In Vivo Prevention of Murine GVHD
小鼠 GVHD 的体内预防
基本信息
- 批准号:10610863
- 负责人:
- 金额:$ 58.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Abstract
Our overall goals are focus on the prevention and treatment of graft-vs-host disease (GVHD) via innate lymphoid
type 2 cell (ILC2) anti-inflammatory and tissue reparative properties. We found that host ILC2s in are eliminated
by total body irradiation {TBI} or chemotherapy and remain depleted for at >/=90 days. This finding is highly
relevant as there is an inverse correlation between peripheral blood activated ILC2s and GVHD. As such. we
sought to determine whether supplemental infusion of mature donor ILC2s could be used to prevent murine
GVHD. We showed for the first time that donor ILC2s could prevent or partially treat GVHD in an amphiregulin
(AREG) dependent process. Whether AREG or ILC2 direct contact with intestinal stem cells {ISC) supports small
intestine epithelial cell repair in TBI treated mice or organoids is unknown. Additionally, third-party ILC2 infusion
also significanUy reduced murine GVHD lethality. lmportanUy for translational purposes, we found ILC2s to be
relatively steroid resistant. Peri-BMT {bone marrow transplant) IL-33 increased ST2/IL33R+ ILC2s at BMT day
0 and reduced GVHD. Ko mice had accelerated GVHD; IL-33 given pre-BMT prevented the full lLC2 loss. IL-33
ko recipients have hypo-proliferative epithelial cells, reduced ISCs and Paneth cells, and smaller crypt height
and numbers. Ex vivo intestine organoid culture modeling revealed that IL-33 coordinated regeneration by
inducing epidermal growth factor (EGF), significantly reduced by TBI. EGF restored ISC deficiency, uncovering
a gut repair IL-33/EGF loop between ISCs and Paneth cells. Donor IL-13 ko ILC2s or host IL 13Ra ko mice had
reduced GVHD. ILC2 IL 13 supports both ST2+ tuft cells and goblet cells. Tuft cells produce IL-25 driving ILC2
production and survival. TBI markedly reduced tuft cells for :!:38 days and ko recipients had a striking increase
in GVHD. When given to wildtype mice exogenous IL-25 significantly reduced GVHD. Consequences of ko of
tuft cells (and ILC2s) on donor T cell expansion, trafficking and function are unknown. The role of IL-25 and
IL 17RB has not been examined. We will address the dynamics and interplay between ILC2, IL-33 and
host intestinal cells (tuft cells, ISCs, Paneth cells) after TBI and during GVHD.
Aim 1 will test the hypothesis that: Donor ILC2 repopulation fails due to destruction of ILC2 BM niche
that supports ILC2s. In vitro pre-lLC2 differentiation, maturation and expansion ± proinflammatory
cytokines and ILC2 supporting cytokines will be studied. GATA3-GFPhi pre-lLC2s/mature ILC2s transfer
into lethally irradiated congenic BMT recipients will provide data on the differential ability to repopulate the
BM. If the BM cannot support pre-lLC2s/lLC2s, we will study stem cell deficient mice. Aim 2 will test the
hypothesis that: Pre-lLC2s/lLC2s and their secreted products have direct effects on intestinal cell subsets.
Intestinal organoid cultures from wild-type and IL-33 ko mice with syngeneic Tregs and ILC2s will measure
organoid size, number, and gene expression related to proliferation, cell cycle regulation, and specific
epithelial lineage markers under homeostasis or after TBI. Anti-AREG mAbs or co-cultures with AREG ko
lymphocytes will be characterized for promoting epithelial regeneration. Aim 3 will test the hypothesis that: Tuft
cells are essential for ILC2 development and survival via an ILC2 release of IL-13 that stimulates tuft cells to
release IL-25 that causes ILC2 proliferation (aim 3). Tuft cell and ILC2 ko hosts have accelerated GVHD. We
hypothesize that IL-25 effects are due to direct stimulation of ILC2s or alternatively, with donor IL-17RB+ T
cells.
Significance. Studies in the R37 extension phase will provide fundamental information as to the mechanisms
by which peri-BMT IL-33 diminish GVHD lethality via effects on ST2+ host ILC2s and regulatory T cells,
both of which produce AREG, and the EGF/IL-33 loop that occurs between ISCs and Paneth cells resulting in
small intestine repair. Further, the key role of host ILC2s in subduing GVHD, the nature of post-BMT ILC2
deficiency that occurs after pre-BMT conditioning regimens and predisposes patients to GVHD, and the
essential requirement for tuft cells or their product, IL-25 will be elucidate. LasUy, critical insights will be
gained as to the inability of pre-lLC2s generation, gut migration or differentiation.
Translational Impact: The efficacy of donor and third-party ILC2 infusion in preventing and treating GVHD
support our planned human ILC2 clinical trial, funded via other auspices, that will infuse "off-the-shelf' third
party ILC2s to treat steroid refractory gut GVHD, that portends a particularly poor prognosis, in a 2-
institutional study at the University of Minnesota and UNC-CH.
摘要
项目成果
期刊论文数量(94)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance.
- DOI:10.1084/jem.20182232
- 发表时间:2021-01-04
- 期刊:
- 影响因子:0
- 作者:Tan CL;Kuchroo JR;Sage PT;Liang D;Francisco LM;Buck J;Thaker YR;Zhang Q;McArdel SL;Juneja VR;Lee SJ;Lovitch SB;Lian C;Murphy GF;Blazar BR;Vignali DAA;Freeman GJ;Sharpe AH
- 通讯作者:Sharpe AH
Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORγt.
- DOI:10.4049/jimmunol.1200858
- 发表时间:2012-08-15
- 期刊:
- 影响因子:0
- 作者:Fulton LM;Carlson MJ;Coghill JM;Ott LE;West ML;Panoskaltsis-Mortari A;Littman DR;Blazar BR;Serody JS
- 通讯作者:Serody JS
Molecular modification of a recombinant anti-CD3epsilon-directed immunotoxin by inducing terminal cysteine bridging enhances anti-GVHD efficacy and reduces organ toxicity in a lethal murine model.
- DOI:10.1182/blood.v96.3.1157
- 发表时间:2000-08
- 期刊:
- 影响因子:20.3
- 作者:D. Vallera;D. Kuroki;A. Panoskaltsis‐Mortari;D. Buchsbaum;B. Rogers;B. Blazar
- 通讯作者:D. Vallera;D. Kuroki;A. Panoskaltsis‐Mortari;D. Buchsbaum;B. Rogers;B. Blazar
Current Concepts and Advances in Graft-Versus-Host Disease Immunology.
- DOI:10.1146/annurev-immunol-102119-073227
- 发表时间:2021-04-26
- 期刊:
- 影响因子:29.7
- 作者:Hill GR;Betts BC;Tkachev V;Kean LS;Blazar BR
- 通讯作者:Blazar BR
Chronic GvHD NIH Consensus Project Biology Task Force: evolving path to personalized treatment of chronic GvHD.
- DOI:10.1182/bloodadvances.2022007611
- 发表时间:2023-09-12
- 期刊:
- 影响因子:7.5
- 作者:Buxbaum, Nataliya P.;Socie, Gerard;Hill, Geoffrey R.;Macdonald, Kelli P. A.;Tkachev, Victor;Teshima, Takanori;Lee, Stephanie J.;Ritz, Jerome;Sarantopoulos, Stefanie;Luznik, Leo;Zeng, Defu;Paczesny, Sophie;Martin, Paul J.;Pavletic, Steven Z.;Schultz, Kirk R.;Blazar, Bruce R.
- 通讯作者:Blazar, Bruce R.
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Bruce R Blazar其他文献
Challenges and solutions for cellular therapy development in autoimmune diseases
自身免疫性疾病中细胞治疗发展的挑战与解决方案
- DOI:
10.1016/s2665-9913(24)00274-1 - 发表时间:
2024-11-01 - 期刊:
- 影响因子:16.400
- 作者:
Elizabeth R Volkmann;John Varga;Bruce R Blazar;Steven Z Pavletic - 通讯作者:
Steven Z Pavletic
Five-Year Outcomes of the “Abatacept Combined with a Calcineurin Inhibitor and Methotrexate for Graft Versus Host Disease (GVHD) Prophylaxis: A Randomized Controlled Trial” (‘ABA2‘)
- DOI:
10.1182/blood-2024-205130 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Lev Gorfinkel;Muna Qayed;Brandi Bratrude;Kayla Betz;Kyle Hebert;Sung W. Choi;Jeffrey Davis;Christine Duncan;Roger H. Giller;Michael S. Grimley;Andrew Harris;David A Jacobsohn;Nahal Lalefar;Nosha Farhadfar;Michael A. Pulsipher;Shalini Shenoy;Aleksandra Petrovic;Kirk R. Schultz;Gregory Yanik;Bruce R Blazar - 通讯作者:
Bruce R Blazar
IL-33 Induces Paneth Cell Production of EGF and Soluble ST2, Regulating Epithelial Regeneration after Intestinal Injury
- DOI:
10.1182/blood-2023-191189 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Marco Calafiore;YA-Yuan Fu;Paola Vinci;Viktor Arnhold;Winston Chang;Suze Jansen;Anastasiya Egorova;Shuichiro Takashima;Jason Kuttiyara;Takahiro Ito;Jonathan Serody;Susumu Nakae;Heth Turnquist;Johan van Es;Hans Clevers;Caroline A. Lindemans;Bruce R Blazar;Alan M. Hanash - 通讯作者:
Alan M. Hanash
Cyclosporine and Voclosporin Resistant Immune Effector Cells to Improve Outcomes after Stem Cell Transplantation
- DOI:
10.1182/blood-2023-180218 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Holly Wobma;Jiayi Dong;Francesca Alvarez Calderon;Xianliang Rui;Katherine Michaelis;Bruce R Blazar;Victor Tkachev;Ulrike Gerdemann;Leslie Kean - 通讯作者:
Leslie Kean
Mitochondrial Pyruvate Carrier Inhibition Mitigates Murine Chronic Graft Versus Host Disease By Attenuating the Germinal Center Reaction
- DOI:
10.1182/blood-2023-185200 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Fathima A Mohamed;Stephanie Y Rhee;Joanna Ly;Ethan G Aguilar;Haley Melin;Peter T Sage;Tanner Schumacher;Govindarajan Thangavelu;Michael C Zaiken;Juan Liu;Venkatram Mereddy;Jason W Locasale;Bruce R Blazar - 通讯作者:
Bruce R Blazar
Bruce R Blazar的其他文献
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{{ truncateString('Bruce R Blazar', 18)}}的其他基金
University of Minnesota Clinical and Translational Science Institute (UMN CTSI)
明尼苏达大学临床与转化科学研究所 (UMN CTSI)
- 批准号:
10763967 - 财政年份:2023
- 资助金额:
$ 58.97万 - 项目类别:
Exploiting the VISTA Pathway to Prevent Acute GVHD and Control Steroid Refractory Disease
利用 VISTA 途径预防急性 GVHD 和控制类固醇难治性疾病
- 批准号:
10560605 - 财政年份:2021
- 资助金额:
$ 58.97万 - 项目类别:
Exploiting the VISTA Pathway to Prevent Acute GVHD and Control Steroid Refractory Disease
利用 VISTA 途径预防急性 GVHD 和控制类固醇难治性疾病
- 批准号:
10092348 - 财政年份:2021
- 资助金额:
$ 58.97万 - 项目类别:
Exploiting the VISTA Pathway to Prevent Acute GVHD and Control Steroid Refractory Disease
利用 VISTA 途径预防急性 GVHD 和控制类固醇难治性疾病
- 批准号:
10348683 - 财政年份:2021
- 资助金额:
$ 58.97万 - 项目类别:
Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia
范可尼贫血基因治疗和同种异体移植的非基因毒性调理
- 批准号:
10305635 - 财政年份:2019
- 资助金额:
$ 58.97万 - 项目类别:
Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia
范可尼贫血基因治疗和同种异体移植的非基因毒性调理
- 批准号:
10656502 - 财政年份:2019
- 资助金额:
$ 58.97万 - 项目类别:
Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia
范可尼贫血基因治疗和同种异体移植的非基因毒性调理
- 批准号:
9888096 - 财政年份:2019
- 资助金额:
$ 58.97万 - 项目类别:
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