The immobilization of radioiodine produced from reprocessing used nuclear fuel is a growing priority for research and development of nuclear waste forms. This review provides a comprehensive summary ...of the current issues surrounding processing and containment of 129I, the isotope of greatest concern due to its long half-life of 1.6 × 107 y and potential incorporation into the human body. Strategies for disposal of radioiodine, captured by both wet scrubbing and solid sorbents, are discussed, as well as potential iodine waste streams for insertion into an immobilization process. Next, consideration of direct disposal of salts, incorporation into glasses, ceramics, cements, and other phases is discussed. The bulk of the review is devoted to an assessment of various sorbents for iodine and of waste forms described in the literature, particularly inorganic minerals, ceramics, and glasses. This review also contains recommendations for future research needed to address radioiodine immobilization materials and processes.
Programmed death-1 (PD-1) is a cell surface molecule that regulates the adaptive immune response. Engagement of PD-1 by its ligands PD-L1 or PD-L2 transduces a signal that inhibits T-cell ...proliferation, cytokine production, and cytolytic function. While a great deal is known concerning the biologic roles PD-1 plays in regulating the primary immune response and in T-cell exhaustion, comparatively little is known regarding how PD-1 ligation alters signaling pathways. PD-1 ligation is known to inhibit membrane-proximal T-cell signaling events, while ligation of the related inhibitory molecule cytotoxic T-lymphocyte antigen-4 appears to target more downstream signaling pathways. A major obstacle to an in-depth understanding of PD-1 signaling is the lack of physiologic models in which to study signal transduction. This review focuses on: (i) signaling pathways altered by PD-1 ligation, (ii) factors recruited upon PD-1 phosphorylation, and (iii) exploring the hypothesis that PD-1 ligation induces distinct signals during various stages of immune-cell differentiation. Lastly, we describe models to dissect the function of the PD-1 cytoplasmic tail using primary cells in the absence of agonist antibodies.
Functionally exhausted T cells have high expression of the PD-1 inhibitory receptor, and therapies that block PD-1 signaling show promise for resolving chronic viral infections and cancer. By using ...human and murine systems of acute and chronic viral infections, we analyzed epigenetic regulation of PD-1 expression during CD8
+ T cell differentiation. During acute infection, naive to effector CD8
+ T cell differentiation was accompanied by a transient loss of DNA methylation of the
Pdcd1 locus that was directly coupled to the duration and strength of T cell receptor signaling. Further differentiation into functional memory cells coincided with
Pdcd1 remethylation, providing an adapted program for regulation of PD-1 expression. In contrast, the
Pdcd1 regulatory region was completely demethylated in exhausted CD8
+ T cells and remained unmethylated even when virus titers decreased. This lack of DNA remethylation leaves the
Pdcd1 locus poised for rapid expression, potentially providing a signal for premature termination of antiviral functions.
►
Pdcd1 locus demethylation is coupled to naive to effector CD8
+ T cell differentiation ► After
Pdcd1 remethylation, select CpGs remain unmethylated in memory CD8
+ T cells ► Exhausted virus-specific CD8
+ T cells retain an unmethylated
Pdcd1 regulatory region ► Human CD8
+ T cells specific to chronic viruses retain an unmethylated
PDCD1 locus
Genetically engineered T cell immunotherapies have provided remarkable clinical success to treat B cell acute lymphoblastic leukaemia by harnessing a patient's own T cells to kill cancer, and these ...approaches have the potential to provide therapeutic benefit for numerous other cancers, infectious diseases and autoimmunity. By introduction of either a transgenic T cell receptor or a chimeric antigen receptor, T cells can be programmed to target cancer cells. However, initial studies have made it clear that the field will need to implement more complex levels of genetic regulation of engineered T cells to ensure both safety and efficacy. Here, we review the principles by which our knowledge of genetics and genome engineering will drive the next generation of adoptive T cell therapies.
Wolchok et al.
1
and Hamid et al.
2
report in the
Journal
the results of phase 1 clinical trials showing that the combination of PD-1 and CTLA-4 antibody blockers leads to improved treatment outcomes ...in patients with melanoma, without an escalation of toxic effects. The results of these trials are striking and complementary. In the trial by Hamid et al., a PD-1 monoclonal antibody was administered in patients who had had a relapse after CTLA-4 antibody monotherapy (ipilimumab); the authors found that durable and clinically significant responses were as common and robust as were those observed in patients who had not . . .
Chimeric antigen receptors (CARs) have shown remarkable ability to re-direct T cells to target CD19-expressing tumours, resulting in remission rates of up to 90% in individuals with paediatric acute ...lymphoblastic lymphoma. Lessons learned from these clinical trials of adoptive T cell therapy for cancer, as well as investments made in manufacturing T cells at commercial scale, have inspired researchers to develop CARs for additional applications. Here, we explore the challenges and opportunities of using this technology to target infectious diseases such as with HIV and undesired immune responses such as autoimmunity and transplant rejection. Despite substantial obstacles, the potential of CAR T cells to enable cures for a wide array of disease settings could be transformational for the medical field.
PD-1 (programmed cell death-1) is the central inhibitory receptor regulating CD8 T cell exhaustion during chronic viral infection and cancer. Interestingly, PD-1 is also expressed transiently by ...activated CD8 T cells during acute viral infection, but the role of PD-1 in modulating T cell effector differentiation and function is not well defined. To address this question, we examined the expression kinetics and role of PD-1 during acute lymphocytic choriomeningitis virus (LCMV) infection of mice. PD-1 was rapidly up-regulated in vivo upon activation of naive virus-specific CD8 T cells within 24 h after LCMV infection and in less than 4 h after peptide injection, well before any cell division had occurred. This rapid PD-1 expression by CD8 T cells was driven predominantly by antigen receptor signaling since infection with a LCMV strain with a mutation in the CD8 T cell epitope did not result in the increase of PD-1 on antigen-specific CD8 T cells. Blockade of the PD-1 pathway using anti–PD-L1 or anti–PD-1 antibodies during the early phase of acute LCMV infection increased mTOR signaling and granzyme B expression in virus-specific CD8 T cells and resulted in faster clearance of the infection. These results show that PD-1 plays an inhibitory role during the naive-to-effector CD8 T cell transition and that the PD-1 pathway can also be modulated at this stage of T cell differentiation. These findings have implications for developing therapeutic vaccination strategies in combination with PD-1 blockade.
High surface expression of programmed death 1 (PD-1) is associated with T-cell exhaustion; however, the relationship between PD-1 expression and T-cell dysfunction has not been delineated. We ...developed a model to study PD-1 signaling in primary human T cells to study how PD-1 expression affected T-cell function. By determining the number of T-cell receptor/peptide-MHC complexes needed to initiate a Ca ²⁺ flux, we found that PD-1 ligation dramatically shifts the dose–response curve, making T cells much less sensitive to T-cell receptor–generated signals. Importantly, other T-cell functions were differentially sensitive to PD-1 expression. We observed that high levels of PD-1 expression were required to inhibit macrophage inflammatory protein 1 beta production, lower levels were required to block cytotoxicity and IFN-γ production, and very low levels of PD-1 expression could inhibit TNF-α and IL-2 production as well as T-cell expansion. These findings provide insight into the role of PD-1 expression in enforcing T-cell exhaustion and the therapeutic potential of PD-1 blockade.
Merkel cell carcinoma (MCC) is a lethal skin cancer that metastasizes rapidly. Few effective treatments are available for patients with metastatic MCC. Poor intratumoral T cell infiltration and ...activation are major barriers that prevent MCC eradication by the immune system. However, the mechanisms that drive the immunologically restrictive tumor microenvironment remain poorly understood. In this study, we discovered that the innate immune regulator stimulator of IFN genes (STING) is completely silenced in MCCs. To reactivate STING in MCC, we developed an application of a human STING mutant, STINGS162A/G230I/Q266I, which we found to be readily stimulated by a mouse STING agonist, DMXAA. This STING molecule was efficiently delivered toMCC cells via an AAV vector. Introducing STINGS162A/G230I/Q266I expression and stimulating its activity by DMXAA in MCC cells reactivates their antitumor inflammatory cytokine/chemokine production. In response to MCC cells with restored STING, cocultured T cells expressing MCPyV-specific T cell receptors (TCRs) showincreased cytokine production,migration toward tumor cells, and tumor cell killing. Our study therefore suggests that STING deficiency contributes to the immune suppressive nature of MCCs. More importantly, DMXAA stimulation of STINGS162A/G230I/Q266I causes robust cell death in MCCs as well as several other STING-silenced cancers. Because tumor antigens and DNA released by dying cancer cells have the potential to amplify innate immune response and activate antitumor adaptive responses, our finding indicates that targeted delivery and activation of STINGS162A/G230I/Q266I in tumor cells holds great therapeutic promise for the treatment of MCC and many other STING-deficient cancers.
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a ...CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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