Title
Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
New York ,
Subject
Human medicine
Source (journal)
The journal of experimental medicine. - New York
Volume/pages
211(2014) :12 , p. 2373-2383
ISSN
0022-1007
ISI
000345268800010
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Abstract
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. CD40/IL-2 as compared with young lean mice. Macrophage depletion or TNF blockade in conjunction with. CD40/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. CD40/IL-2 administration. Our data demonstrate that adiposity is a critical factor in the age-associated pathological responses to systemic anti-cancer IT.
E-info
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