Safety and effectiveness of clofarabine in Japanese patients with relapsed/refractory acute lymphoblastic leukaemia: a post-marketing surveillance study.

OBJECTIVE: Clofarabine is used to treat acute lymphoblastic leukaemia, but evidence of its safety and effectiveness in Japanese patients is limited. We evaluated the safety and effectiveness of clofarabine in patients with relapsed/refractory acute lymphoblastic leukaemia in real-world clinical practice in Japan. METHODS: An observational, multicenter, post-marketing, all-case surveillance was conducted for safety. Effectiveness analyses were conducted in patients aged ≤21 years and those treated with clofarabine monotherapy and combination therapy (clofarabine plus etoposide and cyclophosphamide). RESULTS: In the all-case survey, 260 of 264 registered patients were eligible for safety analysis. Among the 225 patients eligible for effectiveness analysis, 139 were aged ≤21 years. For monotherapy and combination therapy, 20/31 and 34/88 patients were eligible, respectively. In the all-case survey, the median age was 16.0 years, and 47.7% of patients were <15 years old. Adverse drug reaction incidence was 83.5% and the most common were hematologic toxicities. The best overall response rates in the population aged ≤21 years were complete remission, 29.7%; complete remission without platelet recovery, 7.3% and partial remission, 10.9%. The rest (52.2%) were classified as ineffective. The sum of complete remission, complete remission without platelet recovery and partial remission rates (effectiveness rate) was 47.8% (66/138 patients). The effectiveness rates in the monotherapy and combination therapy surveys were 10.0% (2/20 patients) and 58.8% (20/34 patients), respectively. CONCLUSIONS: These post-marketing surveys provide real-world evidence of the safety and effectiveness of clofarabine regimens, including monotherapy and combination therapy in Japanese patients with relapsed/refractory acute lymphoblastic leukaemia. The safety and effectiveness profiles were comparable with those of previous prospective studies.

Baseline characteristics may impact treatment duration of cabazitaxel in patients with mCRPC: a subanalysis of data from a post-marketing surveillance.

OBJECTIVE: Cabazitaxel has demonstrated improvements in overall survival among patients with metastatic castration-resistant prostate cancer (mCRPC) in the pivotal comparison clinical trials TROPIC, PROSELICA and CARD. However, these trials include mCRPC patients with similar characteristics, and there are limited data on how baseline characteristics affect treatment discontinuation in the patient population. METHODS: To assess individual factors that may impact the discontinuation rate of cabazitaxel treatment, we conducted a post hoc analysis of data from a nationwide all-case, post-marketing surveillance of cabazitaxel in Japan. Patients were grouped according to the number of cabazitaxel treatment cycles received (1-2 and ≥3 cycles). Predictive factors were identified through multivariate logistic regression analysis. RESULTS: Across 660 patients with metastatic castration-resistant prostate cancer, 70.2% received ≥3 cycles of cabazitaxel treatment. Those receiving 1-2 cycles of cabazitaxel had a greater proportion of patients with poorer Eastern Cooperative Oncology Group Performance Status, presence of lung and liver metastases, higher prostate-specific antigen level and prior radiation therapy at baseline. Regardless of the number of cabazitaxel cycles received, the primary reason for discontinuation was progression of disease rather than adverse events. Compared with those receiving 1-2 cycles, a lower proportion of patients receiving 3-10 and ≥11 cycles of cabazitaxel treatment experienced adverse events. Multivariate analysis showed a significant association between early discontinuation and presence of liver lesions, poorer Eastern Cooperative Oncology Group Performance Status and higher prostate-specific antigen level at baseline. CONCLUSIONS: Post-marketing surveillance data suggest physicians should individualize cabazitaxel treatment based on certain patient characteristics at baseline.

Real-world effectiveness of third-line cabazitaxel in patients with metastatic castration-resistant prostate cancer: CARD-like analysis of data from a post-marketing surveillance in Japan.

BACKGROUND: The CARD trial was conducted in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received docetaxel and experienced disease progression within 1 year on an androgen receptor-axis-targeted therapy (ARAT). Subsequent treatment with cabazitaxel had improved clinical outcomes compared with an alternative ARAT. This study aims to confirm the effectiveness of cabazitaxel in real-world patients in Japan and compare their characteristics with those of patients from the CARD trial. METHODS: This was a post-hoc analysis of a nationwide post-marketing surveillance registering all patients who were prescribed cabazitaxel in Japan between September 2014 and June 2015. Included patients had received docetaxel and ≤ 1 year of an ARAT (abiraterone or enzalutamide) prior to receiving cabazitaxel or an alternative ARAT, as their third-line therapy. The primary effectiveness endpoint was the time to treatment failure (TTF) of the third-line therapy. Patients were matched (1:1) from the cabazitaxel and second ARAT arms based on propensity score (PS). RESULTS: Of the 535 patients analysed, 247 received cabazitaxel and 288 the alternative ARAT as their third-line therapy, of which, 91.3% (n = 263/288) received abiraterone and 8.7% (n = 25/288) received enzalutamide as their second third-line ARAT. Patients in the cabazitaxel and second ARAT arms had TNM classification of M1 or MX in 73.3% and 68.1%, Gleason score of 8-10 in 78.5% and 79.2% and mean (standard deviation) serum PSA levels of 483 (1370) and 594 (1241) ng/mL, respectively. Initial cabazitaxel dose was ≤ 20 mg/m2 in 61.9% (n = 153/247) of the patients in the cabazitaxel arm. The median TTF (95% confidence interval [CI]) of the third-line therapy was 109 (94-128) days for cabazitaxel and 58 (57-66) days for the second ARAT, with a hazard ratio (95% CI) of 0.339 (0.279-0.413) favouring cabazitaxel. Similar results were obtained after PS-matching, with a hazard ratio (95% CI) of 0.323 (95% CI 0.258-0.402) favouring cabazitaxel. CONCLUSIONS: Consistent with the CARD trial, cabazitaxel demonstrated superior effectiveness over a second alternative ARAT in a real-world patient population in Japan, despite the population having more advanced disease status and a lower dose of cabazitaxel being more frequently administered, than in the CARD trial.

Model-based simulation to support the approval of isatuximab alone or with dexamethasone for the treatment of relapsed/refractory multiple myeloma in Japanese patients.

This study aimed to support dosing regimen selection for isatuximab as a single agent or in combination with dexamethasone for Japanese patients with relapsed/refractory multiple myeloma (RRMM). A joint model characterizing the dynamics of serum M-protein kinetics and its association with progression-free survival (PFS) was developed using data from 201 evaluable Japanese and non-Japanese patients with RRMM enrolled in two monotherapy phase I/II trials, where Japanese patients (n = 31) received isatuximab at 10 or 20 mg/kg once weekly (qw) for 4 weeks then every 2 weeks (q2w) in subsequent cycles (10 or 20 mg/kg qw-q2w). Among non-Japanese patients, 38 received isatuximab 20 mg/kg qw-q2w in combination with dexamethasone. Trial simulations were then performed to evaluate the effect of the isatuximab dosing regimens on both serum M-protein and PFS with and without dexamethasone. The model identified instantaneous changes in serum M-protein as the best on-treatment predictor for PFS. Trial simulations demonstrated that 20 mg/kg qw-q2w induced a greater decrease (30% vs. 22%) of serum M-protein at week 8 and prolonged median PFS by 2.4 weeks compared with 10 mg/kg qw-q2w. Although Japanese patients did not receive isatuximab plus dexamethasone in the phase I/II trial, simulations predicted that isatuximab 20 mg/kg qw-q2w plus dexamethasone would induce a greater decrease (67% vs. 43%) of serum M-protein and a prolonged median PFS by 7.2 weeks compared with isatuximab alone. Trial simulations support the approved isatuximab 20 mg/kg qw-q2w regimen when administered as a single agent and in combination with dexamethasone in Japanese patients.

Aflibercept with FOLFIRI in Japanese patients with metastatic colorectal cancer: results of a post-marketing surveillance.

BACKGROUND: Safety and effectiveness of aflibercept with 5-fluorouracil/levofolinate/irinotecan have not been reported in Japanese patients with metastatic colorectal cancer (mCRC) in a real-world clinical setting. METHODS: This post-marketing surveillance enrolled patients with un-resectable advanced or recurrent mCRC who were prescribed aflibercept from December 2017 to June 2019 in Japan. Data, collected up to 1 year from starting treatment, included patient background, safety, and effectiveness assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or physician's evaluation. RESULTS: Of 261 patients registered from 64 centers, 235 [53.2% male with a median age of 67 years (range 28-84)] received treatment and were included in the safety analysis. Aflibercept was received at 1st, 2nd, and ≥ 3rd line in 1.3%, 48.1%, and 50.2% of patients, respectively. Median number of treatment cycles was 6 (range 1-22) and relative dose intensity was 75.4% (range 14.3-101.8%). Adverse events (all grades) were reported in 88.5% of patients, including neutropenia (34.5%), proteinuria (24.7%), hypertension (17.0%), diarrhea (17.0%), and decreased appetite (15.3%). Three treatment-related deaths occurred by perforation of the digestive tract, pneumonia and gastrointestinal bleeding, and sudden death. The effectiveness analysis included 198 patients. Overall response rate was 6.1% (1st line, 0%; 2nd line, 10.1%; ≥ 3rd line, 2.1%) and disease control rate was 47.5% (1st line, 100%; 2nd line, 58.6%; ≥ 3rd line, 34.4%). CONCLUSION: No new risks of aflibercept were identified in real clinical practice. Effectiveness in patients at the 2nd line was consistent with previous reports.

Comprehensive analysis of the associations between clinical factors and outcomes by machine learning, using post marketing surveillance data of cabazitaxel in patients with castration-resistant prostate cancer.

BACKGROUND: We aimed to evaluate relationships between clinical outcomes and explanatory variables by network clustering analysis using data from a post marketing surveillance (PMS) study of castration-resistant prostate cancer (CRPC) patients. METHODS: The PMS was a prospective, multicenter, observational study of patients with metastatic, docetaxel-refractory CRPC treated with cabazitaxel in Japan after its launch in 2014. Graphical Markov (GM) model-based simulations and network clustering in 'R' package were conducted to identify correlations between clinical factors and outcomes. Factors shown to be associated with overall survival (OS) in the machine learning analysis were confirmed according to the clinical outcomes observed in the PMS. RESULTS: Among the 660 patients analyzed, median patient age was 70.0 years, and median OS and time-to-treatment failure (TTF) were 319 and 116 days, respectively. In GM-based simulations, factors associated with OS were liver metastases, performance status (PS), TTF, and neutropenia (threshold 0.05), and liver metastases, PS, and TTF (threshold 0.01). Factors associated with TTF were OS and relative dose intensity (threshold 0.05), and OS (threshold 0.01). In network clustering in 'R' package, factors associated with OS were number of treatment cycles, discontinuation due to disease progression, and TTF (threshold 0.05), and liver and lung metastases, PS, discontinuation due to adverse events, and febrile neutropenia (threshold 0.01). Kaplan-Meier analysis of patient subgroups demonstrated that visceral metastases and poor PS at baseline were associated with worse OS, while neutropenia or febrile neutropenia and higher number of cabazitaxel cycles were associated with better OS. CONCLUSIONS: Neutropenia may be a predictive factor for treatment efficacy in terms of survival. Poor PS and distant metastases to the liver and lungs were shown to be associated with worse outcomes, while factors related to treatment duration were shown to positively correlate with better OS.

Medical database analysis of japanese multiple myeloma patients with planned stem cell transplantation (MEDALIST) - a focus on healthcare resource utilization and cost.

This study explored the burden associated with stem cell mobilization, with or without cyclophosphamide (CPA), in patients who intended to receive autologous stem cell transplantation (ASCT) for multiple myeloma (MM). A Japanese health care claims database (MDV) was used to analyze the health care resource utilization patterns and medical cost between 2013 and 2016 (pre-plerixafor launch). The patients were further categorized into groups who received granulocyte-colony stimulating factor (G-CSF) alone or G-CSF + CPA group and analyzed in both mobilization and ASCT phases of treatment. Overall, there were more MM patients who were treated with G-CSF + CPA combination therapy than G-CSF alone. Length-of-stay was 1.6 times longer in the combination group during the mobilization phase. A reverse trend was observed during the ASCT phase. Direct cost was approximately 1.2 million yen during the mobilization phase and 2.3 million yen during the ASCT phase, with hospitalization basic fee accounting for the highest proportion in both groups and phases. A substantial amount of healthcare resource and cost was consumed in both phases. This study may serve as a basic reference for further health technology assessment of new medicines such as plerixafor. Further investigation of differences between treatment groups is warranted.

Real-world efficacy and safety of two doses of cabazitaxel (20 or 25 mg/m2) in patients with castration-resistant prostate cancer: results of a Japanese post-marketing surveillance study.

BACKGROUND: The recommended starting dose of cabazitaxel for castration-resistant prostate cancer (CRPC) is 25 mg/m2 in Japan and Europe. Although lower doses are established alternatives based on randomized controlled trials, the safety and efficacy of 25 and 20 mg/m2 in real-world settings are not well established. Therefore, we investigated the safety and efficacy of cabazitaxel at the recommended starting dose or a lower dose (20 mg/m2) in real-world clinical practice. METHODS: We compared the safety and efficacy of cabazitaxel between patients who received cabazitaxel at starting doses of 25 and 20 mg/m2 (C25 and C20, respectively) in a Japanese post-marketing surveillance study of 662 patients with docetaxel-refractory CRPC. Safety was assessed in terms of adverse drug reactions (ADRs). Prostate-specific antigen (PSA) response rate, overall survival (OS), and time-to-treatment failure (TTF) were compared between the C25 and C20 groups in unmatched patients and after applying propensity score matching. RESULTS: The C20 and C25 groups comprised 190 and 159 patients without matching and 112 patients per group after matching. In unmatched patients, any-grade (C25 vs C20: 89.3% vs 78.4%, Fisher's p < 0.01) and grade ≥ 3 (81.1% vs 61.1%) ADRs were more frequent in the C25 group. Neutropenia (any grade: 61.6% vs 54.2%; grade ≥ 3: 55.3% vs 42.6%) and febrile neutropenia (grade ≥ 3: 30.2% vs 14.7%) were more frequent in the C25 group. In matched patients, the PSA response rate (reduction in PSA ≥30% from a baseline ≥5 ng/mL) was 26.4 and 32.0% in the C20 and C25 groups, respectively, median OS was 291 days (95% CI 230-not reached) versus not reached (hazard ratio 0.73, 95% CI 0.50-1.08), and TTF favored C25 (hazard ratio 0.75, 95% CI 0.57-0.99). CONCLUSIONS: Clinicians should consider the patient's risk of clinically significant ADRs and prophylactic granulocyte colony stimulating factor when selecting the starting dose of cabazitaxel for CRPC. Some patients at high risk of ADRs or unfit patients may benefit from a lower starting dose of 20 mg/m2, whereas fit patients may be candidates for a starting dose of 25 mg/m2. TRIAL REGISTRATION: Not applicable.

Cabazitaxel in patients aged ≥80 years with castration-resistant prostate cancer: Results of a post-marketing surveillance study in Japan.

OBJECTIVES: Data on the safety and efficacy of cabazitaxel in patients aged ≥80 years with castration-resistant prostate cancer (CRPC) are limited. We report the safety (adverse drug reactions [ADRs]) and efficacy (overall survival [OS], time to treatment failure [TTF], and prostate-specific antigen [PSA] response rates) in patients aged <80 or ≥80 years treated with cabazitaxel for CRPC in clinical practice. MATERIALS AND METHODS: We performed post-hoc subgroup analyses of a Japanese post-marketing surveillance study involving 662 patients with CRPC treated with cabazitaxel between September 2014 and June 2016. RESULTS: In patients aged <80 (n = 610) and ≥80 years (n = 49), median PSA at baseline was 168.7 and 109.0 ng/mL, and 86.7% and 83.7% of patients were previously treated with enzalutamide and/or abiraterone. ADRs (all grade) occurred in 77.2% and 79.6% of patients aged <80 and ≥80 years, with grade three/worse ADRs in 61.8% and 63.3% of patients. Hematologic toxicities were the most common grade three/worse ADRs, including neutropenia, febrile neutropenia, and anemia in both subgroups. No specific ADRs were observed in patients aged ≥80 years. The PSA response and median OS and TTF were 28.3%, 292 days, and 116 days in patients aged ≥80 years, and 29.7%, 319 days, and 125 days in patients aged <80 years. CONCLUSION: Cabazitaxel could be a treatment option for CRPC in patients aged ≥80 years based on its safety and efficacy profiles. This is the first report to investigate the safety and efficacy of cabazitaxel in patients aged ≥80 years with CRPC.

Safety and efficacy of cabazitaxel in 660 patients with metastatic castration-resistant prostate cancer in real-world settings: results of a Japanese post-marketing surveillance study.

OBJECTIVE: To evaluate the real-world safety and efficacy of cabazitaxel in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen. METHODS: This prospective multicenter observational study registered all patients with mCRPC treated with cabazitaxel following its launch in Japan in September 2014. Patient enrollment continued until at least 500 patients were enrolled. Adverse drug reactions (ADRs) were evaluated according to CTCAE ver. 4.0. Efficacy endpoints were assessed for up to 1 year, and included prostate specific antigen (PSA) response rates (defined as a decrease of ≥30% or ≥50% from baseline), overall survival (OS), and time to treatment failure (TTF). RESULTS: A total of 660 mCRPC patients were enrolled across 316 centers by June 2016. Frequent ADRs (any grade) were neutropenia (49.1%), febrile neutropenia (18.0%) and anemia (15.0%). Most ADRs occurred in cycle 1. Neutropenia and febrile neutropenia were significantly less frequent in patients who received prophylactic granulocyte colony-stimulating factor. The PSA response rates for decrease of ≥30% or ≥50% from baseline were 28.1% and 17.5%, respectively, in patients with baseline PSA of ≥5 ng/ml. Median OS and TTF were 319 days (95% confidence interval: 293.0-361.0) and 116 days (95% confidence interval: 108.0-135.0), respectively. CONCLUSIONS: This study of cabazitaxel in 660 Japanese patients treated in real-world settings, the largest study of cabazitaxel to date, demonstrated a safety profile that was generally consistent with those of pivotal clinical studies. Cabazitaxel was also effective in terms of the PSA response, OS, and TTF.

Pancreatic safety in Japanese patients with type 2 diabetes treated with once weekly dulaglutide 0.75 mg up to 52 weeks in phase 3 clinical trials.

The effects of incretin therapies on pancreatic safety are currently being evaluated. In 3 phase 3 clinical studies of once weekly dulaglutide 0.75 mg (dulaglutide) in Japanese patients with type 2 diabetes (T2D), symptoms suggestive of acute pancreatitis as well as pancreatic enzymes were assessed and the risk of acute pancreatitis was evaluated. Patients who met any of the predefined criteria (clinical signs/symptoms of acute pancreatitis, confirmed amylase or lipase level ≥3 times the upper limit of normal [ULN], abdominal imaging of the pancreas) were adjudicated for acute pancreatitis by a blinded external committee. A total of 43 events in 40 patients (dulaglutide, 35/917 patients; liraglutide, 2/137 patients; insulin glargine, 2/180 patients; and placebo, 2/70 patients) were adjudicated (1 patient had events adjudicated during both placebo and dulaglutide treatment); 2 patients treated with dulaglutide had acute pancreatitis confirmed (2/917 [0.2%]; 2.651 patients/1,000 patient-years). One of these patients was diagnosed by the investigator with acute pancreatitis related to dulaglutide, but there was no typical abdominal pain. The event in the other patient occurred following an endoscopic ultrasound-guided fine needle aspiration. Transient increases in lipase ≥3×ULN were observed in 2% of patients in both the dulaglutide and liraglutide groups; the incidence in dulaglutide-treated patients was not significantly different from the incidences in liraglutide, placebo-, or insulin glargine-treated patients. Results of systematic assessments of pancreatic safety in 3 phase 3 studies for up to 52 weeks do not suggest an increased risk of acute pancreatitis in Japanese patients treated with dulaglutide.

Identification of a novel type 2 innate immunocyte with the ability to enhance IgE production.

Fas (CD95), a member of the tumor necrosis factor receptor superfamily, mediates apoptosis-inducing signals in its expressing cells, especially in self-reactive cells. We recently reported that Fas(-/-) mice with a BALB/c background (BALB/c Fas(-/-) mice) developed blepharitis with allergic inflammation that was accompanied by hyper-IgE production. Here, we found a novel type of immunocyte in the spleen of BALB/c Fas(-/-) mice, which enhanced the production of IgE by B cells in the presence of IL-4 and CD40 signaling in vitro. The immunocyte did not express lineage markers but expressed Thy-1 and Sca-1 just like recently identified type 2 innate lymphoid cells, such as natural helper (NH) cells and nuocytes. However, they did not express c-Kit, IL-7R and IL-33R (T1/ST2), important markers of type 2 innate lymphoid cells. Instead, our identified Lin(-)Thy-1(+)Sca-1(+) cells expressed IL-18R and secreted Th2 cytokines when co-cultured with B cells or when stimulated with IL-18 and IL-2. Moreover, we found essentially the same type of cells in BALB/c wild-type mice as in BALB/c Fas(-/-) mice, which enhanced IgE production in contact with B cells in vitro. These cells from BALB/c wild-type mice expressed Fas and were sensitive to Fas-mediated apoptosis. Collectively, the newly identified Lin(-)Thy-1(+)Sca-1(+) cell, which we designated a F-NH cell (Fas-expressing natural helper cell), is a novel type 2 innate immunocyte with activity to enhance IgE production from B cells with the help of IL-4 and CD40 signaling. F-NH cells may play an important role in the development of chronic allergic inflammation.

Bim regulates B-cell receptor-mediated apoptosis in the presence of CD40 signaling in CD40-pre-activated splenic B cells differentiating into plasma cells.

B-cell receptor (BCR)-mediated apoptosis is critical for B-cell development and homeostasis. CD40 signaling has been shown to protect immature or mature B cells from BCR-mediated apoptosis. In this study, to understand the fate of CD40-pre-activated splenic B cells stimulated by BCR engagement in the presence of CD40 signaling, murine splenic B cells were cultured with anti-Igκ and anti-CD40 antibodies after pre-activation with anti-CD40 antibody. We found that apoptosis was induced in the cultured B cells even in the presence of CD40 signaling during the 3-4 days cultivation. We detected up-regulation of Bim expression followed by Bax activation in this apoptotic process and cessation of the apoptosis in Bim-deficient B cells, indicating that Bim is a key regulator of the BCR-mediated apoptosis in the presence of CD40 signaling in CD40-pre-activated B cells. Importantly, this BCR-mediated apoptosis in CD40-pre-activated B cells was shown to be induced at the initiation of plasma cell differentiation at around the preplasmablast stage, and Bim-deficient B cells cultured under these conditions differentiated into plasma cells. Additionally, transforming growth factor-ß was found to protect CD40-pre-activated B cells from BCR-mediated apoptosis in the presence of CD40 signaling. Our identified BCR-mediated apoptosis, which is unpreventable by CD40 signaling, suggests a potential mechanism that regulates the elimination of peripheral B cells, which should be derived from nonspecific T-dependent activation of bystander B cells and continuous stimulation with antigens including self-antigens in the presence of T cell help through CD40.

Sepsis-induced apoptosis leads to active suppression of delayed-type hypersensitivity by CD8+ regulatory T cells through a TRAIL-dependent mechanism.

Patients who survive severe sepsis often display severely compromised immune function. One hallmark of such immune suppression in septic patients is an impaired delayed-type hypersensitivity (DTH) response, manifested by a loss of skin testing to recall Ags. Because sepsis induces significant apoptosis in lymphoid and myeloid cells, and apoptotic cells are themselves tolerogenic, we tested the hypothesis that suppression of DTH is mediated by tolerogenic properties of the apoptotic cells generated during sepsis. Mice subjected to cecal ligation and puncture demonstrated a loss of DTH for the 7 d following cecal ligation and puncture; however, the immune response returned to normal by day 10. Blocking sepsis-induced apoptosis via Bcl-2 overexpression or Bim deficiency prevented the loss of DTH. Importantly, injection of apoptotic cells into Bim-/- mice prevented an effective DTH response, thereby suggesting a causal link between apoptotic cells and immune suppression. Surprisingly, when TRAIL null mice were examined, we found that these animals had significant apoptosis but retained their DTH responses. Further studies revealed that apoptotic cells generated during sepsis induced a CD8+ regulatory T cell that suppressed DTH by TRAIL production. These results establish a link between apoptotic cells and immune suppression during sepsis and suggest TRAIL may be a viable therapeutic target for boosting the adaptive immune response following sepsis.

Apoptotic cells induce tolerance by generating helpless CD8+ T cells that produce TRAIL.

The decision to generate a productive immune response or immune tolerance following pathogenic insult often depends on the context in which T cells first encounter Ag. The presence of apoptotic cells favors the induction of tolerance, whereas immune responses generated with necrotic cells promote immunity. We have examined the tolerance induced by injection of apoptotic cells, a system in which cross-presentation of Ag associated with the dead cells induces CD8+ regulatory (or suppressor) T cells. We observed that haptenated apoptotic cells induced CD8+ suppressor T cells without priming CD4+ T cells for immunity. These CD8+ T cells transferred unresponsiveness to naive recipients. In contrast, haptenated necrotic cells stimulated immunity, but induced CD8+ suppressor T cells when CD4+ T cells were absent. We further found that CD8+ T cells induced by these treatments displayed a "helpless CTL" phenotype and suppress the immune response by producing TRAIL. Animals deficient in TRAIL were resistant to tolerance induction by apoptotic cells. Thus, the outcome of an immune response taking place in the presence of cell death can be determined by the presence of CD4+-mediated Th cell function.

Signals from dying cells: tolerance induction by the dendritic cell.

Uncontrolled immune responses are central to the pathogenesis of sustained viral infection, tumor growth, autoimmune diseases, and organ rejection. Dendritic cells (DCs) are critical to determining the outcome of immune responses by directing the function of T-cells. When DCs encounter antigen together with maturation signals immunity results; however, when they encounter apoptotic cells immune tolerance can be induced. It is thought that this is a mechanism to help prevent responses to self antigens because apoptotic cells can enter antigen-processing pathways. Our interest is the mechanisms by which DCs induce tolerance to the antigens associated with apoptotic cells. Here, we examine evidence showing a pivotal role for interleukin-10 (IL-10) in regulating the response of DCs to apoptotic cells. We show that although tolerogenic DCs are CD11c+ and CD8alpha+, the important DCs reside in a subpopulation of these cells that also express IL-10R. Current studies are designed to isolate and characterize this extremely small, but potent, subpopulation of tolerance-inducing DCs.