Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice
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- Annie Mirsoian
- Department of Dermatology 1 , 2 , 3 , and 4
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- Myriam N. Bouchlaka
- Department of Dermatology 1 , 2 , 3 , and 4
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- Gail D. Sckisel
- Department of Dermatology 1 , 2 , 3 , and 4
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- Mingyi Chen
- Department of Dermatology 1 , 2 , 3 , and 4
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- Chien-Chun Steven Pai
- Department of Dermatology 1 , 2 , 3 , and 4
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- Emanuel Maverakis
- Department of Dermatology 1 , 2 , 3 , and 4
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- Richard G. Spencer
- National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
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- Kenneth W. Fishbein
- National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
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- Sana Siddiqui
- National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
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- Arta M. Monjazeb
- Department of Dermatology 1 , 2 , 3 , and 4
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- Bronwen Martin
- National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
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- Stuart Maudsley
- National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
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- Charles Hesdorffer
- National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
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- Luigi Ferrucci
- National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
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- Dan L. Longo
- National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
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- Bruce R. Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455 6
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- Robert H. Wiltrout
- National Cancer Institute, Frederick, MD 21702 7
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- Dennis D. Taub
- Department of Dermatology 1 , 2 , 3 , and 4
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- William J. Murphy
- Department of Dermatology 1 , 2 , 3 , and 4
Description
<jats:p>Aging is a contributing factor in cancer occurrence. We recently demonstrated that systemic immunotherapy (IT) administration in aged, but not young, mice resulted in induction of rapid and lethal cytokine storm. We found that aging was accompanied by increases in visceral fat similar to that seen in young obese (ob/ob or diet-induced obese [DIO]) mice. Yet, the effects of aging and obesity on inflammatory responses to immunotherapeutics are not well defined. We determine the effects of adiposity on systemic IT tolerance in aged compared with young obese mice. Both young ob/ob- and DIO-generated proinflammatory cytokine levels and organ pathologies are comparable to those in aged ad libitum mice after IT, culminating in lethality. Young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNF+ macrophages in response to αCD40/IL-2 as compared with young lean mice. Macrophage depletion or TNF blockade in conjunction with αCD40/IL-2 prevented cytokine storms in young obese mice and protected from lethality. Calorie-restricted aged mice contain less visceral fat and displayed reduced cytokine levels, protection from organ pathology, and protection from lethality upon αCD40/IL-2 administration. Our data demonstrate that adiposity is a critical factor in the age-associated pathological responses to systemic anti-cancer IT.</jats:p>
Journal
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- Journal of Experimental Medicine
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Journal of Experimental Medicine 211 (12), 2373-2383, 2014-11-03
Rockefeller University Press
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Details 詳細情報について
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- CRID
- 1363388843317760256
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- ISSN
- 15409538
- 00221007
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- Data Source
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- Crossref