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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Immune Response Resetting in Ongoing Sepsis

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Author(s):
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Nowill, Alexandre E. [1] ; Fornazin, Marcia C. [1] ; Spago, Maria C. [1] ; Dorgan Neto, Vicente [2] ; Pinheiro, Vitoria R. P. [1] ; Alexandre, Simonia S. S. [1] ; Moraes, Edgar O. [3] ; Souza, Gustavo H. M. F. [4] ; Eberlin, Marcos N. [3] ; Marques, Lygia A. [5] ; Meurer, Eduardo C. [5] ; Franchi, Jr., Gilberto C. [1] ; de Campos-Lima, Pedro O. [6]
Total Authors: 13
Affiliation:
[1] State Univ Campinas UNICAMP, Integrated Ctr Pediat OncoHaematol Res, Rua Vital Brasil 100, POB 6141, BR-13083888 Campinas, SP - Brazil
[2] Santa Casa Sch Med Sci, Dept Surg, BR-01221020 Sao Paulo - Brazil
[3] Univ Prebiteriana Mackenzie, Sch Engn, BR-01302907 Sao Paulo - Brazil
[4] Waters Corp, Dept Hlth Sci, Mass Spectrometry Res & Dev Lab, BR-06455020 Barueri - Brazil
[5] Univ Estadual Campinas, Inst Chem, ThoMSon Mass Spectrometry Lab, BR-13083859 Campinas, SP - Brazil
[6] Boldrini Childrens Ctr, BR-13083210 Campinas, SP - Brazil
Total Affiliations: 6
Document type: Journal article
Source: JOURNAL OF IMMUNOLOGY; v. 203, n. 5, p. 1298-1312, SEP 1 2019.
Web of Science Citations: 0
Abstract

Cure of severe infections, sepsis, and septic shock with antimicrobial drugs is a challenge because morbidity and mortality in these conditions are essentially caused by improper immune response. We have tested the hypothesis that repeated reactivation of established memory to pathogens may reset unfavorable immune responses. We have chosen for this purpose a highly stringent mouse model of polymicrobial sepsis by cecum ligation and puncture. Five weeks after priming with a diverse Ag pool, high-grade sepsis was induced in C57BL/6j mice that was lethal in 24 h if left untreated. Antimicrobial drug (imipenem) alone rescued 9.7% of the animals from death, but >5-fold higher cure rate could be achieved by combining imipenem and two rechallenges with the Ag pool (p < 0.0001). Antigenic stimulation fine-tuned the immune response in sepsis by contracting the total CD3(+) T cell compartment in the spleen and disengaging the hyperactivation state in the memory T subsets, most notably CD8(+) T cells, while preserving the recovery of naive subsets. Quantitative proteomics/lipidomics analyses revealed that the combined treatment reverted the molecular signature of sepsis for cytokine storm, and deregulated inflammatory reaction and proapoptotic environment, as well as the lysophosphatidylcholine/phosphatidylcholine ratio. Our results showed the feasibility of resetting uncontrolled hyperinflammatory reactions into ordered hypoinflammatory responses by memory reactivation, thereby reducing morbidity and mortality in antibiotic-treated sepsis. This beneficial effect was not dependent on the generation of a pathogen-driven immune response itself but rather on the reactivation of memory to a diverse Ag pool that modulates the ongoing response. (AU)

FAPESP's process: 14/10068-4 - Multi-User Equipment approved in grant 13/08711-3: mass spectrometer waters SYNAPT G2-Si HDMS + nanoACQUITY UPLC
Grantee:Daniel Martins-de-Souza
Support Opportunities: Multi-user Equipment Program