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Motonobu Nakamura
Published: 1 July 2021
Trends in Immunotherapy, Volume 5, pp 14-17; https://doi.org/10.24294/ti.v5.i1.1280

Abstract:
Treatment of malignant melanoma has made great strides in the last decade. On the one hand, immune checkpoint inhibitors and molecular targeted drugs improved the prognosis of patients. On the other hand, it is very important to be aware of the causes of malignant melanoma based on the latest knowledge. In this review, I will briefly review the carcinogenic mechanism of malignant melanoma from the aspects of ultraviolet rays, mechanical stress, trauma and so on.
Fukumi Furukawa
Published: 1 July 2021
Trends in Immunotherapy, Volume 5, pp 7-13; https://doi.org/10.24294/ti.v5.i1.1269

Abstract:
In recent years of immunology, the understanding of innate immunity has deepened, and the concept of innate immunity has been proposed even in the area of acquired immune subjects. The conventional immunosuppressive treatments have mainly controlled the step of acquired immunity. However, the involvement of innate immunity was clarified for hydroxychloroquine (HCQ), which has been confirmed to be very effective for cutaneous lupus erythematosus (CLE). This review introduces the mechanism of development of CLE from the viewpoint of autoantibodies, cytokines, and innate immunity. Furthermore, the mechanism of HCQ is introduced and discussed.
Mami Ishibashi
Published: 1 July 2021
Trends in Immunotherapy, Volume 5, pp 18-20; https://doi.org/10.24294/ti.v5.i1.1286

Abstract:
Dupilumab is a monoclonal antibody against the alpha subunit of the interleukin (IL)-4 receptor that inhibits IL-4 and IL-13 signaling, which plays a central role in Th2 inflammation in AD.Here, we report the first Asian case of psoriasis unexpectedly induced by dupilumab therapy for AD. Compared with European and American AD phenotype, Asian AD phenotype is characterized by changes in the psoriasiform phenotype, associating with higher Th17 activation. The blockade of IL-4/IL-13 signaling by dupilumab may induce psoriasis eruption corresponding to shift from a Th2- to Th17- mediated inflammatory response in the skin.
Shoya Yano, Aika Okuno, Fukumi Furukawa
Published: 17 May 2021
Trends in Immunotherapy, Volume 5, pp 1-4; https://doi.org/10.24294/ti.v5.i1.1247

Abstract:
Immune checkpoint inhibitors can sometimes cause unexpected skin side effects. Special attention should be paid to a severe form of erythema multiforme (EM), toxic epidermal necrolysis and Stevens-Johnson syndrome. We experienced a patient who took 10 weeks from drug discontinuation to the onset of EM major.
Takuhiro Yamada, Akihiro Aioi
Published: 7 December 2020
Trends in Immunotherapy, Volume 4, pp 23-80; https://doi.org/10.24294/ti.v4.i2.1130

Abstract:
Perturbation of cutaneous homeostasis including immune dysregulation and skin barrier dysfunction evokes skin disorders. In this study, we examined the effect of Eucalyptus citriodora (Euc-c) extract on cytokine production, cell proliferation and cell differentiation in HaCaT cells to elucidate its influence on cutaneous homeostasis. Euc-c suppressed significantly LPS-induced IL-6 and TNF-a-induced IL-8 production from HaCaT cells. Conversely IL-1ra production was significantly enhanced by Euc-c. The expressions of IVL, CERS3 and CERS4, keratinocyte differentiation markers, were upregulated to 3.1, 2.8 and 2.7-fold respectively by Euc-c treatment, compared to the control, while the proliferation was downregulated. The lipid contents in Euc-c-treated cells tended to increase, compared with non-treated cells. To explore the underlying mechanism of these effect, we next performed siRNA experiments against PPAR-b/d. Euc-c enhanced PPAR-b/d mRNA expression to 3.25-fold, while PPAR-b/d mRNA expression in transfected cells was suppressed. The expressions of IVL, CERS3 and CERS4 in transfected cells were suppressed to 1.48, 0.82 and 0.72-fold respectively, concomitant with suppression of PPAR-b/d mRNA expression. These results indicated that Euc-c exerts anti-inflammatory effects and regulates keratinocyte differentiation via the modulation of PPAR-b/d pathway. Therefore, the application of Euc-c is expected to exert beneficial effect on skin disorders evoked by perturbation of skin homeostasis.
Ichiko Morino, Aika Okuno, Yuka Hirakawa, Yumiko Saya, Yumi Murakami, Fukumi Furukawa, Hiroshi Matsunaka
Published: 15 November 2020
Trends in Immunotherapy, Volume 4, pp 35-86; https://doi.org/10.24294/ti.v4.i2.1187

Abstract:
Although epidermal growth factor receptor (EGFR) inhibitors are one of the most effective treatment options for lung cancer, they frequently cause cutaneous toxicity that can lead to treatment discontinuation. Dryness, which is a common form of cutaneous toxicity, is usually treated using medical moisturizing agents. We aimed to investigate the treatment of cutaneous toxicity caused by EGFR inhibitors by comparing patients who used a cosmetic moisturizer with those who used conventional medical moisturizers. This study included 12 patients with lung cancer, who were receiving EGFR inhibitors and using topical medical moisturizers. The participants were assigned to a group that continued using medical moisturizers or a group that began using NOV® skin cream D. The study’s findings showed that like conventional medical moisturizers, NOV®skin cream D improved the cutaneous dryness caused by EGFR inhibitors and that it might additionally improve patients’ quality of life. Also, we obtained novel findings that NOV® skin cream D normalized keratinization, which is a component of normal skin cell differentiation impeded by EGFR inhibitors. Hence, the cosmetic moisturizer may help to prevent the discontinuation of EGFR inhibitors, thereby ensuring their continuous therapeutic effects.
Akihiro Aioi
Published: 26 October 2020
Trends in Immunotherapy, Volume 4, pp 55-68; https://doi.org/10.24294/ti.v4.i2.1063

Abstract:
Peroxisome proliferator-activated receptors (PPARs) are fatty acid activated transcription factors that belong to the nuclear hormone receptor family. They are initially known as transcriptional regulators of lipid and glucose metabolism, although further evidence has also been accumulated for other functions. Due to the nature of all PPAR isotypes which are expressed and exert effects by regulating the functions of cell types residing and infiltrating in the skin, PPARs represent a major research target for the understanding and treatment of many skin diseases. Atopic dermatitis (AD) is a chronic and relapsing disease characterized by skin barrier dysfunction and immune dysregulation. Skin barrier disturbance is one of the exacerbation factors of AD, due to facile penetration of molecules such as antigens. From the aspect of immune dysregulation, innate and acquired immunity including cell proliferation, cell differentiation, and cytokine network are involved in the pathogenesis. In this review, the role of PPAR in AD and the possibility of its agonist for the treatment of AD are discussed.
Mana Nishiguchi, Yuki Yamamoto, Masatoshi Jinnin
Published: 10 October 2020
Trends in Immunotherapy, Volume 4, pp 59-114; https://doi.org/10.24294/ti.v4.i2.1050

Abstract:
Systemic sclerosis (SSc) or scleroderma is an autoimmune disorder characterized by tissue fibrosis of the skin and internal organs. The etiology of the skin fibrosis is thought to be thickened dermis due to uncontrolled excessive deposition of various extracellular matrix, mainly type I collagen.Systemic treatments with anti-inflammatory and cytotoxic immunosuppressive properties, such as corticosteroids and immunosuppressants, are usually considered for skin sclerosis of patients with SSc. However, their approach must be initiated at the early stage, before the fibrosis is completed, and the effects of the corticosteroids and immunosuppressants are known to be reduced in the late stages of the sclerosis. Furthermore, various significant adverse effects of these treatments must be considered.This paper discusses the present day understanding of therapeutic options using disease-modifying drugs against skin sclerosis of SSc patients and the possible mechanisms.
Tahereh Bidmeshki Barzoki, Ali Mohammad Ahadi, Hoda Ayat
Published: 24 August 2020
Trends in Immunotherapy, Volume 4, pp 47-54; https://doi.org/10.24294/ti.v4.i2.891

Abstract:
Nowadays, foodborne diseases are one of the main problems of the world that infect humans due to consumption of contaminated water or food. Typhoid fever is one of the major causes of illness and death in the world caused by Salmonella typhi. Vaccination is one of the most effective approaches in order to reduction of the disease risk. The main goal of this study is designing and characterization of antigenic determinants of a fusion protein originated from S.typhi usable as an effective vaccine. In this study, the outer membrane proteins of salmonella have been considered as candidates conferring protection against typhoid. Considering the evidence, OmpA, OmpF and OmpC proteins of salmonella applied in a multivalent vaccine design. Conserved motives of these proteins were selected using the CLC software and then their extracellular regions of these peptides were identified with PRED-TMBB server. Appropriate motives were combined for design of final fusion protein. Finally epitops of designed protein with high antigenic properties were identified using BCPREDS, Ellipro, ABCpred, EpiJen, NetCTL-1.2, CTLpred, TAPpred, ProPred and VaxiJen servers. Predicted designed protein in this study reached a very high scores for antigenic indexes. Encoding Genetic construction of this fusion protein could be applied for production of the recombinant OmpA.OmpF.OmpC derived fusion protein with effective antigenic properties as a new vaccine against S.typhi. Laboratory experiments and animal challenging analyses is ongoing.
Marvin De Los Santos, Samuel D. Bernal
Published: 18 July 2020
Trends in Immunotherapy, Volume 4, pp 41-104; https://doi.org/10.24294/ti.v4.i2.1064

Abstract:
The recent approval of two CAR-T therapies by US Food and Drug Administration (FDA) marks a very significant development in cell-based cancer immunotherapy. This milestone was demonstrated by the effectiveness of eradicating hematologic cancers using CD19-specific CARs. The success spurred development of immune cell therapies for other cancers, especially solid tumors. The generation of novel CAR constructs for these cancer types represents a major challenge in bringing the technology ‘from-bench-to-bedside‘.In this review, we outline some new technologies we have developed to equip CAR-T cells to enhance efficiency while decreasing toxicity of CAR-T therapies in solid tumors.
Ichiko Morino, Aika Okuno, Yuka Hirakawa, Yumiko Saya, Yumi Murakami, Fukumi Furukawa, Hiroshi Matsunaka
Published: 19 June 2020
Trends in Immunotherapy, Volume 4, pp 1-6; https://doi.org/10.24294/ti.v4.i1.1187

Abstract:
Although epidermal growth factor receptor (EGFR) inhibitors are one of the most effective treatment options for lung cancer, they frequently cause cutaneous toxicity that can lead to treatment discontinuation. Dryness, which is a common form of cutaneous toxicity, is usually treated using medical moisturizing agents. We aimed to investigate the treatment of cutaneous toxicity caused by EGFR inhibitors by comparing patients who used a cosmetic moisturizer with those who used conventional medical moisturizers. This study included 12 patients with lung cancer, who were receiving EGFR inhibitors and using topical medical moisturizers. The participants were assigned to a group that continued using medical moisturizers or a group that began using NOV® skin cream D. The study’s findings showed that like conventional medical moisturizers, NOV®skin cream D improved the cutaneous dryness caused by EGFR inhibitors and that it might additionally improve patients’ quality of life. Also, we obtained novel findings that NOV® skin cream D normalized keratinization, which is a component of normal skin cell differentiation impeded by EGFR inhibitors. Hence, the cosmetic moisturizer may help to prevent the discontinuation of EGFR inhibitors, thereby ensuring their continuous therapeutic effects.
Eriko Adachi, Erina Yokoyama, Yuna Yamagami, Reiko Koga, Yoshiaki Yoshikawa
Published: 19 June 2020
Trends in Immunotherapy, Volume 4, pp 7-9; https://doi.org/10.24294/ti.v4.i1.1210

Abstract:
Immune checkpoint inhibitors, such as nivolumab, have been recognized that the enhanced immune responses often lead to immune-related adverse events (irAEs) in various organs. Although cutaneous toxicity is one of the most common irAEs, bullous pemphigoid (BP) with immune checkpoint inhibitors is rare. Herein, the authors report a case of BP in a patient of the metastatic malignant melanoma of the brain under the treatment of nivolumab. It is notable that this case showed the clear correlation between the status of using of nivolumab and serum levels of anti-BP180 antibody. In addition, the skin eruptions in the case were mainly pruritic erosive or crusted papules and these clinical features may be the clinical characteristics of BP induced by nivolumab.
Yutaka Inaba, Fukumi Furukawa, Seisho Azuma, Kimiye Baba, Masahiko Taniguchi, Yoshinobu Murakami
Published: 19 June 2020
Trends in Immunotherapy, Volume 4; https://doi.org/10.24294/ti.v4.i1.1230

Abstract:
Citrus jabara (CJ) is a rare citrus that originally grew wild only in the southern area of the Kii peninsula in Japan. In the relationship between CJ and atopic dermatitis (AD), improvement of AD by oral intake of CJ fruit juice was reported in AD model mice. Our previous study also showed anti-inflammatory potentials of CJ fruit peels in vitro. In this study, the applicability of CJ fruit peel powder (CJ powder) for topical application in patients with AD was investigated. After confirming both the safety of CJ powder in preclinical studies and the safety of 5% CJ powder cream in healthy volunteers, the safety and usefulness of 5% CJ powder cream were evaluated in 20 patients with AD. Evaluation of 5% CJ powder cream in patients with AD for 4 weeks showed improvement in the mean severity score of the affected area (from 3.0 to 2.0, p=0.001 by Student’s t test), improvement in skin lesions (11 of 20 participants), usefulness (16 of 20 participants), and safety (16 of 20 participants). Although aggravation of symptoms on application areas were observed on 4 participants, their aggravation were systemic, resulting from causes other than tested cream. These results suggested that 5% CJ powder cream is useful and safe for patients with AD.
Hidefumi Inaba, Hiroyuki Ariyasu, Hisako Okuhira, Yuki Yamamoto, Hiroaki Akamatsu, Masahiro Katsuda, Masatoshi Jinnin, Isao Hara, Takashi Akamizu
Published: 7 June 2020
Trends in Immunotherapy, Volume 4, pp 18-26; https://doi.org/10.24294/ti.v4.i1.606

Abstract:
Immune-checkpoint inhibitors (ICIs) are novel agents directed to various malignant tumors. During ICI therapy, however, immune related adverse effects (irAEs) including endocrine dysfunctions have been reported. Dysfunctions in the pituitary gland and the thyroid gland by ICI are often observed, and those in the adrenal glands and the pancreas are less frequent. Positive correlation of the prevalence of endocrine irAEs to clinical antitumor effectiveness during ICI therapy has been reported. The mechanisms of endocrine irAEs by ICI, however, remain unclear, and optimal prevention, prediction, and treatment of the irAEs are still uncertain. This review describes possible mechanisms involved in ICI-related immunity, and discusses clinical management of endocrine irAEs during ICI therapy.
Takashi Yoshimasu, Naoya Mikita, Takaharu Ikeda, Nobuo Kanazawa, Fukumi Furukawa, Masatoshi Jinnin
Published: 21 April 2020
Trends in Immunotherapy, Volume 4, pp 1-4; https://doi.org/10.24294/ti.v4.i1.149

Abstract:
Alopecia totalis (AT) with body hair loss is the most severe type of alopecia areata (AA). The ability to develop hair is suggested to be poor in such severe AA, because AT does not respond to corticosteroid pulses and immunotherapy using squaric acid dibutylester (SADBE) or diphenylcyclopropenone (DPCP). The purpose of this study is to assess the possibility of hair regrowth in AT with body hair loss. Ten patients with AT who did not respond to topical immunotherapies, received triamcinolone acetonide (TA) injections. Undiluted or 2-fold diluted solutions of TA were prepared and 0.1–0.2 mL of either of the two solutions was administered to each patient. In total, 2 mL of the selected solution was injected monthly into each area. In cases where vellus hair developed after the injections, we restarted the immunotherapy using SADBE or DPCP and continued the therapies for more than half a year. The development of vellus hair after TA injections was defined as a good response. Complete response rate to the topical injection of TA was 10% (1/10), however the partially good response rate was 60% (6/10). The good responders showed the anagen stage of hair follicle after TA injections. Furthermore, the complete responder to TA showed susceptibility to the subsequent immunotherapy and more regrowth of hair was seen. Even if patients with AT have suffered for a prolonged period since onset, it is possible to recover the hair cycle if they show susceptibility to intralesional corticosteroid and subsequent immunotherapy.
Seisho Azuma, Yoshinobu Murakami, Eiko Azuma, Kimiye Baba, Masahiko Taniguchi
Published: 15 April 2020
Trends in Immunotherapy, Volume 4, pp 5-14; https://doi.org/10.24294/ti.v4.i1.844

Abstract:
Currently, about half of people in Japan suffer from allergic diseases. Thus, Citrus jabara fruits have been paid attention as one of quite effective anti-allergic functional foods. C. jabara is an endemic species originally grown only in Kitayama village, Wakayama prefecture in Japan. Although genetic characterization and diversity of various Citrus fruits including C. jabara were researched, but there is room for the study on flavonoids characteristics in C. jabara fruit. For the alleviation of allergic symptom, anti-inflammatory effects are also important. In this study, characteristics of flavonoids in C. jabara fruit peels, and the anti-inflammatory effects of these purified flavonoids were investigated. Our results revealed that C. jabara is a unique Citrus that almost all of flavonoids in fruit peels was narirutin. There was no Citrus species with a flavanone glycosides content ratio like C. jabara. Although anti-inflammatory effects of narirutin was weak, but its aglycone naringenin exhibited following inhibitory effects: nitric oxide synthesis (IC50 = 105 μM), nitric oxide synthase induction, Interleukin-6 synthesis (IC50 = 65 μM), and inducible soluble epoxide hydrolase activity (IC50 = 267 μM). Since narirutin is deglycosylated to naringenin that is then absorbed by colonocytes, it is considered that narirutin exists like a prodrug and its aglycone naringenin works as an active form of anti-inflammatory effect in a living body at oral ingestion of C. jabara fruit peels.
Naohiro Seo
Published: 14 April 2020
Trends in Immunotherapy, Volume 4, pp 36-41; https://doi.org/10.24294/ti.v4.i1.433

Abstract:
Immune system is a precise mechanism for maintenance of homeostasis by lymphocyte-mediated elimination of extracellular and intercellular pathogens, and abnormal cells in cytokine-, chemokine-, antibody-, and cytotoxic granule-dependent manners. Extracellular vesicles, e.g. exosomes, released from multivesicular endosome in immune cells have been known to be a part of the immune system. Exosomes released by antigen-presenting cells (APCs) such as macrophages and dendritic cells (DCs) regulate natural killer (NK) cells, CD8+ T cells (Cytotoxic T lymphocytes [CTLs]), and CD4+ T cells (Th cells) including Th1, Th2, and regulatory T (Treg) cells. In the anti-tumor immune system, NK cells and CTLs are mainly involved in the elimination of tumor cells by direct interaction. Recently, we clarified that tumor-infiltrating CD8+ T cells prevent tumor invasion and metastasis by exosome-mediated destruction of tumor stroma consist of mesenchymal stem cells (MSCs) and cancer-associated fibroblasts (CAFs). In this review article, we describe the role of exosomes in controlling immune system and its clinical application.
Chuyen Thi Hong Nguyen, Naotomo Kambe, Ikuko Ueda-Hayakawa, Hiroyuki Okamoto
Published: 26 March 2020
Trends in Immunotherapy, Volume 4, pp 27-35; https://doi.org/10.24294/ti.v4.i1.721

Abstract:
Sarcoidosis is a systemic disorder with unknown etiology and pathogenesis characterized by non-caseating granulomas, and different clinical manifestations of sarcoidosis hinder diagnosis and treatment. Therefore, a comprehensive understanding of serological markers based on clinical observations of sarcoidosis and the progression of granulomas would aid analysis in routine clinical practice. In this review, we overview common serological markers, including angiotensin converting enzyme (ACE) and lysozyme, and describe in detail new promising indices in sarcoidosis such as a T cell serological marker (soluble interleukin 2 receptor; sIL-2R) and thymus and activation-regulated chemokine (TARC/CCL17).
Akihiro Aioi
Published: 22 October 2019
Trends in Immunotherapy, Volume 3, pp 89-95; https://doi.org/10.24294/ti.v3.i2.122

Abstract:
Sirtuins (SIRTs) are initially recognized as NAD+-dependent histone deacetylase. SIRTs attract attention for their role as calorie restriction-induced “longevity proteins” to be expected to extend human life span and to promote health. As advancing studies, SIRTs have been recognized as cell signaling regulators which contribute to anti-inflammation, cell differentiation and so on. Therefore, SIRTs are supposed to affect wound healing which is comprised highly orchestrated complex four phases: hemostasis, inflammation, tissue formation and tissue remodeling. This review highlights the roles of SIRTs in wound healing process and provides a foundation and impetus for future basic and clinical research.
Yu Hu, Lin Lin, Pangen Cui, Xu Yao, Chao Luan, Zhimin Hao, Min Chen
Published: 19 October 2019
Trends in Immunotherapy, Volume 3, pp 62-68; https://doi.org/10.24294/ti.v3.i2.42

Abstract:
Severe psoriasis patients are reported to have a higher risk of liver abnormalities. Treatment option for severe psoriasis patients with liver disorder history remains a great challenge. Hepatic toxicity and long-term safety are the major concerns. Hence it is necessary to look for safer and more effective treatment for those patients. This retrospective review evaluated the safety and efficacy of combination therapy of infliximab and total glucosides of paeony (TGP) in treating 13 severe psoriasis patients with liver disorder history. Patients with severe psoriasis, comprising eight men and five women with a mean age of 37.3 ± 12.3, were observed. The patients experienced a mean course of psoriasis of 11.2 ± 7.1 years. The mean psoriasis area and severity index (PASI) score was 29.3 ± 12.9. All patients have the history of liver disorder. In our study, these patients were treated with infliximab at a dose of 5 mg/kg and TGP at a dose of 1.8 g/day. No liver test abnormalities were seen during combination therapy. After treatment, 61.5% patients showed PASI 50 response at week 2, and 81.8% patients have PASI 75 response at week 6. The mean time for achieving PASI 75 and PASI 90 improvement was 4.2 weeks and 9.6 weeks, respectively. Our observation demonstrates that combined therapy of infliximab and TGP is effective and safe in the treatment of severe psoriasis, especially for patients with liver disorder history.
Naoya Mikita, Yutaka Inaba, Takashi Yoshimasu, Nobuo Kanazawa, Fukumi Furukawa
Published: 20 August 2019
Trends in Immunotherapy, Volume 3, pp 69-75; https://doi.org/10.24294/ti.v3.i2.96

Abstract:
Mast cells are involved in many immune reactions and diseases through 1) the expressions of several receptors, 2) productions of various mediators such as histamine, cytokines, and chemokines, 3) direct interactions with immune cells. Besides allergic diseases, mast cells have been also assumed to be involved in autoimmune diseases such as bullous pemphigoid, rheumatoid arthritis, and multiple sclerosis. Moreover, several studies reported the involvement of mast cells in collagen disease. In this article, we review recent findings about the role of mast cells especially in systemic lupus erythematosus and systemic sclerosis. In these diseases, mast cells seem to be involved in local inflammation and tissue damage partially in the targeted organ rather than the development of autoimmunity including production of autoantibodies.
Ru Wen, Afoma C Umeano
Published: 18 August 2019
Trends in Immunotherapy, Volume 3, pp 79-88; https://doi.org/10.24294/ti.v3.i2.95

Abstract:
Cancer immunotherapy involves the delivery of immunogenic compounds and/or the priming, or induction, of the body's natural immune system to target cancer. The use of cancer immunotherapy has led to various means of cancer prevention and treatment that have produced prolonged life expectancy and stabilized disease. Nanoparticles are promising vehicles or adjuvants for effective delivery of therapeutics, antigens, stimulatory effectors, or antibodies for therapeutic invention. Targeting nanoparticles are especially useful due to their capability of accumulating in specific sites of interest like tumors and, thereby, decreasing risks of damage to normal tissue. Targeting can be achieved by incorporation of cell-surface related binding molecules or antibodies. This review explores the role of targeting nanoparticles as delivery or adjuvant sys­tems to modulate immune response, and as imaging tracking systems for cancer immunotherapy.
Wei Boon Yap, Shaktypreya Nadarajah, Nadiah Shidik, Noorjahan Banu Mohammed Alitheen
Published: 15 August 2019
Trends in Immunotherapy, Volume 3, pp 76-78; https://doi.org/10.24294/ti.v3.i2.121

Abstract:
Cancer immunotherapy using cytokines has been sought as an alternative therapeutic approach for treating cancers. Besides remarkable immunoregulatory properties, interleukin (IL)-27 has recently been shown to possess promising anticancer functions; hence, its potential roles in cancer immunotherapy. Although proven to be effective against cancer cell growth and angiogenesis, given its dual immune-regulating functions (pro-inflammatory and anti-inflammatory), the use of IL-27 as a cancer immunotherapeutic cytokine could possibly be a two-edged sword without meticulous and thorough research. This mini-review mainly discusses the functions and future prospects of IL-27 as an effective anticancer cytokine. Hopefully, it imparts useful insights into the potential applications of IL-27 in cancer immunotherapy
Fukumi Furukawa
Published: 13 May 2019
Trends in Immunotherapy, Volume 3; https://doi.org/10.24294/ti.v3.i1.1143

Abstract:
This is the announcement of top 5 PDF from 22 articles in 3 issues of Vol. 1 2017, which is based on the results of Statistical Reports of TI in September 2019. I am very glad to announce the 5 best viewed articles of Volume 1, 2017. And I want to express my sincere thanks for submitting outstanding papers.
Gloria Guerrero Manriquez
Published: 13 May 2019
Trends in Immunotherapy, Volume 3; https://doi.org/10.24294/ti.v3.i1.1122

Abstract:
Leprosy is a still a serious human health problema in developed countries. Environmental and genetic factors are playing a key role in the chronic course of the disease, resistance versus susceptibility. The multidrug treatment is not effective for all infected individuals; “cured” individuals mostly show relapses of neurological disordes and potential as the same as not cured can present physical and deformed constrainst. The unsolved puzzle in leprosy is that clinic spectrum depends of the host immune response.and thus, the outcome of the immune response. In the present review we intended to describe some aspects of the immunotherapy, based on type I IFNs and M. bovis BCG vaccine as a strategy such as sword to target germinal centers, either for the generation or for the enhancement and thus, throughout key signals delivered by folicular CD4+ T cells, and controlled by folicular regulatory CD4+ T cells, B cell differentiation into plasmacytoid cells be highly promoted the induction of protective high affinity neutralyzing antibodies to unlock humoral immunity, protective toward M. leprae infected individuals.
Akihiro Aioi, Takuhiro Yamada
Published: 13 May 2019
Trends in Immunotherapy, Volume 3; https://doi.org/10.24294/ti.v3.i1.1130

Abstract:
Perturbation of cutaneous homeostasis including immune dysregulation and skin barrier dysfunction evokes skin disorders. In this study, we examined the effect of Eucalyptus citriodora (Euc-c) extract on cytokine production, cell proliferation and cell differentiation in HaCaT cells to elucidate its influence on cutaneous homeostasis. Euc-c suppressed significantly LPS-induced IL-6 and TNF-a-induced IL-8 production from HaCaT cells. Conversely IL-1ra production was significantly enhanced by Euc-c. The expressions of IVL, CERS3 and CERS4, keratinocyte differentiation markers, were upregulated to 3.1, 2.8 and 2.7-fold respectively by Euc-c treatment, compared to the control, while the proliferation was downregulated. The lipid contents in Euc-c-treated cells tended to increase, compared with non-treated cells. To explore the underlying mechanism of these effect, we next performed siRNA experiments against PPAR-b/d. Euc-c enhanced PPAR-b/d mRNA expression to 3.25-fold, while PPAR-b/d mRNA expression in transfected cells was suppressed. The expressions of IVL, CERS3 and CERS4 in transfected cells were suppressed to 1.48, 0.82 and 0.72-fold respectively, concomitant with suppression of PPAR-b/d mRNA expression. These results indicated that Euc-c exerts anti-inflammatory effects and regulates keratinocyte differentiation via the modulation of PPAR-b/d pathway. Therefore, the application of Euc-c is expected to exert beneficial effect on skin disorders evoked by perturbation of skin homeostasis.Key words: Eucalyptus citriodora, PPAR-b/d, inflammation, barrier function, cutaneous homeostasis
Fukumi Furukawa
Published: 13 May 2019
Trends in Immunotherapy, Volume 3; https://doi.org/10.24294/ti.v3.i1.1125

Abstract:
CAR-T therapy is breakthrough for intractable autoimmune disease?
Published: 13 May 2019
Trends in Immunotherapy, Volume 3; https://doi.org/10.24294/ti.v3.i1.1140

Abstract:
Hailey-Hailey disease is an autosomal dominant hereditary skin disease. Severe cases are often difficult to treat. We report a recent case that was successfully treated using cyclosporine. The case is described from the aspects of treatment and gene mutation.
Junichi Koseki, Atsushi Kaneko, Yosuke Matsubara, Kyoji Sekiguchi, Satomi Ebihara, Setsuya Aiba, Kenshi Yamasaki
Published: 11 May 2019
Trends in Immunotherapy, Volume 3, pp 26-40; https://doi.org/10.24294/ti.v3.i1.31

Abstract:
Prompt elimination of pathogens including bacteria and dead cells prevents the expansion of secondary and prolonged inflammations and tissue damage. Keigairengyoto (KRT) is a traditional Japanese medicine prescribed for dermatoses such as purulent inflammations. Our aim is to clarify the actions of KRT in bacterial clearance and to examine the cell-kinetic profiles of phagocytes. In a mouse cutaneous infection model using living Staphylococcus aureus, KRT drastically reduced the number of bacteria in the infection sites. To evaluate the bacterial clearance, pseudo-infection was induced in mouse ears by intradermal injection of FITC-conjugated dead S. aureus. Biochemical and histological examinations revealed that KRT promoted bacterial clearance at 6 and 24 h post-injection. The numbers and phagocytic activities of neutrophils and macrophages in the ears were evaluated histologically using anti-Ly6G and F4/80 antibodies. KRT reduced bacterial deposition and increased the accumulation of F4/80+ resident macrophages around the lesion site. FACS analysis was performed on single cell suspensions dispersed enzymatically from skin lesions, followed by an investigation of CD11b+Ly6G+ (neutrophils) and CD11b+Ly6G– (monocytes/macrophages) cells. KRT increased the mean fluorescent intensity of FITC in CD11b+Ly6G–cells and the number of FITC-positive CD11b+Ly6G+ cells, while KRT did not change the numbers of these cells. To investigate the active constituents of KRT, phagocytosis assay using macrophages was performed, resulting in that some flavonoid glucuronides of KRT derivatives augmented phagocytosis. Collectively, KRT promoted bacterial clearance by enhancing the phagocytic capability of neutrophils and macrophages. KRT may exert unique properties in preventive and therapeutic strategies for skin infectious inflammation.
Satoshi Nakamizo, Tetsuya Honda, Kenji Kabashima
Published: 5 May 2019
Trends in Immunotherapy, Volume 3, pp 50-57; https://doi.org/10.24294/ti.v3.i1.98

Abstract:
Obesity has become a significant public health problem since it may cause many chronic diseases, including type 2 diabetes, cardiovascular diseases, liver diseases, and some cancers. Recent studies have shown that obesity is a major risk factor for the development of inflammatory skin diseases, including eczema, atopic dermatitis, and psoriasis. Inflammatory cytokines produced from adipose tissue and activation of innate immunity are considered as important factors in obesity-induced inflammation. However, the molecular mechanisms by which obesity affects the development of inflammatory skin diseases are not well understood. In this review, we will discuss the relationship between the underlying mechanisms linking obesity and inflammatory skin diseases based on the latest researches.
Takuya Tsunoda, Kazunori Shimada, Naoki Uchida, Shinichi Kobayashi, Yasutsuna Sasaki
Published: 4 May 2019
Trends in Immunotherapy, Volume 3, pp 41-49; https://doi.org/10.24294/ti.v3.i1.79

Abstract:
Recently, the analysis of microbiota has been of interest not only for the clarification of the molecular mechanisms of disease etiology, but also the discovery of novel strategies for treatment. Following the development of "next-generation" sequencing, novel areas have been discovered in microbiota; however, in oncology, the relationships between microbiota and cancer have not been fully clarified. In recent literature, surprisingly, detection of gut microbiota in tumor issue itself has been reported. Microbiota might play an important role in carcinogenesis. However, this phenomenon is not well understood, and research in this area has just begun. In the past five years, a paradigm shift has occurred in cancer treatment due to immunotherapy. Immunotherapy has made cure possible even in advanced cancer patients with not only melanoma but also non-small cell lung cancer and others. In this review, we discuss the mechanisms of novel immunotherapies, checkpoint inhibitors, and the relationship between microbiota and immunotherapy. It is of significance to clarify this relationship because it may lead to the discovery of predictive markers for immunotherapy and promote clinical efficacy. Finally, we also mention our activities in the construction of a big database for information on immunotherapy and microbiota, which may lead to excellent possibilities of discovering novel strategies for more effective cancer treatments, and may accelerate the alteration of cancers to the classification of chronic nonfatal disease.
Yuta Sakurai, Yasunori Umemoto, Takashi Kawasaki, Daisuke Kojima, Tokio Kinoshita, Mami Yamashiro, Motohiko Banno, Hideki Arakawa, Fumihiro Tajima
Published: 1 April 2019
Trends in Immunotherapy, Volume 3, pp 19-25; https://doi.org/10.24294/ti.v3.i1.37

Abstract:
Exercise-induced production of interleukin (IL)-6 results in the expression of chemokine CXC-motif ligand 1 (CXCL1) in mice. Recent studies described the increase in serum IL-6 levels during immersion of subjects in hot water. The present study investigated the effects of a 20-min head-out water immersion in 42 °C water (hot-HOI) on serum concentrations of CXCL1 in eight healthy men. Venous blood samples were taken at rest, immediately after hot-HOI, as well as 1, 2, 3, and 4 h after hot-HOI for measurements of serum concentrations of CXCL1, IL-6, tumor necrosis factor (TNF)-α, high-sensitivity C-reactive protein (hsCRP), while assessing counts of blood cells (CBC) and monitoring core temperature (Tcore). Tcore and serum IL-6 increased during hot-HOI and remained high until 4 h after hot-HOI. However, serum CXCL1, TNF-α, hsCRP, and CBC remained constant throughout the experiment. In conclusion, the results from our study demonstrated that 20-min hot-HOI increased serum IL-6, but not CXCL1 in healthy man.
Naotaka Doi, Yumi Nakatani, Yutaka Inaba, Toshikazu Kondo, Fukumi Furukawa, Nobuo Kanazawa
Published: 2 March 2019
Trends in Immunotherapy, Volume 3, pp 10-18; https://doi.org/10.24294/ti.v3.i1.14

Abstract:
The aim of this study is to evaluate the effects of corticosteroid application on each grade of burn, and to clarify the underlying mechanisms of the effects, especially in its acute inflammatory phase. To generate three-graded burn models (epidermal burn, or EB; dermal burn, or DB; and subcutaneous burn, or SB), hot water was applied on the back skin of Hos:HR-1 mice. Strongest-class (or high-potent) corticosteroid ointment (DD group) or petrolatum (control group) was applied on the back immediately after the hot water application on mice. Prednisolone sodium succinate (PDN group), 1 mg/kg was orally applied immediately after the hot water application on mice. The mice were sacrificed 1–3 days after hot water application, and the lesional skin samples were provided for histological assessment to enumerate the number of infiltrating inflammatory cells. The mRNA expression levels of inflammatory cytokines (IL-1b, TNFa, IL-6 and IFNg) in the lesional skin were also investigated. As a result, corticosteroid application suppressed the number of infiltrating inflammatory cells in the DD group of EB and SB at the early phase, and in DB at all time-points. However, the number of infiltrating inflammatory cells increased in EB on day 3. Expression of cytokines was generally suppressed in the PDN group of SB. In the cases of EB and DB, some cytokines had decreased but many of the others showed increased expression. In conclusion, the anti-inflammatory effects of corticosteroids are not simple inhibitory effects on inflammatory cell infiltration and cytokine production, but exert more complicated effects in vivo.
Published: 8 September 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i3.1063

Abstract:
Peroxisome proliferator-activated receptors (PPARs) are fatty acid activated transcription factors that belong to the nuclear hormone receptor family. They are initially known as transcriptional regulators of lipid and glucose metabolism, although further evidence has also been accumulated for other functions. Due to the nature of all PPAR isotypes which are expressed and exert effects by regulating the functions of cell types residing and infiltrating in the skin, PPARs represent a major research target for the understanding and treatment of many skin diseases. Atopic dermatitis (AD) is a chronic and relapsing disease characterized by skin barrier dysfunction and immune dysregulation. Skin barrier disturbance is one of the exacerbation factors of AD, due to facile penetration of molecules such as antigens. From the aspect of immune dysregulation, innate and acquired immunity including cell proliferation, cell differentiation, and cytokine network are involved in the pathogenesis. In this review, the role of PPAR in AD and the possibility of its agonist for the treatment of AD are discussed.
Yuka Hirakawa, Aika Okuno, Atsuko Tanabe, Mutsumi Okada, Naoyuki Anzai, Yuki Yamamoto, Fukumi Furukawa
Published: 8 September 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i4.1079

Abstract:
Voriconazole is a universal anti-fungal prophylaxis, which is frequently taken to the patients after hematopoietic stem cell transplantation and solid organ transplantation. Voriconazole can cause phototoxicity, multiple erythema in sun-exposed areas may develop actinic keratosis and cutaneous squamous cell carcinoma (cSCC) while taking voriconazole. In North America and Europe, case reports of phototoxicity and aggressive cSCC in patients on voriconazole have been documented. Also 4 cases of voriconazole-associated cSCC have recently been reported in Japan. We describe a Japanese woman with multiple cSCC associated with recurrence of cSCC after discontinuing voriconazole.
Published: 8 September 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i3.1078

Abstract:
Nakajo-Nishimura syndrome (NNS) is an autosomal, recessively inherited disorder, which has been reported by Japanese physicians. This disease is characterized by remittent fever, pernio-like skin rashes, nodular erythema-like skin eruptions and partial lipodystrophy. NNS is an immunoproteasome-associated autoinflammatory disorder caused by a mutation of the PSMB8 gene. In general, autoinflammatory diseases are not associated with autoantibody production because it is assumed that autoinflammatory disorders are caused by the dysfunction of innate immunity and/or the dysfunction of proteasomes that have been collectively designated as proteasome-associated autoinflammatory syndromes. Autoinflammatory diseases were originally defined as diseases in which autoantibodies and autoreactive T cells were not detected, without activation of antigen-specific adaptive immune system, unlike autoimmune diseases. However, in recent years, as we previously reported, cases with the appearance of autoantibodies have been reported, and the boundaries are becoming vague. We herein discuss the relationship between ANA and autoinflammatory NNS. We collected 9 cases with NNS, in which 5 cases showed positive ANA or anti-dsDNA antibody during the course. The autoantibodies in NNS is also expected due to abnormal production and response of IFNα, but detailed pathological conditions need to be elucidated by accumulation and examination of further cases in the future. In other words, NNS will become a bridge with research on refractory autoimmune diseases.
Fukumi Furukawa
Published: 8 September 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i3.1065

Abstract:
On October 1, The Nobel Prize in Physiology or Medicine 2018 was awarded jointly to Dr. James P. Allison and Dr. Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation.The Nobel Assembly at Karolinska Institute released the comments that Dr. Allison and Dr. Honjo showed how different strategies for inhibiting the brakes on the immune system could be used in the treatment of cancer [1-5]. The seminal discoveries by the two laureates constitute a landmark in our fight against cancer. https://www.nobelprize.org/prizes/medicine/2018/prize-announcement/I sincerely wish to congratulate two recipients, co-workers and many patients cooperated in clinical trials. In this journal, we have published several reviews and papers on immunity checkpoints so far. The reason is that the mission of this journal is in scientific awareness and dissemination of new immunotherapy.I herein introduce briefly my previous report with some modification [6]. Immune checkpoints inhibitors (ICIs) have opened promising avenues in the treatment of cancer. Various blocking antibodies targeting programmed cell death -1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are approved for human use. They significantly improved disease outcome in a number of cancer patients by boosting anti-tumor immune responses. As Seidel, Otsuka and Kabashima described in their review article [7], mortality among advanced stage patients and the frequency of treatment-related adverse events remain high with current treatment. And, it is also noteworthy that unexpected immune related adverse effects (irAEs) appear, even when it becomes better to be administered to many cancer patients [8]. Unfortunately, the mechanisms of endocrine irAEs by ICIs, remain unclear, and optimal prevention, prediction, and treatment of the irAEs are still uncertain. However, appropriate uses and index setting related to prognosis are being studied in many fields such as dermatology [9] and other organs [6,7].While solving such problems, we have to understand that the mechanisms of immunogenic cell death are now moving from concepts to the clinic. We will explain the mechanism behind ICD and how it will perhaps breathe a new life into chemotherapy use in cancer, not front and center but as a helpful hand to immunotherapy [10].For a long time many scientists or doctors attempted to engage the immune system in the fight against cancer. Many clinicians stared at cancer patients who were to be dying by their side, mourning their inability. However, cancer therapy by inhibition of negative immune regulation checkpoint therapy has fundamentally changed the way we view how cancer can be managed and many patients will receive much better care and cure.
Mana Nishiguchi, Yuki Yamamoto, Masatoshi Jinnin
Published: 8 September 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i3.1050

Abstract:
Systemic sclerosis (SSc) or scleroderma is an autoimmune disorder characterized by tissue fibrosis of the skin and internal organs. The etiology of the skin fibrosis is thought to be thickened dermis due to uncontrolled excessive deposition of various extracellular matrix, mainly type I collagen.Systemic treatments with anti-inflammatory and cytotoxic immunosuppressive properties, such as corticosteroids and immunosuppressants, are usually considered for skin sclerosis of patients with SSc. However, their approach must be initiated at the early stage, before the fibrosis is completed, and the effects of the corticosteroids and immunosuppressants are known to be reduced in the late stages of the sclerosis. Furthermore, various significant adverse effects of these treatments must be considered.This paper discusses the present day understanding of therapeutic options using disease-modifying drugs against skin sclerosis of SSc patients and the possible mechanisms.
Samuel D. Bernal
Published: 8 September 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i3.1064

Abstract:
The recent approval of two CAR-T therapies by US Food and Drug Administration (FDA) marks a very significant development in cell-based cancer immunotherapy. This milestone was demonstrated by the effectiveness of eradicating hematologic cancers using CD19-specific CARs. The success spurred development of immune cell therapies for other cancers, especially solid tumors. The generation of novel CAR constructs for these cancer types represents a major challenge in bringing the technology ‘from-bench-to-bedside‘.In this review, we outline some new technologies we have developed to equip CAR-T cells to enhance efficiency while decreasing toxicity of CAR-T therapies in solid tumors.
Published: 8 September 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i3.1051

Abstract:
Nakajo-Nishimura syndrome (NNS) is a very rare hereditary disorder that has its onset in infancy with pernio-like skin rashes, and is accompanied by remittent fever and nodular erythema-like skin eruptions. The treatment of NNS is still under groping. Recently we encountered a case that was treated by corticosteroid and a humanized anti-human IL-6 receptor monoclonal antibody. As a result, the fever and skin rash was not improved sufficiently, and clinical symptoms of fat atrophy and joint contracture were gradually progressing. We herein report the effects of these agents and discuss the possibilities of new treatment direction.
Tahereh Bidmeshki Barzoki, , Hoda Ayat
Published: 5 September 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i4.891

Abstract:
Nowadays, foodborne diseases are one of the main problems in the world that infect humans due to consumption of contaminated water or food. Typhoid fever is one of the major causes of illness and death in the world caused by Salmonella typhi. Vaccination is one of the most effective approaches in order to reducing the risk of disease. The main goal of this study is designing and characterization of antigenic determinants of a fusion protein originated from S.typhi usable as an effective vaccine. In this study, the outer membrane proteins of salmonella have been considered as candidates conferring protection against typhoid. Considering the evidence, OmpA, OmpF and OmpC proteins of salmonella applied in a multivalent vaccine design. Conserved motives of these proteins were selected using the CLC software and then their extracellular regions of these peptides were identified with PRED-TMBB server. Appropriate motives were combined for design of final fusion protein. Finally epitops of designed protein with high antigenic properties were identified using BCPREDS, Ellipro, ABCpred, EpiJen, NetCTL-1.2, CTLpred, TAPpred, ProPred and VaxiJen servers. Predicted designed protein in this study reached a very high scores for antigenic indexes. Encoding Genetic construction of this fusion protein could be applied for production of the recombinant OmpA.OmpF.OmpC derived fusion protein with effective antigenic properties as a new vaccine against S. typhi. Laboratory experiments and animal challenging analyses is ongoing.
Ajaz Bulbul
Published: 25 April 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i2.970

Abstract:
Although cancer chemotherapy has historically been considered immune suppressive, we now understand that combining chemoimmunotherapy incites a mechanism called Immunogenic cell death. These mechanisms are now moving from concepts to the clinic. Recently dramatic advances in lung cancer treatment by combining chemotherapy with immunotherapy have led the way to this new frontier in cancer medicine. We will explain the mechanism behind ICD and how it will perhaps breathe a new life into chemotherapy use in cancer, not front and center but as a helpful hand to immunotherapy.
, Reiko Kageyama, Takatsune Umayahara, Tomohiro Morio
Published: 25 April 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i2.719

Abstract:
Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is an autoinflammatory disease characterized by destructive inflammation of the skin and joints in association with genetic mutation of the Pombe Cdc15 homology family member PSTPIP1. Because a therapeutic strategy specific to this disease has not been established, treatment is always challenging for clinicians. We herein describe a case of PAPA syndrome with typical clinical features successfully treated with combination therapy of traditional anti-inflammatory drugs. A 39-year-old man presented with painful plaques on his extremities that had been present for several years. Large brown plaques were observed on both arms and legs with numerous fistulae and ulcers. Cystic acne lesions subsequently appeared on his cheeks and upper back. We diagnosed the patient with PAPA syndrome based on the presence of typical clinical features; however, no genetic mutations of exon-1 to 15 of PSTPIP1were found. Although recent reports have emphasized the efficacy of biologics that target inflammatory cytokines such as antibodies to interleukin-1β and tumor necrosis factor-α, use of these agents remains uncovered by health insurance in Japan, showing unresolved discrepancy in practical use for clinicians. The present patient was successfully treated with combined therapy of a corticosteroid, colchicine, and cyclosporine A, encouraging the use of this combination therapy as a novel therapeutic option.
Fukumi Furukawa
Published: 25 April 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i2.930

Abstract:
Immune checkpoint inhibitors and irAEs
Published: 25 April 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i2.721

Abstract:
Sarcoidosis is a systemic disorder with unknown etiology and pathogenesis characterized by non-caseating granulomas, and different clinical manifestations of sarcoidosis hinder diagnosis and treatment. Therefore, a comprehensive understanding of serological markers based on clinical observations of sarcoidosis and the progression of granulomas would aid analysis in routine clinical practice. In this review, we overview common serological markers, including angiotensin converting enzyme (ACE) and lysozyme, and describe in detail new promising indices in sarcoidosis such as a T cell serological marker (soluble interleukin 2 receptor; sIL-2R) and thymus and activation-regulated chemokine (TARC/CCL17).
, , Hisako Okuhira, , Hiroaki Akamatsu, Masahiro Katsuda, Masatoshi Jinnin, Isao Hara,
Published: 25 April 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i2.606

Abstract:
Immune-checkpoint inhibitors (ICIs) are novel agents directed to various malignant tumors. During ICI therapy, however, immune related adverse effects (irAEs) including endocrine dysfunctions have been reported. Dysfunctions in the pituitary gland and the thyroid gland by ICI are often observed, and those in the adrenal glands and the pancreas are less frequent. Positive correlation of the prevalence of endocrine irAEs to clinical antitumor effectiveness during ICI therapy has been reported. The mechanisms of endocrine irAEs by ICI, however, remain unclear, and optimal prevention, prediction, and treatment of the irAEs are still uncertain. This review describes possible mechanisms involved in ICI-related immunity, and discusses clinical management of endocrine irAEs during ICI therapy.
Seisho Azuma, Yoshinobu Murakami, Eiko Azuma, , Masahiko Taniguchi
Published: 25 April 2018
Trends in Immunotherapy, Volume 2; https://doi.org/10.24294/ti.v2.i2.844

Abstract:
Currently, about half of people in Japan suffer from allergic diseases. Thus, Citrus jabara fruits have been paid attention as one of quite effective anti-allergic functional foods. C. jabara is an endemic species originally grown only in Kitayama village, Wakayama prefecture in Japan. Although genetic characterization and diversity of various Citrus fruits including C. jabara were researched, but there is room for the study on flavonoids characteristics in C. jabara fruit. For the alleviation of allergic symptom, anti-inflammatory effects are also important. In this study, characteristics of flavonoids in C. jabara fruit peels, and the anti-inflammatory effects of these purified flavonoids were investigated. Our results revealed that C. jabara is a unique Citrus that almost all of flavonoids in fruit peels was narirutin. There was no Citrus species with a flavanone glycosides content ratio like C. jabara. Although anti-inflammatory effects of narirutin was weak, but its aglycone naringenin exhibited following inhibitory effects: nitric oxide synthesis (IC50 = 105 μM), nitric oxide synthase induction, Interleukin-6 synthesis (IC50 = 65 μM), and inducible soluble epoxide hydrolase activity (IC50 = 267 μM). Since narirutin is deglycosylated to naringenin that is then absorbed by colonocytes, it is considered that narirutin exists like a prodrug and its aglycone naringenin works as an active form of anti-inflammatory effect in a living body at oral ingestion of C. jabara fruit peels.
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