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Risk Factors for Drug Immunogenicity...

Wong, Yat Yee.

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Risk Factors for Drug Immunogenicity in a Macaque Model of HIV Infection.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Risk Factors for Drug Immunogenicity in a Macaque Model of HIV Infection./
Author:	Wong, Yat Yee.
Description:	150 p.
Notes:	Source: Dissertation Abstracts International, Volume: 77-08(E), Section: B.
Contained By:	Dissertation Abstracts International77-08B(E).
Subject:	Toxicology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10095750
ISBN:	9781339599489

Risk Factors for Drug Immunogenicity in a Macaque Model of HIV Infection.
Wong, Yat Yee.

Risk Factors for Drug Immunogenicity in a Macaque Model of HIV Infection. - 150 p.

Source: Dissertation Abstracts International, Volume: 77-08(E), Section: B.

Thesis (Ph.D.)--The University of Wisconsin - Madison, 2016.

HIV-infected patients have a high acquired risk of rash and other delayed hypersensitivity reactions to potentiated sulfonamide antibiotics (trimethoprim/sulfamethoxazole; TMP/SMX), which correlate with low CD4+ counts. Further, this risk is associated with a biomarker, in which patient lymphocytes (especially CD8+ cells) show apoptosis from reactive SMX metabolites in an in vitro lymphocyte toxicity assay (LTA). The mechanisms are not understood, but an underlying SMX detoxification defect has been postulated. We hypothesized that acquired metabolic and immunologic alterations were present in retroviral infection that lead to SMX immunogenicity and LTA susceptibility.

ISBN: 9781339599489Subjects--Topical Terms:

556884
Toxicology.

Risk Factors for Drug Immunogenicity in a Macaque Model of HIV Infection.
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100 1 $a Wong, Yat Yee. $3 3276584
245 1 0 $a Risk Factors for Drug Immunogenicity in a Macaque Model of HIV Infection.
300 $a 150 p.
500 $a Source: Dissertation Abstracts International, Volume: 77-08(E), Section: B.
500 $a Adviser: Lauren A. Trepanier.
502 $a Thesis (Ph.D.)--The University of Wisconsin - Madison, 2016.
520 $a HIV-infected patients have a high acquired risk of rash and other delayed hypersensitivity reactions to potentiated sulfonamide antibiotics (trimethoprim/sulfamethoxazole; TMP/SMX), which correlate with low CD4+ counts. Further, this risk is associated with a biomarker, in which patient lymphocytes (especially CD8+ cells) show apoptosis from reactive SMX metabolites in an in vitro lymphocyte toxicity assay (LTA). The mechanisms are not understood, but an underlying SMX detoxification defect has been postulated. We hypothesized that acquired metabolic and immunologic alterations were present in retroviral infection that lead to SMX immunogenicity and LTA susceptibility.
520 $a SIVmac239-infected rhesus macaques and age-matched controls were administrated TMP/SMX (120 mg/kg/day p.o.) for 14 days, and immune responses were measured. At baseline, blood was assayed for ascorbate, glutathione, IFN-gamma, sCD14, and LPS, and liver biopsies and lymphocytes were collected for expression arrays. After treatment, plasma and 24 hour-urinary SMX metabolites were measured, and macaques were tested for SMX-adducts in lymph nodes, anti-drug antibodies, and drug-responsive T cells. Among 9 SIV-infected and 7 non-infected controls, 3 macaques showed drug-responsive T cells and 4 macaques developed anti-SMX antibodies. Two macaques developed transient rash during dosing, and these animals had the highest percentage of lymph node cells with SMX-adducts. However, no association was found between immunologic response and SMX disposition, antioxidants, or inflammatory mediators.
520 $a Hepatic expression arrays, along with hepatic activity assays, did not support an effect of SIV infection on SMX detoxification. Instead, genes involved in antigen processing, trafficking, and presentation were over-expressed, and this could contribute to SMX hypersensitivity via promiscuous presentation of SMX-adducted peptides.
520 $a Lymphocyte death in the LTA was apparently increased in SIV-infected macaques (29.8% vs. 1.8%, P = 0.06), but CD8+ lymphocyte expression arrays from high and low LTA animals did not support impaired detoxification of SMX metabolites. Instead, several pro-apoptotic and lysosomal degradation genes were up-regulated, which could lower the threshold for cell death from reactive SMX metabolites.
520 $a In summary, this is the first animal model that demonstrates immunogenicity to SMX at therapeutic dosages; studying more animals with CD4+ counts < 200 cells/microl may better model the risk of SMX immunogenicity and hypersensitivity in HIV-infected human patients.
590 $a School code: 0262.
650 4 $a Toxicology. $3 556884
650 4 $a Immunology. $3 611031
650 4 $a Biology. $3 522710
690 $a 0383
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710 2 $a The University of Wisconsin - Madison. $b Pharmaceutical Sciences. $3 2096793
773 0 $t Dissertation Abstracts International $g 77-08B(E).
790 $a 0262
791 $a Ph.D.
792 $a 2016
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10095750