Different cytokine profiles released by CD4+ and CD8+ tumor‐draining lymph node cells involved in mediating tumor regression

We have previously demonstrated that the growth of weakly immunogenic murine sarcomas leads to the induction of immunologically specific preeffector cells in tumor‐draining lymph nodes (TDLN). The in vitro activation of TDLN cells with anti‐CD3 monoclonal antibodies (mAbs) and interleukin‐2 (IL‐2) resulted in the acquisition of effector function as measured by tumor regression in the adoptive immunotherapy of pulmonary metastases. Further studies were performed to characterize the mechanisms associated with in vivo tumor reactivity mediated by activated TDLN cells. By positive selection, CD4+ and CD8+ T cells were purified and activated by the anti‐CD3/IL‐2 method. CD8+, but not CD4+, cells manifested tumor‐specific granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and interferon‐γ (IFN‐γ) release in vitro, and elicited tumor regression in vivo. By contrast, only activated CD4+ were found to release significant amounts of IL‐2 in response to tumor antigen but did not mediate tumor regression in vivo. Mixing the two purified populations enhanced the antitumor activity of the CD8+ T cells. In culture, IL‐2 was found to augment the relative amount of tumor‐specific release of GM‐CSF and IFN‐γ by activated TDLN cells. We found that the tumor‐specific release of GM‐CSF and IFN‐γ by activated lymphocytes was strongly associated with the in vivo therapeutic efficacy of these cells. Evidence in support of this included the following: (1) cytokine release of TDLN derived after different durations of tumor growth correlated with tumor reactivity in adoptive transfer studies, (2) cytokine release of T cells derived from different lymphoid organs corresponded with tumor reactivity in adoptive transfer, and (3) in vivo administration of neutralizing mAb to IFN‐γ and GM‐CSF significantly inhibited the antitumor reactivity of TDLN cells. These studies document the contributory roles of IFN‐γ, GM‐CSF, and IL‐2 released by activated CD4+ and CD8+ T cells involved in tumor regression. J. Leukoc. Biol. 61: 507–516; 1997.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142128/1/jlb0507.pd

Tumor-specific granulocyte/macrophage colony-stimulating factor and interferon γ secretion is associated with in vivo therapeutic efficacy of activated tumor-draining lymph node cells

In this study, cytokine release by tumor-draining lymph node cells sensitized in vitro (IVS-TDLN) was examined and correlated with therapeutic efficacy in adoptive immunotherapy. Mice bearing immunologically distinct MCA 207 and MCA 205 sarcoma tumors were utilized in criss-cross experiments. IVS-TDLN obtained from mice bearing 10-day subcutaneous (s. c.) tumors mediated immunologically specific regression of established 3-day pulmonary metastases, but demonstrated non-specific cytolytic reactivity against both tumors in a 4-h 51 Cr-release assay. By contrast, these IVS-TDLN cells were found specifically to secrete granulocyte/macrophage colony-stimulating factor (GM-CSF) and interferon γ (IFNγ) when restimulated in vitro with irradiated tumor cells. To determine the predictive value of tumor-specific cytokine release with in vivo therapeutic efficacy, a kinetic analysis of antitumor activities of TDLN obtained from animals bearing MCA 207 tumors for increasing lengths of time was performed. IVS-TDLN cells from mice bearing day-7, -10 and-14 s. c. tumors manifested tumor-specific release of GM-CSF and IFNγ, and mediated significant antitumor reactivity in vivo. In contrast IVS-LN cells from day-0 and day-21 tumor-bearing animals did not release significant amounts of GM-CSF and IFNγ, and were not therapeutically efficacious in vivo. Day-4 IVS-TDLN released high levels of GM-CSF and IFNγ non-specifically, and were not therapeutic in adoptive immunotherapy at doses effective for day-7 and day-14 IVS-TDLN cells. In other experiments, IVS cells generated from different lymph node groups in animals bearing 10-day established s. c. tumors were examined and found to have unique profiles of cytokine release. In these studies, the ability of IVS cells to release specifically both cytokines as opposed to one was associated with greater therapeutic efficacy on a per cell basis. Our findings suggest that the tumor-specific releases of GM-CSF and IFNγ are useful parameters to assess the in vivo therapeutic efficacy of immune lymphocytes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46862/1/262_2005_Article_BF01517220.pd

cDNA cloning and sequencing of component C5 of proteasomes from rat hepatoma cells

AbstractProteasomes are multicatalytic proteinase complexes consisting of a set of non-identical polypeptide subunits. A cDNA for component C5 of rat proteasomes was isolated by screening a Reuber H4TG hepatoma cell cDNA library using synthetic oligodeoxynucleotide probes corresponding to partial amino acid sequences of the protein. The polypeptide deduced from the open reading frame consisted of 240 amino acid residues with a calculated molecular weight of 26479. Computer analysis revealed little similarity of C5 to other proteins reported so far. The primary structure of C5 showed partial sequence homology to that of another component C3, but no regions of homology with the sequence of component C2. Thus C5 is concluded to be a new type of subunit of the proteasome complex

Cytokines as an adjuvant to tumor vaccines: Efficacy of local methods of delivery

Background: We examined alternative methods of delivering cytokines as an adjunct for priming lymph node (LN) cells draining sites of vaccine inoculation for the purpose of generating immune cells for adoptive immunotherapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41416/1/10434_2006_Article_BF02305540.pd

Pengaruh Komunikasi Terapeutik Perawat Terhadap Kepuasan Pasien Di Rawat Jalan RSUD Jogja

The Objective of this study is to know influence of nurse therapeutic communication to satisfaction of patients satisfaction in RSUD Yogyakarta. The study was a quantitative research methods such as surveys of descriptive inferential research with cross sectional approach. Number of samples in this research is 285 sample in inpatient and 140 in emergency room. The instrument used a questionnaire. Analysis of data using multiple linear regression. This study show that there is the influence of therapeutic communication nurse to satisfaction of outpatients and Emergency room in RSUD Yogyakarta, and orientation phase is a phase that most influence on patient satisfaction. The most influential to therapeutic communication is termination stage

Comparison of Current Regulatory Status for Gene-Based Vaccines in the U.S., Europe and Japan

Gene-based vaccines as typified by plasmid DNA vaccines and recombinant viral-vectored vaccines are expected as promising solutions against infectious diseases for which no effective prophylactic vaccines exist such as HIV, dengue virus, Ebola virus and malaria, and for which more improved vaccines are needed such as tuberculosis and influenza virus. Although many preclinical and clinical trials have been conducted to date, no DNA vaccines or recombinant viral-vectored vaccines expressing heterologous antigens for human use have yet been licensed in the U.S., Europe or Japan. In this research, we describe the current regulatory context for gene-based prophylactic vaccines against infectious disease in the U.S., Europe, and Japan. We identify the important considerations, in particular, on the preclinical assessments that would allow these vaccines to proceed to clinical trials, and the differences on the regulatory pathway for the marketing authorization in each region

Potential Impact of Accelerated Approval on the Drug Lags for Anticancer Drugs Between the United States and Japan

The term 'drug lag' represents the difference in the timing of drug approval among countries. The impact of accelerated approvals on the drug lag for anticancer drugs between the United States (U.S.) and Japan was evaluated using publicly available information to identify anticancer drugs approved in the U.S. or Japan between January 2006 and March 2017. A logistic regression analysis was conducted to determine the association between the oncology drugs lags and potential factors, including accelerated approval. The median drug lag was 805 days. The drug lag was extended for drugs that were approved in the U.S. under accelerated approval (884 days) compared to the standard approval (606 days). A total of 170 approvals were available for the analysis of drug lags. A multivariate logistic regression analysis revealed that the following factors contributed significantly to the drug lags (p < 0.05): accelerated approval (odds ratio [OR] 4.48), Phase III study (OR 3.69), major cancer (OR 0.38), and international/global development (OR 0.32). Accelerated approval in the U.S. is one of the significant factors that extend the drug lags for anticancer drugs. The current drug development and approval process in Japan may have advantages, however, since a new regulation to reduce drug lag for anticancer drugs, the conditional early approval system, may help minimize drug lags and support decision making not only for regulators but also pharmaceutical companies. https://doi.org/10.21423/jrs-v08nagasaw

Selective Safety Data Collection in Clinical Studies of Oncology Drugs for Marketing Approval in the United States

Optimization of data collection is a key issue in clinical studies of oncology drugs because it affects the workload and financial burden of the clinical infrastructure. Focusing on oncology drugs, which produce many low-grade as well as serious adverse reactions, we investigated the use of selective safety data collection in the pivotal clinical studies for marketing approval in the United States. Drug labels were examined to find clinical studies that evaluated adverse events with limited data, and found ten drugs approved between 2004 and 2015 whose pivotal studies used selective rather than comprehensive safety data collection. Only three were in accordance with the 2001 FDA Guidance for Industry, "Cancer Drug and Biological Products -- Clinical Data in Marketing Applications", which suggests such selectivity when targeting a similar population to the initial approval. Two selective studies were applied to a drug's initial approval. Three adopted the Guidance criteria for safety data collection of only noting grade 4-5 hematologic and 3-5 non-hematologic toxicities.No major problems caused by this approach were found in the description of medical reviews, approval letters and post-marketing revisions to the boxed warnings on labels issued by the FDA. Selective safety data collection can be an efficient approach to streamlining the procedure of clinical studies and should be considered for use in pivotal clinical studies for oncology drugs.https://doi.org/10.21423/jrs-v05n02p036 (DOI assigned 3/11/2019