Cost-effectiveness of latent tuberculosis infection testing and treatment with 6-week regimen among key population in rural communities in China: a decision analysis study.

PURPOSE: Several model studies suggested the implementation of latent tuberculosis infection (LTBI) testing and treatment could greatly reduce the incidence of tuberculosis (TB) and achieve the 2035 target of the "End TB" Strategy in China. The present study aimed to evaluate the cost-effectiveness of LTBI testing and TB preventive treatment among key population (≥ 50 years old) susceptible to TB at community level in China. METHODS: A Markov model was developed to investigate the cost-effectiveness of LTBI testing using interferon gamma release assay (IGRA) and subsequent treatment with 6-month daily isoniazid regimen (6H) (as a standard regimen for comparison) or 6-week twice-weekly rifapentine and isoniazid regimen (6-week H2P2) in a cohort of 10,000 adults with an average initial age of 50 years. RESULTS: In the base-case analysis, LTBI testing and treatment with 6H was dominated (i.e., more expensive with a lower quality-adjusted life year (QALY)) by LTBI testing and treatment with 6-week H2P2. LTBI testing and treatment with 6-week H2P2 was more effective than no intervention at a cost of $20,943.81 per QALY gained, which was below the willingness-to-pay (WTP) threshold of $24,211.84 per QALY gained in China. The one-way sensitivity analysis showed the change of LTBI prevalence was the parameter that most influenced the results of the incremental cost-effectiveness ratios (ICERs). CONCLUSION: As estimated by a Markov model, LTBI testing and treatment with 6-week H2P2 was cost-saving compared with LTBI testing and treatment with 6H, and it was considered to be a cost-effective option for TB control in rural China.

Nervous regulation: beta-2-adrenergic signaling in immune homeostasis, cancer immunotherapy, and autoimmune diseases.

Beta-2-adrenergic receptor (ß2-AR) mediates neural signaling from the sympathetic nervous system (SNS) to the immune system to modulate immunogenic and immunosuppressive responses for maintaining immune homeostasis. ß2-AR regulates various cellular activities on the innate and adaptive immune cells through differential signaling to modulate activation, proliferation, differentiation, and cytokine production. This signaling pathway has been found to be critical for regulating anti-tumor immune responses and autoimmune responses. Recently, ß2-AR has also been implicated in the mobilization of immune cells in peripheral blood and ex-vivo expansion of cytotoxic T cells from donor blood that has clinical implications for improving cancer immunotherapy. This review attempts to provide a comprehensive overview of the established and emerging roles of ß2-AR signaling in immune homeostasis, cancer immunotherapy, and autoimmune diseases.

Murine regulatory T cells utilize granzyme B to promote tumor metastasis.

Regulatory T cells (Tregs) possess a wide range of mechanisms for immune suppression. Among them, Granzyme B (GzmB) and perforin expressed by Tregs were shown to inhibit tumor clearance in previous reports, which contradicted the canonical roles of these cytotoxic molecules expressed by cytotoxic T cells and NK cells in antitumor immune responses. Given the ability of the tumor to manipulate the microenvironment, Treg-derived GzmB function may represent an important approach to aid in tumor growth as well as facilitating tumor metastasis. In this study, we utilized Treg-specific GzmB knockout (Foxp3creGzmBfl/fl) mice to test whether Treg-derived GzmB can aid in tumor progression and metastasis. Using an IL-2 complex to activate GzmB expression in the non-immunogenic B16-F10 tumor model, we provide evidence to show that GzmB produced by Tregs is important for spontaneous metastasis to the lungs. In addition, we depleted CD8 + T cells to selectively measure the impact of Treg-derived GzmB in an experimental lung metastasis model by intravenous injection of B16-F10 tumor cells; our results demonstrate that Treg-derived GzmB plays an important role in increasing the metastatic burden to the lungs.

Declining incidence rate of tuberculosis among close contacts in five years post-exposure: a systematic review and meta-analysis.

BACKGROUND: Individuals in close contact with active pulmonary tuberculosis (TB) patients showed a high risk of recent infection and, once infected, higher risk of developing active TB in the following years post-exposure. But the peak time of active disease onset is unclear. This study aims to estimate post exposure TB incidence risk among close contacts to provide reference for clinical and public health strategies. METHODS: We searched PubMed, Web of Science, and EMBASE for articles published until December 1, 2022. The incidence rates were quantitatively summarized by means of meta-analysis using the random-effect model. RESULTS: Of the 5616 studies, 31 studies included in our analysis. For baseline close contacts results, the summarized prevalence of Mycobacterium tuberculosis (MTB) infection and active TB was found to be 46.30% (95% CI: 37.18%-55.41%) and 2.68% (95% CI: 2.02%-3.35%), respectively. During the follow-up, the 1-year, 2-year and 5-year cumulative incidence of TB in close contacts were 2.15% (95% CI: 1.51%-2.80%), 1.21% (95% CI: 0.93%-1.49%) and 1.11% (95% CI: 0.64%-1.58%), respectively. Individuals with a positive result of MTB infection testing at baseline showed significantly higher cumulative TB incidence as compared to those negatives (3.80% vs. 0.82%, p < 0.001). CONCLUSIONS: Individuals with close contact to active pulmonary TB patients are bearing significant risk of developing active TB, particularly within the first-year post-exposure. Population with recent infections should be an important priority for active case finding and preventive intervention worldwide.

MyD88 Costimulation in Donor CD8+ T Cells Enhances the Graft-versus-Tumor Effect in Murine Hematopoietic Cell Transplantation.

Donor-derived lymphocytes from allogeneic hematopoietic cell transplantation (allo-HCT) or donor lymphocyte infusion can mediate eradication of host tumor cells in a process labeled the graft-versus-tumor (GVT) effect. Unfortunately, these treatments have produced limited results in various types of leukemia because of an insufficient GVT effect. In this context, molecular engineering of donor lymphocytes to increase the GVT effect may benefit cancer patients. Activating MyD88 signaling in CD8+ T cells via TLR enhances T cell activation and cytotoxicity. However, systemic administration of TLR ligands to stimulate MyD88 could induce hyperinflammation or elicit protumor effects. To circumvent this problem, we devised a synthetic molecule consisting of MyD88 linked to the ectopic domain of CD8a (CD8α:MyD88). We used this construct to test the hypothesis that MyD88 costimulation in donor CD8+ T cells increases tumor control following allo-HCT in mice by increasing T cell activation, function, and direct tumor cytotoxicity. Indeed, an increase in both in vitro and in vivo tumor control was observed with CD8α:MyD88 T cells. This increase in the GVT response was associated with increased T cell expansion, increased functional capacity, and an increase in direct cytotoxic killing of the tumor cells. However, MyD88 costimulation in donor CD8+ T cells was linked to increased yet nonlethal graft-versus-host disease in mice treated with these engineered CD8+ T cells. Given these observations, synthetic CD8α:MyD88 donor T cells may represent a unique and versatile approach to enhance the GVT response that merits further refinement to improve the effectiveness of allo-HCT.

Murine myeloid derived suppressor cells possess a range of suppressive mechanisms-Granzyme B is not among them.

This paper addresses the controversy of Granzyme B (GzmB) expression by murine Myeloid Derived Suppressor Cells (MDSCs). MDSCs are a heterogenous immature myeloid population that are generated in chronic inflammatory pathologies for the purpose to suppress inflammatory responses. MDSCs express a multitude of factors to induce suppressive function such as PD-L1, reactive oxygen species (ROS), nitric oxide synthase (iNOS), and Arginase-1. Recently, Dufait et al. sought to demonstrate GzmB as an additional mechanism for suppression by MDSCs. They reported that murine MDSCs not only significantly express GzmB as well as Perforin (Prf1), but this expression is functionally important for tumor growth in vivo as well as tumor migration in vitro. We conducted experiments to address the same question but made confounding observations: MDSCs under stringent developmental process do not express GzmB. Our results show that not only GzmB protein is not produced at functional level, but the mRNA transcript is not detectable either. In fact, the GzmB protein found in the media of MDSC culture was due to T cells or natural killer cells contained in bone marrow and cultured alongside MDSCs. We strengthen this finding by genetically deleting GzmB from the myeloid lineage and measuring tumor burden compared to WT counterpart. Our results show no significant difference in tumor burden, suggesting that even if there is minor expression of GzmB, it is not produced at a functional amount to affect tumor growth. Therefore, this paper proposes alternative theories that align with the known understanding of GzmB expression and secretion.

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1+ CD8+ T cells.

The use of tumor mutation-derived neoantigen represents a promising approach for cancer vaccines. Preclinical and early phase human clinical studies have shown the successful induction of tumor neoepitope-directed responses; however, overall clinical efficacy of neoantigen vaccines has been limited. One major obstacle of this strategy is the prevailing lack of sufficient understanding of the mechanism underlying the generation of neoantigen-specific CD8+ T cells. Here, we report a correlation between antitumor efficacy of neoantigen/toll-like receptor 3 (TLR3)/CD40 agonists vaccination and an increased frequency of circulating antigen-specific CD8+ T cells expressing CX3C chemokine receptor 1 (CX3CR1) in a preclinical model. Mechanistic studies using mixed bone marrow chimeras identified that CD40 and CD80/86, but not CD70 signaling in Batf3-dependent conventional type 1 dendritic cells (cDC1s) is required for the antitumor efficacy of neoantigen vaccine and generation of neoantigen-specific CX3CR1+ CD8+ T cells. Although CX3CR1+ CD8+ T cells exhibited robust in vitro effector function, in vivo depletion of this subset did not alter the antitumor efficacy of neoantigen/TLR3/CD40 agonists vaccination. These findings indicate that the vaccine-primed CX3CR1+ subset is dispensable for antitumor CD8+ T cell responses, but can be used as a blood-based T-cell biomarker for effective priming of CD8+ T cells as post-differentiated T cells. Taken together, our results reveal a critical role of CD40 and CD80/86 signaling in cDC1s in antitumor efficacy of neoantigen-based therapeutic vaccines, and implicate the potential utility of CX3CR1 as a circulating predictive T-cell biomarker in vaccine therapy.

Protective efficacy of 6-week regimen for latent tuberculosis infection treatment in rural China: 5-year follow-up of a randomised controlled trial.

BACKGROUND: Enlarging tuberculosis (TB) preventive treatment among at-risk populations is a critical component of the End TB Strategy. There is an urgent need to develop suitable latent tuberculosis infection (LTBI) testing and treatment tools according to the local TB epidemic and available resources worldwide. METHODS: Based on an open-label randomised controlled trial conducted since 2015 in China among rural residents aged 50-70 years with LTBI, the protective efficacy of a 6-week twice-weekly regimen of rifapentine plus isoniazid was further evaluated in a 5-year follow-up survey. RESULTS: 1298 treated participants and 1151 untreated controls were included in the 5-year protective efficacy analysis. In the per-protocol analysis, the incidence rate was 0.49 (95% CI 0.30-0.67) per 100 person-years in the untreated control group and 0.19 (95% CI 0.07-0.32) per 100 person-years in the treated group; the protection rate was 61.22%. Subgroup analysis showed that the protection rate was 76.82% in the per-protocol analysis among participants with baseline interferon (IFN)-γ levels in the highest quartile (≥3.25 IU·mL-1). Multiple logistic regression analysis indicated that participants with baseline body mass index <18.5 kg·m-2 and with pulmonary fibrotic lesions had increased hazard of developing active disease with an adjusted hazard ratio (aHR) of 3.64 (95% CI 1.20-11.00) and 5.99 (95% CI 2.20-16.27), respectively. In addition, individuals with higher baseline IFN-γ levels showed an increased risk of TB occurrence (aHR 2.27, 95% CI 1.13-4.58). CONCLUSIONS: Our findings suggest the 6-week twice-weekly regimen of rifapentine plus isoniazid for LTBI treatment might be an optional tool for TB control in the Chinese population.

A Critical Role of CD40 and CD70 Signaling in Conventional Type 1 Dendritic Cells in Expansion and Antitumor Efficacy of Adoptively Transferred Tumor-Specific T Cells.

In vivo expansion of adoptively transferred CD8+ T cells is a critical determinant of successful adoptive T cell therapy. Emerging evidence indicates Batf3-dependent conventional type 1 dendritic cells (cDC1s) rarely found within the tumor myeloid compartment are crucial for effector T cell recruitment to the tumor microenvironment. However, the role of cDC1s in expansion of tumor-specific CD8+ T cells remains unclear. In this article, we addressed the role of cDC1s and their costimulatory molecules, CD40, CD70, and CD80/CD86, in expansion and antitumor efficacy of adoptively transferred in vitro-primed CD8+ T cells recognizing nonmutated tumor-associated self-antigens. We found that TLR/CD40-mediated expansion and antitumor efficacy of adoptively transferred tumor-specific CD8+ T cells were abrogated in Batf3-/- mice. Further mechanistic studies using mixed bone marrow chimeric mice identified that CD40 and CD70 but not CD80/CD86 signaling in cDC1s played a critical role in expansion and antitumor efficacy of adoptively transferred CD8+ T cells. Moreover, induction and activation of cDC1s by administration of FMS-like tyrosine kinase 3 ligand (Flt3L) and TLR/CD40 agonists augmented expansion of adoptively transferred CD8+ T cells, delayed tumor growth, and improved survival. These findings reveal a key role for CD40 and CD70 signaling in cDC1s and have major implications for the design of new vaccination strategies with adoptive T cell therapy.

Visible-light-assisted peroxydisulfate activation over Ag6Si2O7/Cu(II)-modified palygorskite composite for the effective degradation of organic pollutants by radical and nonradical pathways.

Photoassisted persulfate activation (PPA) is highly efficient oxidation process, but the eligible catalysts are scarce. Herein, a visible-light-responsive Ag6Si2O7 was anchored on Cu(II)-exchanged attapulgite (Cu-Pal) via a facile precipitation-deposition method to construct a novel PDS activator. The synthesized catalyst was systemically analyzed by a series of characterization techniques. The results revealed that Ag6Si2O7 nanoparticles were evenly dispersed on Cu-Pal to form heterojunction. 16%-Ag6Si2O7/Cu-Pal, an optimal catalyst exhibited excellent catalytic performance and stability in the visible-light-assisted PDS activation for AR18 degradation. The influences of reaction parameters on this process were investigated. Under the optimal conditions ([catalyst] = 1.0 g L-1, [PDS] = 3.9 mM, pHi = 5.1), 50 mg L-1 of AR18 was completely degraded within 30 min. More importantly, quenching experiments and EPR tests revealed that besides the common SO4•- and •OH, 1O2 and O2•- were generated as main reactive oxygen species in the PPA by 16%-Ag6Si2O7/Cu-Pal. Moreover, it was found that surface hydroxyl groups of the catalyst and copper species incorporated in Pal could significantly influence PDS activation and ROS generation. Based on these results, together with PDS decomposition, fluorescent probe analysis, and XPS analysis of the used catalyst, the possible mechanisms of the PPA by 16%-Ag6Si2O7/Cu-Pal were proposed. Finally, the versatility and practicability of the established PPA process were verified by degrading other organic contaminants and testing effects of the coexisting anions and water matrices on AR18 degradation. This study may provide new insights for designing and developing the efficient heterogeneous catalysis for wastewater treatment via persulfate-based AOP.

5-Year Follow-up of Active Tuberculosis Development From Latent Infection in Rural China.

A 5-year follow-up study found declining disease development rates from latent tuberculosis infection. In the latter 3 years, the incidence, per 100 person-years, was 0.26 for interferon-γ release assay positives and 0.19 for tuberculin skin test positives (P = .28). In addition, all round have been checked.

Beta-Adrenergic Signaling in Tumor Immunology and Immunotherapy.

Communication between the nervous and immune systems is required for the body to regulate physiological homeostasis. Beta-adrenergic receptors expressed on immune cells mediate the modulation of immune response by neural activity. Activation of beta-adrenergic signaling results in suppression of antitumor immune response and limits the efficacy of cancer immunotherapy. Beta-adrenergic signaling is also involved in regulation of hematopoietic reconstitution, which is critical to the graft-versus-tumor (GVT) effect and to graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (HCT). In this review, the function of beta-adrenergic signaling in mediating tumor immunosuppression will be highlighted. We will also discuss the implication of targeting beta-adrenergic signaling to improve the efficacy of cancer immunotherapy including the GVT effect, and to diminish the adverse effects including GVHD.

Serum level of IL-1ra was associated with the treatment of latent tuberculosis infection in a Chinese population.

BACKGROUND: Dynamically changed levels of serum cytokines might predict the development of active TB from latent tuberculosis infection (LTBI) and monitor preventive treatment effectiveness. The aim of the study was to identify potential serum cytokines associated with LTBI treatment which might predict active disease development in a Chinese population. METHODS: Based on a randomized controlled trial aiming to explore short-course regimens for LTBI treatment, the dynamic changes of serum cytokines determined by bead-based multiplex assays were investigated for the participants who developed active TB during follow-up and age and gender matched controls stayed healthy. RESULTS: Totally, 21 patients diagnosed with active tuberculosis (TB) during the 2-year follow-up (12 from treated groups and 9 from untreated controls) and 42 age and gender matched healthy controls (24 from treated groups and 18 from untreated controls) were included in the study. Before treatment, serum IL-1ra was statistically higher among those who developed active disease during follow-up as compared with those stayed healthy. As for treated participants, the levels of IL-1ra were significantly lower after treatment in comparison with those before treatment both in active TB group (p = 0.002) and non-TB group (p = 0.009). For untreated participants, the levels of IL-1ra were not statistically different between different time points both in active TB group (p = 0.078) and non-TB group (p = 0.265). CONCLUSION: Our results suggested that declined serum level of IL-1ra was associated with LTBI treatment. Further studies are needed to verify whether it could be used to evaluate LTBI treatment and to predict active disease development.

Blockade of Host ß2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs.

Allogeneic hematopoietic cell transplantation is a potential curative therapy for hematologic malignancies. Host APCs are pivotal to the desired graft-versus-tumor (GVT) effect. Recent studies have shown that ß2-adrenergic receptor (ß2AR) signaling can have an important impact on immune cell function, including dendritic cells (DCs). In this article, we demonstrate that pretreatment of host mice with a ß2AR blocker significantly increases the GVT effect of donor CD8+ T cells by decreasing tumor burden without increasing graft-versus-host disease. ß2AR-deficient host mice have significantly increased effector memory and central memory CD8+ T cells and improved reconstitution of T cells, including CD4+Foxp3+ regulatory T cells. Notably, ß2AR deficiency induces increased CD11c+ DC development. Also, ß2AR-deficient bone marrow-derived DCs induce higher CD8+ T cell proliferation and improved tumor killing in vitro. Metabolic profiling shows that ß2AR deficiency renders DCs more immunogenic through upregulation of mTOR activity and reduction of STAT3 phosphorylation. Altogether, these findings demonstrate an important role for host ß2AR signaling in suppressing T cell reconstitution and GVT activity.

T Cell-Derived CD70 Delivers an Immune Checkpoint Function in Inflammatory T Cell Responses.

The CD27-CD70 pathway is known to provide a costimulatory signal, with CD70 expressed on APCs and CD27 functions on T cells. Although CD70 is also expressed on activated T cells, it remains unclear how T cell-derived CD70 affects T cell function. Therefore, we have assessed the role of T cell-derived CD70 using adoptive-transfer models, including autoimmune inflammatory bowel disease and allogeneic graft-versus-host disease. Surprisingly, compared with wild-type T cells, CD70-/- T cells caused more severe inflammatory bowel disease and graft-versus-host disease and produced higher levels of inflammatory cytokines. Mechanistic analyses reveal that IFN-γ induces CD70 expression in T cells, and CD70 limits T cell expansion via a regulatory T cell-independent mechanism that involves caspase-dependent T cell apoptosis and upregulation of inhibitory immune checkpoint molecules. Notably, T cell-intrinsic CD70 signaling contributes, as least in part, to the inhibitory checkpoint function. Overall, our findings demonstrate for the first time, to our knowledge, that T cell-derived CD70 plays a novel immune checkpoint role in inhibiting inflammatory T cell responses. This study suggests that T cell-derived CD70 performs a critical negative feedback function to downregulate inflammatory T cell responses.

Host-Derived CD70 Suppresses Murine Graft-versus-Host Disease by Limiting Donor T Cell Expansion and Effector Function.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for hematologic and immunologic diseases. However, graft-versus-host disease (GVHD) may develop when donor-derived T cells recognize and damage genetically distinct normal host tissues. In addition to TCR signaling, costimulatory pathways are involved in T cell activation. CD27 is a TNFR family member expressed on T cells, and its ligand, CD70, is expressed on APCs. The CD27/CD70 costimulatory pathway was shown to be critical for T cell function and survival in viral infection models. However, the role of this pathway in allo-HCT is previously unknown. In this study, we have examined its contribution in GVHD pathogenesis. Surprisingly, Ab blockade of CD70 after allo-HCT significantly increases GVHD. Interestingly, whereas donor T cell- or bone marrow-derived CD70 plays no role in GVHD, host-derived CD70 inhibits GVHD as CD70-/- hosts show significantly increased GVHD. This is evidenced by reduced survival, more severe weight loss, and increased histopathologic damage compared with wild-type hosts. In addition, CD70-/- hosts have higher levels of proinflammatory cytokines TNF-α, IFN-γ, IL-2, and IL-17. Moreover, accumulation of donor CD4+ and CD8+ effector T cells is increased in CD70-/- versus wild-type hosts. Mechanistic analyses suggest that CD70 expressed by host hematopoietic cells is involved in the control of alloreactive T cell apoptosis and expansion. Together, our findings demonstrate that host CD70 serves as a unique negative regulator of allogeneic T cell response by contributing to donor T cell apoptosis and inhibiting expansion of donor effector T cells.

Host-Derived Serine Protease Inhibitor 6 Provides Granzyme B-Independent Protection of Intestinal Epithelial Cells in Murine Graft-versus-Host Disease.

Graft-versus-host disease (GVHD) is a serious complication after allogeneic hematopoietic cell transplantation (allo-HCT) that limits the therapeutic potential of this treatment. Host antigen-presenting cells (APCs) play a vital role in activating donor T cells that subsequently use granzyme B (GzmB) and other cytotoxic molecules to damage host normal tissues. Serine protease inhibitor 6 (Spi6), known as the sole endogenous inhibitor of GzmB, has been implicated in protecting T cells and APCs against GzmB-inflicted damage. In this study we used murine models to examine the previously unknown role of host-derived Spi6 in GVHD pathogenesis. Our results indicated that host Spi6 deficiency exacerbated GVHD as evidenced by significantly increased lethality and clinical and histopathologic scores. Using bone marrow chimera system, we found that Spi6 in nonhematopoietic tissue played a dominant role in protecting against GVHD and was significantly upregulated in intestinal epithelial cells after allo-HCT, whereas Spi6 in hematopoietic APCs surprisingly suppressed alloreactive T cell response. Interestingly, the protective effect of Spi6 and its expression in intestinal epithelial cells appeared to be independent of donor-derived GzmB. We used in silico modeling to explore potential targets of Spi6. Interaction tested in silico demonstrated that Spi6 could inhibit caspase-3 and caspase-8 with the same functional loop that inhibits GzmB but was not capable of forming stable interaction with caspase-1 or granzyme A. Using an in vitro co-culture system, we further identified that donor T cell-derived IFN-γ was important for inducing Spi6 expression in an intestinal epithelial cell line. Altogether, our data indicate that host Spi6 plays a novel, GzmB-independent role in regulating alloreactive T cell response and protecting intestinal epithelial cells. Therefore, enhancing host-derived Spi6 function has the potential to reduce GVHD.

Short-course regimens of rifapentine plus isoniazid to treat latent tuberculosis infection in older Chinese patients: a randomised controlled study.

Latent tuberculosis infection (LTBI) management is now a critical component of the World Health Organization's End TB Strategy.In this randomised controlled trial (Chinese Clinical Trial Registry identifier ChiCTR-IOR-15007202), two short-course regimens with rifapentine plus isoniazid (a 3-month once-weekly regimen and a 2-month twice-weekly regimen) were initially designed to be evaluated for rural residents aged 50-69 years with LTBI in China.Due to the increasingly rapid growth and unexpected high frequency of adverse effects, the treatments were terminated early (after 8 weeks for the once-weekly regimen and after 6 weeks for the twice-weekly regimen). In the modified intention-to-treat analysis on the completed doses, the cumulative rate of active disease during 2 years of follow-up was 1.21% (14 out of 1155) in the untreated controls, 0.78% (10 out of 1284) in the group that received the 8-week once-weekly regimen and 0.46% (six out of 1299) in the group that received the 6-week twice-weekly regimen. The risk of active disease was decreased, with an adjusted hazard ratio of 0.63 (95% CI 0.27-1.43) and 0.41 (95% CI 0.15-1.09) for the treatments, respectively. No significant difference was found in the occurrence of hepatotoxicity (1.02% (13 out of 1279) versus 1.17% (15 out of 1279); p=0.704).The short regimens tested must be used with caution among the elderly because of the high rates of adverse effects. Further work is necessary to test the ultrashort regimens in younger people with LTBI.

Granzyme B-Mediated Activation-Induced Death of CD4+ T Cells Inhibits Murine Acute Graft-versus-Host Disease.

Granzyme B (GzmB) has previously been shown to be critical for CD8(+) T cell-mediated graft-versus-host disease (GVHD) but dispensable for GVHD mediated by CD4(+) T cells. However, previous studies used high doses of CD4(+) T cells in MHC-mismatched models that caused rapid and lethal GVHD. Because of the hyperacute lethality, it is possible that the role of GzmB was concealed by the system. Therefore, in this study, we have titrated down the T cell dose to precisely determine the contribution of GzmB in GVHD mediated by CD4(+)CD25(-) T cells. Surprisingly, we have found that GzmB(-/-)CD4(+)CD25(-) T cells cause more severe GVHD compared with wild-type CD4(+)CD25(-) T cells in both MHC-matched and mismatched models. Mechanistic analyses reveal that although GzmB does not affect donor T cell engraftment, proliferation or tissue-specific migration, GzmB(-/-) CD4(+)CD25(-) T cells exhibit significantly enhanced expansion because of GzmB-mediated activation-induced cell death of wild-type CD4(+)CD25(-) T cells. As a result of enhanced expansion, GzmB(-/-) T cells produced higher amounts of proinflammatory cytokines (e.g., TNF-α and IFN-γ) that may contribute to the exacerbated GVHD. These results reveal that GzmB diminishes the ability of CD4(+) T cells to cause acute GVHD, which contradicts its established role in CD8(+) T cells. The differential roles suggest that targeting GzmB in selected T cell subsets may provide a strategy to control GVHD.

Housing Temperature-Induced Stress Is Suppressing Murine Graft-versus-Host Disease through ß2-Adrenergic Receptor Signaling.

Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation, a potentially curative therapy for hematologic diseases. It has long been thought that murine bone marrow-derived T cells do not mediate severe GVHD because of their quantity and/or phenotype. During the course of experiments testing the impact of housing temperatures on GVHD, we discovered that this apparent resistance is a function of the relatively cool ambient housing temperature. Murine bone marrow-derived T cells have the ability to mediate severe GVHD in mice housed at a thermoneutral temperature. Specifically, mice housed at Institutional Animal Care and Use Committee-mandated, cool standard temperatures (∼ 22°C) are more resistant to developing GVHD than are mice housed at thermoneutral temperatures (∼ 30°C). We learned that the mechanism underlying this housing-dependent immunosuppression is associated with increased norepinephrine production and excessive signaling through ß-adrenergic receptor signaling, which is increased when mice are cold stressed. Treatment of mice housed at 22°C with a ß2-adrenergic antagonist reverses the norepinephrine-driven suppression of GVHD and yields similar disease to mice housed at 30°C. Conversely, administering a ß2-adrenergic agonist decreases GVHD in mice housed at 30°C. In further mechanistic studies using ß2-adrenergic receptor-deficient (ß2-AR(-/-)) mice, we found that it is host cell ß2-AR signaling that is essential for decreasing GVHD. These data reveal how baseline levels of ß-adrenergic receptor signaling can influence murine GVHD and point to the feasibility of manipulation of ß2-AR signaling to ameliorate GVHD in the clinical setting.