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Article: Pathological changes in various organs in HLA-B*57:01 transgenic mice with abacavir-induced skin eruption.

Kazaoka, Akira / Kumagai, Kazuyoshi / Matsushita, Junya / Aida, Tetsuo / Kuwahara, Saki / Aoki, Shigeki / Ito, Kousei

2024 Volume 40, Issue 2, Page(s) 223–235

Abstract: Several patients with cutaneous adverse drug reactions exhibit extracutaneous organ damages, and it becomes severe in a few patients resulting in death due to multiorgan failure. Understanding the sequential changes in various organs in patients with ... ...

Abstract	Several patients with cutaneous adverse drug reactions exhibit extracutaneous organ damages, and it becomes severe in a few patients resulting in death due to multiorgan failure. Understanding the sequential changes in various organs in patients with cutaneous eruption following drug administration will help understand disease onset and progression, aiding the development of prevention strategies and interventions. Therefore, we aimed to understand the effects of abacavir (ABC) on various organs in patients with ABC-induced eruptions by evaluating its effects in a mouse model. We found pathological changes in various organs of HLA-B57:01 transgenic mice (B57:01-Tg) following oral administration of ABC (20 mg/body/day). B57:01-Tg exhibited a significant body weight decrease from day 1 of ABC administration, and reddening of the auricle was observed from day 5, and approximately 2/3 mice died by day 7. Histopathological examination revealed severe thymic atrophy after day 3, infiltration of inflammatory cells, predominantly lymphocytes with neutrophils, not only in the skin but also in the liver, kidney, and lung after day 5, and an increased number of lymphocytes with enlarged nuclei and granulocytic hematopoiesis were observed in the spleen after day 5. Blood chemistry revealed that albumin/globulin ratio was below 1.0 on day 5, reflecting a systemic inflammatory response, and the aspartate aminotransferase concentration rose to 193 ± 93.0 U/L on day 7, suggesting that cell damage may have occurred in various organs including liver accompanying inflammatory cell infiltration. These examinations of a mouse model of ABC-induced skin eruption show that disorders in various organs other than the skin should be considered and provide insights into the unexpected early systemic responses dependent on HLA-B57:01. Supplementary information: The online version contains supplementary material available at 10.1007/s43188-023-00220-1.
Language	English
Publishing date	2024-01-06
Publishing country	Singapore
Document type	Journal Article
ZDB-ID	2727978-9
ISSN	2234-2753 ; 1976-8257
ISSN (online)	2234-2753
ISSN	1976-8257
DOI	10.1007/s43188-023-00220-1
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Article ; Online: Immunostimulatory effects on THP-1 cells by peptide or protein pharmaceuticals associated with injection site reactions.

Hamamura-Yasuno, Eri / Aida, Tetsuo / Tsuchiya, Yoshimi / Mori, Kazuhiko

Journal of immunotoxicology

2020 Volume 17, Issue 1, Page(s) 59–66

Abstract: Injection site reaction (ISR) is a common side-effect associated with the use of peptide or protein pharmaceuticals. These types of pharmaceuticals-induced activation of antigen-presenting cells is assumed to be a key step in the pathogenesis of immune- ... ...

Abstract	Injection site reaction (ISR) is a common side-effect associated with the use of peptide or protein pharmaceuticals. These types of pharmaceuticals-induced activation of antigen-presenting cells is assumed to be a key step in the pathogenesis of immune-mediated ISR. The present study was designed to evaluate the immunostimulatory properties of peptide or protein pharmaceuticals using human monocytic THP-1 cells. Here, THP-1 cells, with or without phorbol-12-myristate-13-acetate (PMA) pretreatment, were exposed to enfuvirtide and glatiramer acetate (positive controls) or evolocumab (negative control) for 6 or 24 h. PMA treatment differentiated non-adherent monocytic THP-1 (nTHP-1) cells into adherent macrophagic THP-1 (pTHP-1) cells that highly express CD11b and CD36. Enfuvirtide increased the release of cytokines, e.g. TNFα, MIP-1β, and MCP-1, and expression of CD86 and CD54 on nTHP-1 cells at 24 h. Similar immunostimulatory properties of glatiramer acetate were observed both in the nTHP-1 and pTHP-1 cells at 6 h, but the responses were very weak in the pTHP-1 cells. Evolocumab did not affect cytokine secretion or cell surface marker expression in either cell type. Taken together, these
MeSH term(s)	Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/immunology ; Antigen Presentation/drug effects ; Antigen-Presenting Cells/drug effects ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/metabolism ; Cytokines/metabolism ; Drug Evaluation, Preclinical/methods ; Enfuvirtide/administration & dosage ; Enfuvirtide/immunology ; Glatiramer Acetate/administration & dosage ; Glatiramer Acetate/immunology ; Humans ; Injection Site Reaction/immunology ; Injections, Subcutaneous/adverse effects ; THP-1 Cells
Chemical Substances	Antibodies, Monoclonal, Humanized ; Cytokines ; Enfuvirtide (19OWO1T3ZE) ; Glatiramer Acetate (5M691HL4BO) ; evolocumab (LKC0U3A8NJ)
Language	English
Publishing date	2020-02-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2205064-4
ISSN	1547-6901 ; 1547-691X
ISSN (online)	1547-6901
ISSN	1547-691X
DOI	10.1080/1547691X.2020.1727071
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Article ; Online: Highly sensitive

Ito, Shiho / Miwa, Kyoko / Hattori, Chiharu / Aida, Tetsuo / Tsuchiya, Yoshimi / Mori, Kazuhiko

Journal of immunotoxicology

2021 Volume 18, Issue 1, Page(s) 136–143

Abstract: Immunostimulatory effects of monoclonal antibodies (mAb) through binding to ... ...

Abstract	Immunostimulatory effects of monoclonal antibodies (mAb) through binding to F
MeSH term(s)	Antibodies, Monoclonal ; Cytokine Release Syndrome ; Cytokines ; Humans ; Leukocytes, Mononuclear
Chemical Substances	Antibodies, Monoclonal ; Cytokines
Language	English
Publishing date	2021-10-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2205064-4
ISSN	1547-6901 ; 1547-691X
ISSN (online)	1547-6901
ISSN	1547-691X
DOI	10.1080/1547691X.2021.1984617
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Article ; Online: Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2-targeting Ab-drug conjugate, in monkeys.

Kumagai, Kazuyoshi / Aida, Tetsuo / Tsuchiya, Yoshimi / Kishino, Yuki / Kai, Kiyonori / Mori, Kazuhiko

Cancer science

2020 Volume 111, Issue 12, Page(s) 4636–4645

Abstract: Trastuzumab deruxtecan (T-DXd: DS-8201a) is an anti-human epidermal growth factor receptor 2 (HER2) Ab-drug conjugated with deruxtecan (DXd), a derivative of exatecan. The objective of this study was to characterize T-DXd-induced lung toxicity in ... ...

Abstract	Trastuzumab deruxtecan (T-DXd: DS-8201a) is an anti-human epidermal growth factor receptor 2 (HER2) Ab-drug conjugated with deruxtecan (DXd), a derivative of exatecan. The objective of this study was to characterize T-DXd-induced lung toxicity in cynomolgus monkeys. Trastuzumab deruxtecan was injected i.v. into monkeys once every 3 weeks for 6 weeks (10, 30, and 78.8 mg/kg) or for 3 months (3, 10, and 30 mg/kg). To evaluate the involvement of DXd alone in T-DXd-induced toxicity, DXd monohydrate was given i.v. to monkeys once a week for 4 weeks (1, 3, and 12 mg/kg). Interstitial pneumonitis was observed in monkeys given T-DXd at 30 mg/kg or more. The histopathological features of diffuse lymphocytic infiltrates and slight fibrosis were similar to interstitial lung diseases (ILD)/pneumonitis related to anticancer drugs in patients, with an incidence that was dose-dependent and dose-frequency-dependent. Monkeys receiving DXd monohydrate did not suffer lung toxicity, although the DXd exposure level was higher than that of DXd in the monkeys given T-DXd. The HER2 expression in monkey lungs was limited to the bronchial level, although the lesions were found at the alveolar level. Immunohistochemical analysis confirmed that T-DXd localization was mainly in alveolar macrophages, but not pulmonary epithelial cells. These findings indicate that monkeys are an appropriate model for investigating T-DXd-related ILD/pneumonitis. The results are also valuable for hypothesis generation regarding the possible mechanism of T-DXd-induced ILD/pneumonitis in which target-independent uptake of T-DXd into alveolar macrophages could be involved. Further evaluation is necessary to clarify the mechanism of ILD/pneumonitis in patients with T-DXd therapy.
MeSH term(s)	Animals ; Camptothecin/administration & dosage ; Camptothecin/adverse effects ; Camptothecin/analogs & derivatives ; Camptothecin/metabolism ; Cathepsin B/analysis ; Drug Administration Schedule ; Female ; Immunoconjugates/administration & dosage ; Immunoconjugates/adverse effects ; Immunoconjugates/metabolism ; Lung/drug effects ; Lung/metabolism ; Lung/pathology ; Lung Diseases, Interstitial/chemically induced ; Lung Diseases, Interstitial/metabolism ; Lung Diseases, Interstitial/pathology ; Macaca fascicularis ; Male ; Receptor, ErbB-2/metabolism ; Time Factors ; Trastuzumab/administration & dosage ; Trastuzumab/adverse effects ; Trastuzumab/metabolism
Chemical Substances	Immunoconjugates ; trastuzumab deruxtecan (5384HK7574) ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Cathepsin B (EC 3.4.22.1) ; exatecan (OC71PP0F89) ; Trastuzumab (P188ANX8CK) ; Camptothecin (XT3Z54Z28A)
Language	English
Publishing date	2020-11-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2115647-5
ISSN	1349-7006 ; 1347-9032
ISSN (online)	1349-7006
ISSN	1347-9032
DOI	10.1111/cas.14686
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Article ; Online: DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody-Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models.

Yamato, Michiko / Hasegawa, Jun / Maejima, Takanori / Hattori, Chiharu / Kumagai, Kazuyoshi / Watanabe, Akiko / Nishiya, Yumi / Shibutani, Tomoko / Aida, Tetsuo / Hayakawa, Ichiro / Nakada, Takashi / Abe, Yuki / Agatsuma, Toshinori

Molecular cancer therapeutics

2022 Volume 21, Issue 4, Page(s) 635–646

Abstract: B7-H3 is overexpressed in various solid tumors and has been considered as an attractive target for cancer therapy. Here, we report the development of DS-7300a, a novel B7-H3-targeting antibody-drug conjugate with a potent DNA topoisomerase I inhibitor, ... ...

Abstract	B7-H3 is overexpressed in various solid tumors and has been considered as an attractive target for cancer therapy. Here, we report the development of DS-7300a, a novel B7-H3-targeting antibody-drug conjugate with a potent DNA topoisomerase I inhibitor, and its in vitro profile, pharmacokinetic profiles, safety profiles, and in vivo antitumor activities in nonclinical species. The target specificity and species cross-reactivity of DS-7300a were assessed. Its pharmacologic activities were evaluated in several human cancer cell lines in vitro and xenograft mouse models, including patient-derived xenograft (PDX) mouse models in vivo. Pharmacokinetics was investigated in cynomolgus monkeys. Safety profiles in rats and cynomolgus monkeys were also assessed. DS-7300a specifically bound to B7-H3 and inhibited the growth of B7-H3-expressing cancer cells, but not that of B7-H3-negative cancer cells, in vitro. Additionally, treatment with DS-7300a and DXd induced phosphorylated checkpoint kinase 1, a DNA damage marker, and cleaved PARP, an apoptosis marker, in cancer cells. Moreover, DS-7300a demonstrated potent in vivo antitumor activities in high-B7-H3 tumor xenograft models, including various tumor types of high-B7-H3 PDX models. Furthermore, DS-7300a was stable in circulation with acceptable pharmacokinetic profiles in monkeys, and well tolerated in rats and monkeys. DS-7300a exerted potent antitumor activities against B7-H3-expressing tumors in in vitro and in vivo models, including PDX mouse models, and showed acceptable pharmacokinetic and safety profiles in nonclinical species. Therefore, DS-7300a may be effective in treating patients with B7-H3-expressing solid tumors in a clinical setting.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Humans ; Immunoconjugates/therapeutic use ; Macaca fascicularis ; Mice ; Neoplasms/pathology ; Rats ; Topoisomerase I Inhibitors/pharmacology ; Topoisomerase I Inhibitors/therapeutic use
Chemical Substances	Antineoplastic Agents ; Immunoconjugates ; Topoisomerase I Inhibitors
Language	English
Publishing date	2022-02-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-21-0554
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Article ; Online: Detection of Abacavir-Induced Structural Alterations in Human Leukocyte Antigen-B*57 : 01 Using Phage Display.

Shirayanagi, Tomohiro / Aoki, Shigeki / Fujimori, Sota / Watanabe, Kenji / Aida, Tetsuo / Hirasawa, Makoto / Kumagai, Kazuyoshi / Hoshino, Tyuji / Ito, Kousei

Biological & pharmaceutical bulletin

2020 Volume 43, Issue 6, Page(s) 1007–1015

Abstract: The interaction of human leukocyte antigen (HLA) with specific drugs is associated with delayed-type hypersensitivity reactions, which cause severe cutaneous toxicity. Such interactions induce structural alterations in HLA complexes via several different ...

Abstract	The interaction of human leukocyte antigen (HLA) with specific drugs is associated with delayed-type hypersensitivity reactions, which cause severe cutaneous toxicity. Such interactions induce structural alterations in HLA complexes via several different mechanisms such as the hapten theory, p-i concept, and altered peptide repertoire model, leading to the activation of cytotoxic T cells. To date, comprehensive detection of such structural alterations in preclinical studies has been difficult. Here, we evaluated structural alterations in HLA complexes focusing on the interaction between the HLA-B57 : 01 allele and abacavir (an anti-human immunodeficiency virus drug), representing a model of abacavir hypersensitivity syndrome induced by changes in the peptide repertoire on the HLA molecule. We employed a phage display method using a commercially available antibody library to screen specific phage antibodies able to recognize HLA-B57 : 01. The affinity of selected phage antibodies increased because of structural alterations in HLA-B57 : 01 following exposure to abacavir, indicating that specific phage antibodies can identify drug-mediated structural changes in HLA complexes. We also identified an unreported structural change in HLA-B57 : 01 using the phage display method, whereby abacavir increased the expression of peptide-deficient HLA-B*57 : 01 on the cell surface. These results suggest that phage display technology is a useful method for detecting structural changes in HLA complexes. This technology represents a potential novel strategy for predicting HLA-associated hypersensitivity reactions by drugs in pre-clinical studies.
MeSH term(s)	Anti-HIV Agents/pharmacology ; Antibodies/immunology ; Cell Surface Display Techniques ; Dideoxynucleosides/pharmacology ; HLA-B Antigens/chemistry ; HLA-B Antigens/genetics ; HLA-B Antigens/immunology ; HeLa Cells ; Humans
Chemical Substances	Anti-HIV Agents ; Antibodies ; Dideoxynucleosides ; HLA-B Antigens ; HLA-B57 antigen ; abacavir (WR2TIP26VS)
Language	English
Publishing date	2020-05-15
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1150271-x
ISSN	1347-5215 ; 0918-6158
ISSN (online)	1347-5215
ISSN	0918-6158
DOI	10.1248/bpb.b20-00102
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Zs.A 1474: Show issues

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Article ; Online: Immune responses induced by diclofenac or carbamazepine in an oral exposure model using TNP-Ficoll as reporter antigen.

Kwast, Lydia / Aida, Tetsuo / Fiechter, Daniëlle / Kruijssen, Laura / Bleumink, Rob / Boon, Louis / Ludwig, Irene / Pieters, Raymond

Journal of immunotoxicology

2016 Volume 13, Issue 6, Page(s) 918–926

Abstract: Immune-mediated drug hypersensitivity reactions (IDHR) may result from immuno-sensitization to a drug-induced neo-antigen. They rarely occur in patients and are usually not predicted preclinically using standard toxicity studies. To assess the potential ... ...

Abstract	Immune-mediated drug hypersensitivity reactions (IDHR) may result from immuno-sensitization to a drug-induced neo-antigen. They rarely occur in patients and are usually not predicted preclinically using standard toxicity studies. To assess the potential of a drug to induce T-cell sensitization, trinitrophenyl (TNP)-Ficoll was used here as a bystander antigen in animal experiments. TNP-Ficoll will only elicit TNP-specific IgG antibodies in the presence of non-cognate T-cell help. Therefore, the presence of TNP-specific IgG antibodies after co-injection of drug and TNP-Ficoll was indicative of T-cell sensitization potential. This TNP-Ficoll-approach was used here to characterize T-cell help induced by oral exposure to diclofenac (DF) or carbamazepine (CMZ). DF or CMZ was administered orally to BALB/c mice and after 3 w, the mice were challenged in a hind paw with TNP-Ficoll and a dose of the drug that by itself does only elicit a sub-optimal popliteal lymph node assay (PLNA) response. T-cell-dependent responses were then evaluated in paw-draining popliteal lymph nodes (PLN). Also, shortly after oral exposure, mesenteric lymph nodes (MLN) were excised for evaluation of local responses. Both drugs were able to increase PLN cellularity and TNP-specific IgG
MeSH term(s)	Administration, Oral ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Antigens/immunology ; Carbamazepine/adverse effects ; Carbamazepine/therapeutic use ; Diclofenac/adverse effects ; Diclofenac/therapeutic use ; Drug Hypersensitivity/immunology ; Ficoll/analogs & derivatives ; Ficoll/immunology ; Immunoglobulin G/metabolism ; Interferon-gamma/metabolism ; Lymph Nodes/pathology ; Lymphocyte Activation ; Mice ; Mice, Inbred BALB C ; T-Lymphocytes/immunology ; Trinitrobenzenes/immunology
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; Antigens ; Immunoglobulin G ; TNP-ficoll ; Trinitrobenzenes ; Diclofenac (144O8QL0L1) ; Ficoll (25702-74-3) ; Carbamazepine (33CM23913M) ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2016-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2205064-4
ISSN	1547-6901 ; 1547-691X
ISSN (online)	1547-6901
ISSN	1547-691X
DOI	10.1080/1547691X.2016.1247929
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Article ; Online: Datopotamab Deruxtecan, a Novel TROP2-directed Antibody-drug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells.

Molecular cancer therapeutics

2021 Volume 20, Issue 12, Page(s) 2329–2340

Abstract: Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a ... ...

Abstract	Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in preclinical models.The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models. Safety profiles were also assessed in rats and cynomolgus monkeys.Dato-DXd bound specifically to TROP2 and was internalized into tumor cells followed by intracellular trafficking to lysosome and DXd release, which induced DNA damage and apoptosis in TROP2-expressing tumor cells
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Drug Delivery Systems/methods ; Humans ; Immunoconjugates/pharmacology ; Immunoconjugates/therapeutic use ; Macaca fascicularis ; Male ; Mice ; Mice, Nude ; Rats
Chemical Substances	Antineoplastic Agents ; Immunoconjugates
Language	English
Publishing date	2021-08-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-21-0206
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Article ; Online: Evaluation of canine T-cell dependent antibody response to the primary and secondary immunization with keyhole limpet hemocyanin.

Kawai, Ryota / Aida, Tetsuo / Hattori, Hiroyuki / Furukawa, Tadashi / Mori, Kazuhiko / Takasaki, Wataru / Takahashi, Nobuyuki / Kawada, Teruo

The Journal of toxicological sciences

2013 Volume 38, Issue 4, Page(s) 571–579

Abstract: T-cell dependent antibody response (TDAR) incorporating both primary and secondary responses to keyhole limpet hemocyanin (KLH) in canine models have not yet been fully understood. To develop a practical dog TDAR model, we characterized primary and ... ...

Abstract	T-cell dependent antibody response (TDAR) incorporating both primary and secondary responses to keyhole limpet hemocyanin (KLH) in canine models have not yet been fully understood. To develop a practical dog TDAR model, we characterized primary and secondary antibody responses by intravenous or intramuscular immunization of KLH twice at intervals of 8 days during a 28-day course of study. Primary immunization with KLH by both routes induced a maximum IgM response on 6 to 8 days after the treatment, whereas the IgG response started 6 to 8 days after the treatment with relatively low levels. Remarkable increases in anti-KLH IgG levels (about 10-times compared with the primary response) were produced 5 to 7 days after the secondary KLH immunization by both routes. These results indicate that IgM-predominant and IgG-predominant responses were respectively induced by the primary and secondary immunization. Furthermore, the intravenous route showed higher baseline titers of primary and secondary anti-KLH IgM responses, suggesting that intravenous immunization of KLH might be a more suitable method for immunotoxicity evaluation. No remarkable inter-individual variability was noted in our canine models. Treatment with cyclophosphamide at 2 mg/kg/day for a consecutive 28 days significantly suppressed primary and secondary anti-KLH IgM and IgG responses induced by KLH injection on Days 15 and 23 of CPA treatment. These results demonstrate that these experimental designs could provide valuable information about the influence on both the primary and secondary humoral immune responses in dogs when exposed to potential immunomodulatory drugs.
MeSH term(s)	Adjuvants, Immunologic ; Animals ; Antibody Formation/immunology ; Cyclophosphamide/pharmacology ; Dogs ; Female ; Hemocyanins/administration & dosage ; Hemocyanins/immunology ; Humans ; Immunity, Humoral/immunology ; Immunization, Secondary ; Immunoglobulin G/blood ; Immunosuppressive Agents/pharmacology ; Injections, Intramuscular ; Injections, Intravenous ; Male ; T-Lymphocytes/immunology
Chemical Substances	Adjuvants, Immunologic ; Immunoglobulin G ; Immunosuppressive Agents ; Cyclophosphamide (8N3DW7272P) ; Hemocyanins (9013-72-3) ; keyhole-limpet hemocyanin (FV4Y0JO2CX)
Language	English
Publishing date	2013-07-02
Publishing country	Japan
Document type	Journal Article
ZDB-ID	770623-6
ISSN	1880-3989 ; 0388-1350
ISSN (online)	1880-3989
ISSN	0388-1350
DOI	10.2131/jts.38.571
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Zs.A 1682: Show issues

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Article ; Online: Evaluation of primary and secondary responses to a T-cell-dependent antigen, keyhole limpet hemocyanin, in rats.

Kawai, Ryota / Ito, Shiho / Aida, Tetsuo / Hattori, Hiroyuki / Kimura, Tsutomu / Furukawa, Tadashi / Mori, Kazuhiko / Sanbuissho, Atsushi / Kawada, Teruo

Journal of immunotoxicology

2013 Volume 10, Issue 1, Page(s) 40–48

Abstract: To develop a rat T-cell-dependent antibody response (TDAR) model evaluating both primary and secondary antibody responses, keyhole limpet hemocyanin (KLH) was used to immunize rats twice during a 14-day course of study, a pattern closely linked to that ... ...

Abstract	To develop a rat T-cell-dependent antibody response (TDAR) model evaluating both primary and secondary antibody responses, keyhole limpet hemocyanin (KLH) was used to immunize rats twice during a 14-day course of study, a pattern closely linked to that of a short-term general toxicity study. Female rats of four representative strains (e.g., Sprague-Dawley, Wistar, Fischer, and Lewis) were immunized twice with intravenous administrations of KLH (300 µg/rat) on Days 5 and 9 during a 14-day treatment regimen with cyclophosphamide (CPA) at 1, 3, or 6 mg/kg/day. The primary and secondary immunizations of KLH markedly elevated serum anti-KLH IgM and IgG levels in all strains on Days 9 and 15. Remarkable higher levels of anti-KLH IgG (≈ 1000 µg/ml) were noted in all strains, which were more than 4-times compared with those of anti-KLH IgM levels at Day 9, indicating that predominant IgG reactions were induced by the dual immunizations. A large inter-individual variability in KLH-specific IgM and IgG production was observed in all strains. However, levels of the KLH-specific antibodies were considered sufficient for the evaluation, even in Sprague-Dawley and Wistar rats reported as strains with a wide range of variability since immunosuppression of CPA on responses in both anti-KLH IgM and IgG were observed in all strains to the same extent. In addition, the sensitivity of the KLH-ELISA assay system detecting the immunosuppressive effects of CPA was comparable to other assay systems with PFC assay or ELISA using SRBC. The results here demonstrated that these experimental designs could provide valuable information about the influence on both the primary and secondary humoral immune responses in rats when exposed to potential immunomodulatory drugs. Furthermore, the design of the presented TDAR study would support comprehensive evaluation together with the outcome of the conventional general toxicity study.
MeSH term(s)	Animals ; Antibody Formation ; Female ; Hemocyanins/immunology ; Immunization, Secondary ; Immunologic Memory ; Lymphocyte Activation ; Rats ; Rats, Inbred F344 ; Rats, Inbred Lew ; Rats, Sprague-Dawley ; Rats, Wistar ; T-Lymphocytes, Helper-Inducer/immunology
Chemical Substances	Hemocyanins (9013-72-3) ; keyhole-limpet hemocyanin (FV4Y0JO2CX)
Language	English
Publishing date	2013-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2205064-4
ISSN	1547-6901 ; 1547-691X
ISSN (online)	1547-6901
ISSN	1547-691X
DOI	10.3109/1547691X.2012.691122
Database	MEDical Literature Analysis and Retrieval System OnLINE

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