In Vivo Prevention of Murine GVHD

小鼠 GVHD 的体内预防

• 批准号: 10610863
• 负责人: Bruce R Blazar
• 金额: $ 58.97万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10610863
• 关键词: Mus; Prevention; S-7; in vivo

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

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: The Journal of experimental medicine
• 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: Journal of immunology (Baltimore, Md. : 1950)
• 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: Blood
• 影响因子: 20.3
• 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: Annual review of immunology
• 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: BLOOD ADVANCES
• 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.