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Structure-Based Cytokine Engineering.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Structure-Based Cytokine Engineering./
作者:	Glassman, Caleb Randall.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	172 p.
附註:	Source: Dissertations Abstracts International, Volume: 84-01, Section: B.
Contained By:	Dissertations Abstracts International84-01B.
標題:	Growth factors. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29176524
ISBN:	9798835549177

Structure-Based Cytokine Engineering.
Glassman, Caleb Randall.

Structure-Based Cytokine Engineering. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 172 p.

Source: Dissertations Abstracts International, Volume: 84-01, Section: B.

Thesis (Ph.D.)--Stanford University, 2021.

This item must not be sold to any third party vendors.

As a distributed network of cells, the immune system relies on secreted factors such as cytokines and chemokines to coordinate the induction and resolution of inflammation. Cytokine signaling is characterized by a high degree of pleiotropy in which a single cytokine acts on multiple cell types, often with countervailing effects. In many cases, this pleiotropy is critical for ensuring a robust immune response and maintaining tissue homeostasis but can present a problem for the clinical use of cytokines due to multiple responsive cell types. Pleiotropy is managed in vivo by local cytokine secretion and differences in sensitivity across cell-types due to expression of cytokine receptors and signaling pathway components, however, these mechanisms breakdown under conditions of systemic cytokine administration as is used therapeutically. To manage cytokine pleiotropy, we generated partial agonists of cytokine receptors by attenuating receptor dimerization. Cytokine partial agonists exploit intrinsic differences in cytokine sensitivity across cell-types to reduce pleiotropy and enhance therapeutic efficacy. We applied this concept to two cytokines with different biological functions, interleukin 2 (IL-2) and IL12.IL-2 was originally described as a T cell growth factor; however, subsequent work uncovered a critical role for IL-2 in regulatory T cells (Tregs) which act to constrain inflammation by suppressing conventional T cells. Using a previously published structure of the complete IL-2 receptor complex, we targeted the interaction between IL-2 and the common gamma chain (gc) to modulate receptor dimerization. By profiling a diverse set of IL-2 partial agonists with reduced receptor dimerization, we identified a Treg biased agonist, IL-2-REH, which exploits two key features of Treg sensitivity to IL-2, constitutive expression of the IL-2 receptor alpha chain (IL-2Ra) and reduced expression of Suppressor of Cytokine Signaling 1 (SOCS1), a negative regulator of IL-2 signaling.The heterodimeric cytokines IL-12 and IL-23 signal through receptor complexes that share the IL-12Rb1 subunit. Using a combination of crystallography and cryoelectron microscopy, we uncovered a modular receptor assembly mechanism of IL-12 and IL-23 in which the shared p40 subunit of the cytokine binds to the shared IL-12Rb1 receptor while unique four-helix bundles, IL-12p35 and IL-23p19, interact specifically v with unique receptors, IL-12Rb2 and IL-23R. Guided by the structural basis of IL-12 receptor assembly, we generated IL-12 partial agonists which preserve T cell mediated anti-tumor immunity without NK cell induced toxicity relative to wild-type IL-12.Cytokine partial agonists present a path to translate structural understanding of cytokine receptor assembly to new molecules with distinct cell-type specific activity. Such agonists may have use clinically by enhancing efficacy, reducing toxicity, or both. In addition, cytokine partial agonists may also serve as probes to uncover cell-type specific functions of cytokine signaling.

ISBN: 9798835549177Subjects--Topical Terms:

657607
Growth factors.

Structure-Based Cytokine Engineering.
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520 $a As a distributed network of cells, the immune system relies on secreted factors such as cytokines and chemokines to coordinate the induction and resolution of inflammation. Cytokine signaling is characterized by a high degree of pleiotropy in which a single cytokine acts on multiple cell types, often with countervailing effects. In many cases, this pleiotropy is critical for ensuring a robust immune response and maintaining tissue homeostasis but can present a problem for the clinical use of cytokines due to multiple responsive cell types. Pleiotropy is managed in vivo by local cytokine secretion and differences in sensitivity across cell-types due to expression of cytokine receptors and signaling pathway components, however, these mechanisms breakdown under conditions of systemic cytokine administration as is used therapeutically. To manage cytokine pleiotropy, we generated partial agonists of cytokine receptors by attenuating receptor dimerization. Cytokine partial agonists exploit intrinsic differences in cytokine sensitivity across cell-types to reduce pleiotropy and enhance therapeutic efficacy. We applied this concept to two cytokines with different biological functions, interleukin 2 (IL-2) and IL12.IL-2 was originally described as a T cell growth factor; however, subsequent work uncovered a critical role for IL-2 in regulatory T cells (Tregs) which act to constrain inflammation by suppressing conventional T cells. Using a previously published structure of the complete IL-2 receptor complex, we targeted the interaction between IL-2 and the common gamma chain (gc) to modulate receptor dimerization. By profiling a diverse set of IL-2 partial agonists with reduced receptor dimerization, we identified a Treg biased agonist, IL-2-REH, which exploits two key features of Treg sensitivity to IL-2, constitutive expression of the IL-2 receptor alpha chain (IL-2Ra) and reduced expression of Suppressor of Cytokine Signaling 1 (SOCS1), a negative regulator of IL-2 signaling.The heterodimeric cytokines IL-12 and IL-23 signal through receptor complexes that share the IL-12Rb1 subunit. Using a combination of crystallography and cryoelectron microscopy, we uncovered a modular receptor assembly mechanism of IL-12 and IL-23 in which the shared p40 subunit of the cytokine binds to the shared IL-12Rb1 receptor while unique four-helix bundles, IL-12p35 and IL-23p19, interact specifically v with unique receptors, IL-12Rb2 and IL-23R. Guided by the structural basis of IL-12 receptor assembly, we generated IL-12 partial agonists which preserve T cell mediated anti-tumor immunity without NK cell induced toxicity relative to wild-type IL-12.Cytokine partial agonists present a path to translate structural understanding of cytokine receptor assembly to new molecules with distinct cell-type specific activity. Such agonists may have use clinically by enhancing efficacy, reducing toxicity, or both. In addition, cytokine partial agonists may also serve as probes to uncover cell-type specific functions of cytokine signaling.
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