immunogenicity and tumor immune suppression.

Autoimmunity in Autologous Islet Transplantation.

Total pancreatectomy (TP) is increasingly being utilized for definitive treatment in patients with debilitating chronic pancreatitis (CP). In an effort to prevent surgical diabetes, the procedure can be performed in conjunction with transplantation of islets of Langerhans recovered from the patients' own resected pancreas (autologous islet transplantation, AIT). Given that patients undergoing TP and AIT are traditionally assumed not to be at risk for the development of beta-cell autoimmunity, it is possible that the presence of autoimmune islet graft failure has been overlooked and underreported in this patient population.

Temozolomide renders murine cancer cells susceptible to oncolytic adenovirus replication and oncolysis.

The preclinical evaluation of oncolytic adenoviruses (OAds) has been limited to cancer xenograft mouse models because OAds replicate poorly in murine cancer cells. The alkylating agent temozolomide (TMZ) has been shown to enhance oncolytic virotherapy in human cancer cells; therefore, we investigated whether TMZ could increase OAd replication and oncolysis in murine cancer cells. To test our hypothesis, three murine cancer cells were infected with OAd (E1b-deleted) alone or in combination with TMZ.

Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation.

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary.

Triplebody Mediates Increased Anti-Leukemic Reactivity of IL-2 Activated Donor Natural Killer (NK) Cells and Impairs Viability of Their CD33-Expressing NK Subset.

Natural killer cells (NK) are essential for the elimination of resistant acute myeloid and acute lymphoblastic leukemia (AML and ALL) cells. NK cell-based immunotherapies have already successfully entered for clinical trials, but limitations due to immune escape mechanisms were identified. Therefore, we extended our established NK cell protocol by integration of the previously investigated powerful trispecific immunoligand ULBP2-aCD19-aCD33 [the so-called triplebodies (TBs)] to improve the anti-leukemic specificity of activated NK cells.