SHIP and Immunoregulatory Cell Function

SHIP 和免疫调节细胞功能

• 批准号: 7935342
• 负责人: William Garrow Kerr
• 金额: $ 35.58万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935342
• 关键词: Ablation; Acute; Adult; Allogeneic Bone Marrow Transplantation; Allogenic; Antigen-Presenting Cells; Bone Marrow Transplantation; Cell Count; Cell Lineage; Cell physiology; Engraftment; Genes; Graft Rejection; Homologous Transplantation; Immune; Lymphoid; Mediating; Modeling; Mus; Myelogenous; Myeloid Cells; Organ; Organ Transplantation; Peripheral; Procedures; RNA Interference; Regulatory T-Lymphocyte; Solid; Suppressor-Effector T-Lymphocytes; System; T cell response; T-Lymphocyte; Testing; Transplant Recipients; Transplantation; allograft rejection; cell type; in vivo; prevent; public health relevance; response; success

DESCRIPTION (provided by applicant): We previously demonstrated that SHIP expression is necessary for rejection of allogeneic BM grafts(1) and the GvHD that limits the utility of such transplants.(1,2) We have recently shown that induction of SHIP-deficiency for a one week period prior to allogeneic BMT is sufficient to protect a recipient from acute GvHD.(3) Host antigen presenting cells (APC) are responsible for triggering allogeneic T cell responses(4) that mediate GVHD.(5) A profound expansion of Myeloid Suppressor Cells (MySC) in the peripheral lymphoid organs of SHIP-/- mice antagonizes APC priming of allgeneic T cell responses (2,3). We have recently shown that purified SHIP-/- MySC have greater suppressive capacity than WT MySC.(3) In addition, we have shown that Treg cell numbers and function are increased in germline SHIP-deficient mice and mice with induced SHIP- deficiency. We hypothesize then that increased MySC and/or Treg cell function in SHIP-deficient transplant recipients protects them from GvHD and may also reduce solid organ allograft rejection. We have recently established lineage-specific SHIP deletion models for both myeloid cells and T cells. We will now determine whether myeloid- or T cell-restricted ablation of SHIP expression in transplant recipients is sufficient to abrogate acute GvHD (Aim 1). Having recently established an inducible flox/flox SHIP deletion model (MxCreSHIP ) and demonstrated that this is an effective system in which we can protect adult recipients from GvHD in a myeloablative transplant, we will now determine whether induced SHIP-deficiency is also protective from GvHD with other allogeneic BMT procedures (Aim 2). In Aim 3, we will use the MX-CreSHIP model and RNAi targeting of SHIP to determine whether induced SHIP deficiency can enhance the success of allogeneic organ transplantation. We have also developed RNAi approaches to reversibly inhibit SHIP expression in vivo. RNAi targeting of SHIP expression will also be tested in Aim 2 for its ability to protect recipients from GvHD and in Aim 3 to determine if it can facilitate engraftment of solid organ allografts. The Specific Aims are: Aim 1: Define the SHIP-deficient cell lineages required for host protection from GvHD. Aim 2: Define the manner in which SHIP-deficiency can be used to enhance allogeneic BM transplantation. Aim 3: Determine whether SHIP-deficiency can facilitate the transplantation of allogeneic organ grafts. PUBLIC HEALTH RELEVANCE We believe these studies will demonstrate that turning off one specific gene can prevent the rejection of transplanted bone marrow and organs that are not matched to the recipient. In addition, these studies will identify the types of immune cell types required for acceptance of these unmatched transplants.

描述（由申请人提供）：我们之前证明了 SHIP 表达对于同种异体 BM 移植物的排斥是必需的 (1) 以及限制此类移植物实用性的 GvHD。(1,2) 我们最近表明 SHIP 缺陷的诱导同种异体 BMT 之前一周的时间足以保护受者免受急性 GvHD。(3) 宿主抗原呈递细胞 (APC) 负责触发同种异体 T 细胞反应(4)介导 GVHD。(5) SHIP-/- 小鼠外周淋巴器官中骨髓抑制细胞 (MySC) 的深度扩张会拮抗 APC 引发的同种异体 T 细胞反应 (2,3)。 我们最近表明，纯化的 SHIP-/- MySC 比 WT MySC 具有更强的抑制能力。(3) 此外，我们还表明，种系 SHIP 缺陷小鼠和诱导 SHIP 缺陷的小鼠中 Treg 细胞数量和功能有所增加。然后我们假设 SHIP 缺陷的移植受者中 MySC 和/或 Treg 细胞功能的增加可以保护他们免受 GvHD 的影响，并且还可能减少实体器官同种异体移植物的排斥反应。我们最近为骨髓细胞和 T 细胞建立了谱系特异性 SHIP 缺失模型。我们现在将确定移植受者中 SHIP 表达的骨髓或 T 细胞限制性消融是否足以消除急性 GvHD（目标 1）。最近建立了诱导性 flox/flox SHIP 缺失模型 (MxCreSHIP )，并证明这是一个有效的系统，我们可以在清髓移植中保护成年受者免受 GvHD 的影响，现在我们将确定诱导的 SHIP 缺陷是否也能保护免受 GvHD与其他同种异体 BMT 程序（目标 2）。在目标 3 中，我们将使用 MX-CreSHIP 模型和 SHIP 的 RNAi 靶向来确定诱导的 SHIP 缺陷是否可以提高同种异体器官移植的成功率。我们还开发了 RNAi 方法来可逆地抑制体内 SHIP 表达。针对 SHIP 表达的 RNAi 还将在目标 2 中测试其保护受体免受 GvHD 侵害的能力，并在目标 3 中测试以确定它是否可以促进实体器官同种异体移植物的植入。具体目标是： 目标 1：定义保护宿主免受 GvHD 侵害所需的 SHIP 缺陷细胞谱系。目标 2：定义 SHIP 缺陷可用于增强同种异体骨髓移植的方式。目标 3：确定 SHIP 缺陷是否可以促进同种异体器官移植。公共健康相关性我们相信这些研究将证明关闭一种特定基因可以防止移植的骨髓和与受体不匹配的器官发生排斥反应。此外，这些研究将确定接受这些不匹配的移植所需的免疫细胞类型。