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      Modulation of Alloimmunity by Heat Shock Proteins

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          Abstract

          The immunological mechanisms that evolved for host defense against pathogens and injury are also responsible for transplant rejection. Host rejection of foreign tissue was originally thought to be mediated mainly by T cell recognition of foreign MHC alleles. Management of solid organ transplant rejection has thus focused mainly on inhibition of T cell function and matching MHC alleles between donor and host. Recently, however, it has been demonstrated that the magnitude of the initial innate immune responses upon transplantation has a decisive impact on rejection. The exact mechanisms underlying this phenomenon have yet to be characterized. Ischemic cell death and inflammation that occur upon transplantation are synonymous with extracellular release of various heat shock proteins (Hsps), many of which have been shown to have immune-modulatory properties. Here, we review the impact of Hsps upon alloimmunity and discuss the potential use of Hsps as accessory agents to improve solid organ transplant outcomes.

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          The danger model: a renewed sense of self.

          For over 50 years immunologists have based their thoughts, experiments, and clinical treatments on the idea that the immune system functions by making a distinction between self and nonself. Although this paradigm has often served us well, years of detailed examination have revealed a number of inherent problems. This Viewpoint outlines a model of immunity based on the idea that the immune system is more concerned with entities that do damage than with those that are foreign.
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            The heat shock response: life on the verge of death.

            Organisms must survive a variety of stressful conditions, including sudden temperature increases that damage important cellular structures and interfere with essential functions. In response to heat stress, cells activate an ancient signaling pathway leading to the transient expression of heat shock or heat stress proteins (Hsps). Hsps exhibit sophisticated protection mechanisms, and the most conserved Hsps are molecular chaperones that prevent the formation of nonspecific protein aggregates and assist proteins in the acquisition of their native structures. In this Review, we summarize the concepts of the protective Hsp network. Copyright © 2010 Elsevier Inc. All rights reserved.
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              HMGB1 signals through toll-like receptor (TLR) 4 and TLR2.

              In response to bacterial endotoxin (e.g., LPS) or endogenous proinflammatory cytokines (e.g., TNF and IL-1beta), innate immune cells release HMGB1, a late cytokine mediator of lethal endotoxemia and sepsis. The delayed kinetics of HMGB1 release makes it an attractive therapeutic target with a wider window of opportunity for the treatment of lethal systemic inflammation. However, the receptor(s) responsible for HMGB1-mediated production of proinflammatory cytokines has not been well characterized. Here we demonstrate that in human whole blood, neutralizing antibodies against Toll-like receptor 4 (TLR4, but not TLR2 or receptor for advanced glycation end product) dose-dependently attenuate HMGB1-induced IL-8 release. Similarly, in primary human macrophages, HMGB1-induced TNF release is dose-dependently inhibited by anti-TLR4 antibodies. In primary macrophages from knockout mice, HMGB1 activates significantly less TNF release in cells obtained from MyD88 and TLR4 knockout mice as compared with cells from TLR2 knockout and wild-type controls. However, in human embryonic kidney 293 cells transfected with TLR2 or TLR4, HMGB1 effectively induces IL-8 release only from TLR2 overexpressing cells. Consistently, anti-TLR2 antibodies dose-dependently attenuate HMGB1-induced IL-8 release in human embryonic kidney/TLR2-expressing cells and markedly reduce HMGB1 cell surface binding on murine macrophage-like RAW 264.7 cells. Taken together, our data suggest that there is a differential usage of TLR2 and TLR4 in HMGB1 signaling in primary cells and in established cell lines, adding complexity to studies of HMGB1 signaling which was not previously expected.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/44869
                URI : http://frontiersin.org/people/u/274011
                URI : http://frontiersin.org/people/u/352188
                URI : http://frontiersin.org/people/u/33457
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                09 August 2016
                2016
                : 7
                : 303
                Affiliations
                [1] 1Faculdade de Biociências e Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul , Porto Alegre, Rio Grande do Sul, Brazil
                [2] 2Department of Radiation Oncology, Center for Life Sciences, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA, USA
                Author notes

                Edited by: Nurit Hollander, Tel Aviv University, Israel

                Reviewed by: Haval Shirwan, University of Louisville, USA; Elizabeth Ann Repasky, Roswell Park Cancer Institute, USA

                *Correspondence: Cristina Bonorino, cbonorino@ 123456pucrs.br

                Specialty section: This article was submitted to Immunotherapies and Vaccines, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2016.00303
                4977877
                27555846
                b5d4841b-235e-41f8-8329-9da93483e701
                Copyright © 2016 Borges, Lang, Lopes and Bonorino.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 April 2016
                : 27 July 2016
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 65, Pages: 6, Words: 5126
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul 10.13039/501100004263
                Award ID: 11/0903-1
                Funded by: Financiadora de Estudos e Projetos 10.13039/501100004809
                Award ID: 01.08.0600-00
                Categories
                Immunology
                Mini Review

                Immunology
                hsps,transplantation,alloimmunity,dendritic cells,immune regulation
                Immunology
                hsps, transplantation, alloimmunity, dendritic cells, immune regulation

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